04.19APRIL 2019 : VOLUME 15 : NUMBER 4

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Building a new toolboxUniversity at Buffalo lab receives NIH grant to develop tools for an inside look at cells’ responses to drugsBY KELSEY KAUSTINEN

BUFFALO, N.Y.—A recent grant will support chemists at the University at Buffalo (UB) in their work to develop intracellular bio-chemical tools that can provide an inside look at how exactly pharmaceuticals impact the inner workings of cells during treatment.

“Our project utilizes chemistry as a research tool to study biological problems inside living cells,” said lead scientist Dr. Qing Lin, professor of chemistry in the UB College of Arts and Sciences. “Even when a drug works in treating disease, we often don’t understand the details of how it does its job. The tools we are developing will hopefully help to fill this gap in knowledge.”

The grant in question provides $2 mil-lion from the National Institute of General Medical Sciences, part of the U.S. Institutes of Health, and is expected to help fund devel-opment and testing of the biochemical tools.

Lin’s lab, as noted on the UB website, is focused on research that “aims to develop and apply new chemical tools and principles to solve biological problems that are difficult to solve, if not impossible, by standard bio-logical techniques. A central theme of our research is to harness the power of organic reactions to study protein dynamics, function and protein-protein interactions and their assembly in living organisms.”

Lin is particularly interested in cellular receptors and bioorthogonal chemistry.

“Compared with the noncovalent binding-based approach, bioorthogonal chemistry relies upon a specific, covalent attachment of a probe molecule to the biomolecule(s) of interest,” as noted on his laboratory’s website. “Over the past few years, we have developed several bioorthogonal reactions,

Crowning the rodentsCrownBio strikes deals with Charles River for rats and JAX for miceBY JEFFREY BOULEY

SAN DIEGO—Global drug discovery and development services company Crown Bio-science Inc. has been busy on the animal front lately when it comes to rodent mod-els, with two deals in the first half of March with big-name life-sciences labs—Wilming-ton, Mass.-based Charles River Laboratories and Bar Harbor, Maine-based The Jackson Laboratory (JAX).

With Charles River’s Research Models and Services business, CrownBio has entered into an agreement to expand access to the ZDSD (Zucker Diabetic Sprague-Dawley) rat model, with an eye toward enabling greater global model availability for drug discovery in obesity, diabetes and metabolic syndrome.

The agreement provides Charles River, a global leader in research model distribution, an exclusive license to breed and distribute the ZDSD model. The agreement also guar-antees CrownBio a premium quality and prioritized supply of ZDSD models to sup-port their global service platforms. Charles River’s commercial distribution of the model is expected to begin by mid-summer 2019.

The ZDSD rat is a highly translatable model of metabolic syndrome, obesity, dyslipidemia

and diabetes, with complications such as cardiac dysfunction, proteinuria and impaired wound healing. It has a polygenic background and intact leptin pathway. Unlike some other rat models of metabolic disease, the ZDSD rat does not rely on monogenic leptin or leptin receptor mutations for development of obesity and type 2 diabetes,

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CROWN CONTINUED ON PAGE 34

TransCon hGH scores with superiorityOnce-weekly growth hormone demonstrates superiority on primary endpoint compared to daily growth hormone in Phase 3BY MEL J. YEATES

COPENHAGEN, Denmark—Ascendis Pharma A/S, a biopharmaceutical com-pany that utilizes its TransCon technol-ogy to address unmet medical needs, has announced positive top-line results from the Phase 3 heiGHt Trial, a randomized, open-label, active-controlled trial that compared once-weekly TransCon Growth Hormone (hGH) to a daily growth hor-mone (Genotropin) in children with pedi-atric growth hormone deficiency (GHD).

The heiGHt Trial evaluated 161 treat-

ment-naïve children with GHD ran-domized in a 2:1 ratio to receive either once-weekly TransCon hGH (0.24 mg/kg/week subcutaneously, n=105) or daily Genotropin (34 µg/kg/day or 0.24 mg/kg/week subcutaneously, n=56) for 52 weeks. The trial met its primary objec-tive, demonstrating that TransCon hGH was observed to be non-inferior and, as a bonus, superior to daily hGH on the primary endpoint of annualized height velocity (AHV) at 52 weeks.

Bioinformatics infrastructure finds funding through UK Research and Innovation .............................12Synthetic sebum ..................................................................21A ‘Mammoth’ licensing victory .........................................30

NEUROSCIENCE SPECIAL REPORT:

Holding out hopeTrying to reframe the depression conversation

SHOW PREVIEW:

American Association of ImmunologistsAnnual Meeting 2019 in San Diego

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WHAT’S INSIDEDISCOVERY 6

TOOLS & TECHNOLOGY

PRECLINICAL 21

RESEARCH & DEVELOPMENT 12

CLINICAL TRIALS 24

DIAGNOSTICS 30

BUSINESS & GOVERNMENT POLICY 35

MARKET NEWS 3EDITORIAL/COMMENTARY 10LATE-BREAKING NEWS 38

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Recent work at the University at Buffalo includes developing tools to study how cellular receptors change shape once activated by drugs, and how molecules within the cells respond upon activation.

With both the ZDSD rat model and the FATZO mouse model that it recently struck deals around, CrownBio says that its rodents are ideal for modeling human metabolic disease states.

CNS DISCOVERIES START HERE.From target identifi cation through in vitro and in vivo pharmacology, modeling of CNS diseases and preclinical testing, Charles River has extensive expertise and technology to support your drug discovery program. We help clients identify the most promising candidates and accelerate the development of potential neurological therapies.

Visit us at www.criver.com/therapeutic-area/neuroscience

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Positive results and new technology give rise to antibody dominancePOINT ROBERTS, Wash. & DELTA, British Columbia—Toward the end of March, Investorideas.com, an investor news resource cover-ing biotech and pharma stocks, released a snapshot looking at the biopharmaceutical market and how monoclonal antibody research is gaining market dominance.

For example, the news outlet noted that GE Healthcare’s Life Sciences division wrote on its web-site regarding the antibody boom: “Many small and start-up compa-nies are developing new ideas as to how antibodies can be used. In many cases, these companies will go on to be acquired by larger com-panies with the financial capability to progress their ideas further. But with costs to establish manufactur-ing capability in suitable existing buildings at not much more than $10-15 M, this strategic opportunity lies within reach even for smaller businesses. Despite steep compe-tition and the need for significant investment, the antibody space is a lucrative opportunity with vari-ous therapeutic avenues that can be explored.”

Investorideas.com also took a look around at specific corporate activity in the sector and noted that one such company—Immu-noPrecise Antibodies Ltd. (IPA), a therapeutic antibody discovery company—recently received a five-year indefinite delivery/indefinite quantity subcontract from Leidos Biomedical Research, Inc., which currently operates the Frederick National Laboratory for Cancer Research for the National Cancer Institute (NCI). Under the subcon-tract, IPA will discover and pro-duce rabbit monoclonal antibodies using its proprietary B-Cell Select

platform. The rabbit monoclonal antibodies discovered and pro-duced under this subcontract will be used in the key applications of immunohistochemistry and immu-no-multiple reaction monitoring (immuno-MRM), and they will be generated for the NCI’s Antibody Characterization Program.

Immuno-MRM is a targeted mass spectrometry technique that relies on antibodies to enrich peptides from complex biological samples that are then quantified by mass spectrometry. Rabbit mono-clonal antibodies are highly sought after for this purpose because

they exhibit high specificity and bind their target with high affin-ity. Immuno-MRM is being used to discover novel biomarkers and develop a new generation of clini-cal diagnostic tests that could lead to improved cancer detection, diag-nosis and treatment.

Also, Zymeworks Inc., a clinical-stage biopharmaceutical company developing multifunctional thera-peutics, reported in January the achievement of a new development milestone in its collaboration with Eli Lilly and Co. In accordance with Zymeworks’ 2014 licensing and collaboration agreement with

Lilly, Zymeworks will receive a milestone payment of $8 million for Lilly’s submission of an IND application for an immuno-oncol-ogy bispecific antibody enabled by Zymeworks’ proprietary Azymetric platform.

In addition, Investorideas.com noted that Sesen Bio Inc., a late-stage clinical company advancing targeted fusion protein therapeu-tics for the treatment of cancer, recently reported positive prelimi-nary efficacy data for the primary endpoint of its ongoing Phase 3 registration trial, the VISTA Trial, of Vicinium for the treatment

of patients with high-grade non-muscle invasive bladder cancer who have been previously treated with bacillus Calmette-Guérin (BCG) and deemed BCG-unre-sponsive. The data reported show clinically meaningful complete response rates in evaluable carci-noma in-situ patients at three, six, nine and 12 months of follow-up in the trial consistent with the data in the completed Phase 1 and Phase 2 clinical trials. Importantly, Vicini-um continues to be generally well tolerated in treated patients.

Finally, there was ProMIS Neu-rosciences Inc.—a biotechnology company focused on the discovery and development of antibody ther-apeutics targeting toxic oligomers implicated in the development of neurodegenerative diseases—of which it was reported that the com-pany was presenting preclinical data for new antibody candidates that show stringent selectivity for the toxic forms of alpha-synuclein, considered a root cause of Parkin-son’s disease, at a podium pre-sentation on March 31, as well as co-moderating a March 30 panel discussion on disease mechanisms in Alzheimer’s disease and Parkin-son’s disease.

Beyond the individual company news, Investorideas.com also noted that Research & Markets, in a bio-pharma market overview, recently noted that the global biopharma-ceuticals market was valued at around $237.3 billion in 2018, and is estimated to be grow to around $389 million by 2024, witnessing a compound annual growth rate of 8.59 percent. Within the segments related to this market, monoclonal antibodies are expected to gain the largest market size. n

Biopharma in 2018: Stocks and M&A slump; venture financing and IPOs surgeLONDON, BOSTON & TOKYO—Macroeconomic trends in the fourth quarter (Q4) wiped out bio-pharma’s stock market gains from earlier in 2018, with the S&P Phar-maceuticals Index the only major biopharma index to finish the year in the black, according to the recent “Pharma, Biotech and Medtech 2018 in Review” report from Eval-uate Ltd.’s independent editorials arm, Vantage. M&A and product licensing volumes were also down, despite notable deals such as Take-da’s $64-billion acquisition of Shire and Bristol-Myers Squibb’s $1-bil-

lion payment to Nektar. Deal-mak-ing slowed in the medtech sector too, with fewer acquisitions closed and a corresponding decrease in venture investment rounds.

Falling share prices in Q4 turned a 15-percent nine-month climb for the Nasdaq Biotechnology Index into a 9-percent year-end decline, while the S&P Pharmaceuticals Index only managed a 5-percent gain. Moreover, M&A activity hit its lowest level since 2009, with 173 total deals; licensing activity also dropped from 2017 levels by both deal count (112) and value measures

($4.94 billion). The total value of medtech M&A deals came to $27.4 billion, a precipitous decline from 2017’s figure of nearly $100 billion.

Conversely, 2018 was a banner year for venture financing, with $16.8 billion invested in drug development startups. Biotech initial public offerings (IPOs) set new records, with two of the big-gest flotations—Moderna and Allogene—occurring in the final months of the year. Medtech IPOs also flourished in Q4 2018, giving the smaller players a welcome cash injection. The FDA set records as

well, with 62 novel drugs approved, and managed a slight reduction in average approval times.

All told, 37 drug developers raised over $100 million in financ-ing, more than double the num-ber in 2017. Biotech IPOs raised a record $7.23 billion, with the aver-age amount raised tipping over $100 million for the first time.

Also, a total of $695 million was raised by device companies going public in the fourth quarter, more than any other three-month peri-od since Vantage started tracking medtech listings in 2013.

Finally, the FDA’s 2018 class of novel drugs is forecast to sell $24 billion by 2023, including new migraine drugs Aimovig, Emgality and Ajovy; Alnylam’s RNAi thera-peutic Onpattro; and 17 new cancer drugs.

“The progress of biopharma and medtech companies last year paints a mixed picture,” said Amy Brown, co-author of the report. “However, there are signs of health, if the indus-try is able to capitalize on them.”

To download a complimentary copy of the report, visit www.evalu-ate.com/2018Review. n

MARKET NEWS4 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

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SHOWING THE MONEYA S WE SO OFTEN DO, let’s have

a roundup of some recent financing rounds in pharma and biotech, going from the biggest down to the smallest of

this sampling. We’ll start with Boston-based Karuna Therapeutics Inc.—focused on tar-geting muscarinic cholinergic receptors for the treatment of neuropsychiatric disorders, including psychosis in schizophrenia, psy-chosis in Alzheimer’s disease and pain—which recently announced the completion of a $68-million Series B financing round, including the issuance of $5 million in shares upon conversion of debt into equity.

KarXT, Karuna’s lead product candidate, is currently being evaluated in a Phase 2 clini-cal trial as a potential treatment for acute psychosis in patients with schizophrenia. Proceeds from the financing will be used to advance the development of KarXT into sev-eral new indications, including geriatric psy-chosis and pain; progress new formulations of KarXT; expand the pipeline; and continue to build company infrastructure.

“Patients living with schizophrenia often must choose among treatment options that only partly address their disabling psychotic and cognitive symptoms, often with unde-sirable side effects. Karuna’s mission is to deliver a more effective and better-tolerated treatment for this large and underserved patient population. We believe this financing will enable us to deliver multiple milestones across our product-focused pipeline while expanding the capabilities and potential of our muscarinic receptor platform,” said Dr. Steve Paul, CEO and chairman of the board of Karuna.

Cold Genesys closes $22M Series CSANTA ANA, Calif.—Cold Genesys Inc., a clinical-stage biopharmaceutical company focused on the development of novel immu-notherapies, in late March closed a $22-mil-lion Series C preferred stock financing. The financing will accelerate the growth of Cold Genesys’ ongoing clinical programs and the

continued advancement of its lead oncolytic immunotherapy CG0070, which has com-pleted a Phase 2 study (BOND2) and dem-onstrated clinical safety and efficacy in more than 100 patients to date for the treatment of non-muscle invasive bladder cancer.

“Cold Genesys has reached an exciting stage in its development, and this financing demonstrates continued investor confidence in our leadership and future in the field of oncolytic immunotherapy,” said Arthur Kuan, CEO of Cold Genesys. “We have made significant progress within the last year, from new leadership appointments to our partner-ship with Merck to evaluate their anti-PD-1 therapy, Keytruda (pembrolizumab), in com-bination with CG0070 in a Phase 2 clinical study. Our robust pipeline based on our onco-lytic immunotherapy platform, partnerships with leading institutions, and key advance-ments in our clinical program demonstrate our commitment to rapidly advancing thera-pies that will change the lives of patients with bladder cancer and other solid tumors.”

Harrow Health announces $11M Series A for subsidiarySAN DIEGO & BOSTON—Melt Pharma-ceuticals Inc., an affiliated company of Har-row Health, Inc., recently announced it has entered into definitive stock purchase agreements with accredited and institutional investors to raise proceeds of approximately $11 million in a private placement sale of its Series A preferred stock at $5 per share. Proceeds will advance the development of MELT-100, Melt’s patented flagship 505(b)(2) drug candidate.

Concurrent with the financing, Greg Mad-ison has been hired as CEO of Melt Pharma-ceuticals. Most recently, Madison was CEO of Keryx Biopharmaceuticals, where he led the company’s transformation from develop-ment stage to a fully integrated commercial organization and drove impressive revenue growth by expanding the label for the com-pany’s lead product. Before Keryx, he was chief commercial officer at specialty pharma company AMAG Pharmaceuticals and spent 12 years at Genzyme/Sanofi.

Following the close of the Series A financ-ing, Melt Pharmaceuticals will be decon-solidated from Harrow Health and Harrow will hold approximately 44 percent of the ownership interests in Melt, consisting of 3,500,000 shares of common stock.

Sphere Fluidics gains $2 million CAMBRIDGE, U.K.—Early this year, Sphere Fluidics, a company commercializ-ing single cell analysis systems underpinned by its patented picodroplet technology, announced that it had closed a $2-million investment round. The funds raised will be used to accelerate growth in operations and support sales of its Cyto-Mine Single Cell Analysis System.

Cyto-Mine is an automated platform which integrates single cell screening, sort-ing, dispensing, imaging and clone verifica-tion. It can process up to 40 million cells per day, and assesses and isolates those that produce a specific biologic to help streamline workflows and improve throughput in anti-body discovery and cell line development. n

“Patients living with schizophrenia often must choose among treatment options that only partly address their disabling psychotic and cognitive symptoms, often with undesirable side effects. Karuna’s mission is to deliver a more effective and better-tolerated treatment for this large and underserved patient population.”Dr. Steve Paul, CEO of Karuna Advances and unmet

needs in diabetesLONDON—Advances in diabetes thera-peutics, such as anti-diabetic oral medica-tions, incretin therapies and novel insu-lin formulations have been made over the past century, but many unmet needs remain for this complex and difficult-to-treat disease, says data and analytics com-pany GlobalData.

According to key opinion leaders inter-viewed late last year by the firm, there are several pressing unmet needs in the diabe-tes space that apply broadly for both type 1 diabetes (T1D) and type 2 diabetes (T2D).

“There is a need for additional treat-ments that provide both glycemic and non-glycemic benefits, especially since the control of diabetes comorbidities is less than optimal in most patients,” said Dr. Jesus Cuaron, a managing analyst at GlobalData. “Incretin-based therapies and sodium glucose cotransporter inhibi-tors (SGLTIs) are partially addressing this need in T2D by inducing weight loss, low-ering blood pressure and providing CV [cardiovascaular] benefit.”

Reducing the occurrence of hypoglyce-mia, or low blood sugar levels, in insulin-dependent diabetic patients is another vital area in the diabetes space that requires ongoing attention. Currently, all available

insulin therapies are associated with the risk of hypoglycemia, despite the fact that new-generation insulins such as Novo Nor-disk’s Tresiba have lowered the risk.

Continued Cuaron: “The issue of sig-nificantly decreased compliance among patients using injectable therapies such as insulin continues to be partially addressed by drug developers. Hypoglycemia is one of the top safety concerns associated with diabetics taking insulin. But most attempts to bring a commercially successful non-injectable insulin to market have been met with failure, as seen with Pfizer’s Exubera.”

But the most pressing unmet need in the diabetes space is the development of breakthrough treatments that address the underlying cause of the disease. In T1D, this would be a treatment that would interfere with either the etiology or the pathogenic processes involved in the eradication of the β cells. In T2D, the treatment would have to effectively target the root of the disease: insulin resistance.

“Whether or not a truly curative treat-ment will be discovered and developed is yet to be seen. In the meantime, developers should continue focusing on tackling the multiple unmet needs that remain in this space,” concluded Cuaron. n

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WELLESLEY, Mass.—Owing to issues that include a rising num-ber of new lung cancer cases, the increasing geriatric popula-tion and increased exposure to environmental carcinogens, the global lung cancer therapeutics market has seen ample growth in recent years, according to BCC Research. According to the report “Lung Cancer Therapeu-tics: Global Markets,” the global market for lung cancer therapeu-tics was valued at $17.9 billion in 2018 and is expected to reach $26.3 billion by 2023, growing at a compound annual growth rate (CAGR) of 8 percent during the forecast period.

Prominent players in the indus-try include Eli Lilly and Co., Pfizer Inc., Roche Holding AG, Astra-Zeneca plc, Novartis International AG and Merck & Co. Inc., among others.

Research highlights:■n The lung cancer therapeu-tics market landscape is rap-idly developing, bringing new options to oncologists, health-care payers, healthcare provid-ers and governments looking to provide patients with qual-ity care.

■n In the U.S., about $83 mil-lion was spent on lung cancer research and development between 2007 and 2017. Through the LUNG FORCE initiative, about $2.2 million was dedicated to lung cancer research in 2017.

■n Among the five regions ana-lyzed in the report, the Asia-Pacific is expected to register the largest number of lung cancer incident cases.

“Funding for lung cancer research is critical due to the dis-ease’s prominence and because doctors often find lung cancer in later stages when it’s less treat-able,” the report notes. “New advances hold great promise for screening, early detection and personalized therapies.”

BCC Research also comment-ed on the blood cancer market around the same time, noting that as a result of the rising inci-dence of blood cancer, increased funding for cancer treatment and the development of highly sensitive tests, the global blood cancer therapeutics market is progressing at a rapid rate. The company’s report, “Blood Cancer Therapeutics: Global Markets to 2023,” says that the global mar-ket for blood cancer therapeutics was valued at $38.5 billion in 2018 and is expected to reach $64.8 bil-lion by 2023, with a CAGR of 11.0 percent.

Major players in the mar-ket include Roche Holding AG,

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Novartis, Celgene Corp., Pfizer Inc., Bristol-Meyers Squibb Co., Johnson and Johnson, Merck & Co. Inc., AstraZeneca plc, Eli Lilly and Co., Takeda Pharmaceutical Co. Ltd., Astellas Pharma Inc., AbbVie and Sanofi.

Research highlights:■n North America holds 39.5

percent of the global market, driven by the increase in the incidence of blood cancers in developed countries and higher socioeconomic groups due to genetic factors.

■n Lymphoma is the fastest-grow-ing segment in the overall market, with a CAGR of 12.2

percent during the forecast period.

■n The multiple myeloma pipe-line is dominated by several investigational therapies, which include both small mol-ecules and immunotherapeu-tic approaches.

“Governments and non-govern-

ment organizations have launched several screening and testing pro-grams to diagnose blood cancer,” the report states. “Early blood cancer diagnosis and prompt, effective treatment can reduce the risk of leukemia, lymphoma and myeloma transmission, and deliver clinical benefits.” n

Lung and blood cancer therapeutics markets expand

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A new target for obesityJUPITER, Fla.—Recent research out of Scripps Research has pinpointed a group of neurons that could play a role in obesity. The work was led by neuroscientist Dr. Baoji Xu, who explained that “The bottom line is that we identified a new population of neurons, that when acti-vated, suppress appetite and increase energy expenditure.” Xu and his team found neurons in the brain that express the receptor TrkB, a signaling target for the protein BDNF (brain-derived neurotrophic factor), which is involved in energy balance. Some mutations in genes that express TrkB and BDNF are linked to extreme obesity. Additionally, the team also looked at the dorsomedial hypothalamus, which is where leptin binds to suppress appetite and which plays a role in energy expenditure. Xu noted that neurons in the dorsomedial hypothalamus that express TrkB could potentially be a drug target for treating obesity.

Slow but steady growth in drug discovery

DUBLIN—Research and Markets is forecasting a compound annual growth rate of approximately 8 percent for the global drug discovery market between 2018 and 2023, according to a recent report, though the market is hampered by low profit margins and strict regulatory approval pro-cesses. North America is expected to lead the market as the most lucrative region, thanks to a high concentration of pharmaceutical and bio-technology companies and a supportive regulatory environment, while Asia-Pacific is expected to see healthy growth thanks to economic growth and an increasing rate of investment from the pharma-ceutical and biotechnology industries. Increasing collaboration with contract research organizations and contract development and manufacturing organizations by pharmaceutical companies is one driver for the market, as are technological advancements, rising disease prevalence and rising healthcare expenditure.

IN THIS SECTIONAntibody therapeuticsAbCellera acquires multiple multiyear deals ......................................... 6

Artificial intelligenceMerck and Iktos collaborate on compounds ....................... 6

Market newsSlow but steady growth in drug discovery ...................................... 6

Metabolic/NeurologyA new target for obesity .......................... 6

Oncology/MicrobiomeMining microbiomes ................................. 6

Merck and Iktos collaborate on compoundsAgreement grants Merck KGaA access to Iktos’ AI technology across three drug discovery projectsBY MEL J. YEATES

DARMSTADT, Germany—In March, Merck KGaA of Germany announced a collaboration agreement with Iktos for the use of its generative modeling artificial intelligence (AI) technology, in order to facilitate the rapid and cost-effective discovery and design of promising new compounds.

As Klaus Urbahns, head of Discov-ery & Development Technologies at Merck, tells DDNews, “We identified the generative AI technology from Iktos as a great strategic fit to lever-age AI to complement our discovery efforts with speed and precision. The decision to proceed with the collabo-ration was a mutual one. The com-pany looks for partners such as Iktos which share its passion for discovery and whose expertise complements its existing portfolio, and who share its mission to discover treatments that improve patient lives.”

Iktos’ deep generative models-based AI technology helps bring speed and efficiency to the drug discovery pro-cess by automatically designing virtual novel molecules that have the desired activities for treating a given disease. This tackles one of the key challenges in drug design: rapid identification of molecules which simultaneously satis-fy multiple drug-like criteria for clini-cal testing. The technology is already successfully established in other fields, such as image processing and automat-ic translation, but has only recently been applied to chemistry.

“The agreement enables Merck access to Iktos AI technology across three drug discovery projects. Iktos technology can help accelerate drug

Mining microbiomesSeres Therapeutics and AstraZeneca to explore the interaction of the microbiome and immunotherapiesBY KRISTEN SMITH

CAMBRIDGE, Mass. & LONDON—The human microbiome is a current darling of research-ers, with its potential attracting top talent and top dollars to explore its promise. While “microbiome mania” has permeated popular culture, with unproven guarantees assuring the cure for everything from bipolar disorder to rheumatoid arthritis to migraines, rigor-ous research is underway to understand and advance the mechanistic underpinnings that will allow microbiome modification to help cure disease.

Seres Therapeutics is a clinical biopharma-ceutical company using a proprietary plat-form that identifies healthy versus dysbiotic microbiomes and the characteristics of each, leading to the development of new drugs to treat diseases in multiple areas of medicine. According to the company’s website, their drug discovery process “interrogates how diverse microorganisms work together to form ‘functional ecological networks’ that perform specific biological functions, and how the diversity of microbes present in the gut can have a significant impact on the healthy function of the human gastrointes-tinal tract ecosystem.”

Seres recently announced a three-year research collaboration with pharmaceutical giant AstraZeneca (AZ). The collaboration will seek to isolate the ways in which the microbiome might augment the efficacy of cancer immunotherapy protocols, including

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AbCellera acquires multiple multiyear dealsCompany collaborates with Novartis, Denali Therapeutics and the Bill & Melinda Gates FoundationBY MEL J. YEATES

VANCOUVER, British Columbia—AbCellera, a technology leader in therapeutic antibody discovery from natural immune repertoires, has been busy lately, making deals with sev-eral big-name organizations, with the com-pany most recently announcing a multitar-get, multiyear collaboration with Novartis. Under the agreement, AbCellera will apply its expertise in antibody discovery and its sin-gle-cell screening technology to advance pro-grams on up to 10 targets elected by Novartis.

According to Véronique Lecault, co-

founder and director of AbCellera, “Novar-tis is one of the largest and most innovative pharmaceutical companies in the world, and they have a sophisticated team of scientists working on antibody discovery. When global pharmas come to AbCellera, it is because they recognize that some antibody discovery problems cannot be efficiently tackled with existing platforms. We have an expansive toolbox with IP around multiple technologies that allows us to tailor our approach for each target. We understand that every target is dif-ferent and comes with unique challenges. For each program, we work in close collaboration with our partners to design the strategy that has the highest chance of success.”

“At AbCellera, we get excited when we have the opportunity to push the boundaries of

ABCELLERA CONTINUED ON PAGE 8 AI CONTINUED ON PAGE 9

The microbiome continues to be an enticing area of research in pharma and life sciences, and now Seres and AstraZeneca have inked a deal to explore the interaction of the microbiome and immunotherapies.

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potential synergy with AstraZeneca compounds.

“We are very pleased to be col-laborating with AstraZeneca, a global leader in oncology, to advance the development of poten-tial microbiome-based therapies for cancer. Through the activities under this collaboration and in our SER-401 Phase 1b clinical study in metastatic melanoma, we hope to meaningfully advance our under-standing of the potential for micro-biome therapeutics to magnify the impact of cancer immunotherapy,” said Eric Shaff, president and CEO of Seres Therapeutics.

The partnership will capitalize on distinct and complementary assets from each entity. Seres will gain access to AZ’s breadth of approved drugs and pipeline candidates, while AZ will benefit from Seres’ capacity to quickly and decisively hone in on the specific microbiome mechanisms that make specific treatments effective. Researchers intend to focus specifically on how the microbiome climate in a cancer patient may augment immunother-apy approaches and serve as a poten-tial predictor for an individual’s response to cancer immunotherapy.

“We are bringing together two dynamic and creative organizations with lots of very talented people generating a huge number of exciting ideas,” remarks Dr. Kevin Horgan, executive vice president and chief medical officer at Seres. “What is most exciting is how we’ve found the sweet spot where both company’s talents and interests are perfectly in tune. We will be able to look at concrete scientific ques-tions about various compounds and their mechanisms, and devise ways to deploy them more effectively.”

The partnership will include further research into Seres’ oral SER-401, a potential therapy that is collected from healthy individuals who have shown a microbiome bac-terial profile similar to that found in patients with high response to cancer immunotherapy. Scientists will explore SER-401 in conjunc-tion with different AZ compounds known to treat cancer.

“Our new collaboration with Seres Therapeutics represents an important opportunity to advance our understanding of the relation-ship between the microbiome and the immune system’s ability to respond to cancer therapy,” Dr. Jean-Charles Soria, senior vice president of the Research & Development Oncology division at AstraZen-eca, commented in a press release. “Despite progress in the field of immunotherapy, we are only at the tip of the iceberg. Too many patients are still unable to benefit from exist-ing therapies, so we must continue following the science in pursuit of new and innovative solutions.”

AstraZeneca will provide Seres $20 million, and reimburse any

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research-related expenses. Seres will maintain rights to promising candi-dates, while AZ will have the right to negotiate for any resulting key inven-tions. Conveniently enough, Horgan joined Seres after a successful stint at AZ focusing on inflammation, oncol-ogy and immunotherapy. As a gas-troenterologist and immunologist, the companies see him as the ideal person to oversee the collaboration and guide it towards its maximum

potential, according the company. “Kevin has the perfect hybrid

background for this work. He knows what’s under the hood at both organi-zations, so he can optimize the part-nership, and accelerate our collabo-ration,” says Shaff. “We are delighted to be working with AZ, and very pleased with the terms of the agree-ment. The opportunity set in micro-biome science is as significant as it’s ever been, and we see great potential in this exciting new space.” nEDITCONNECT: E041904

“Our new collaboration with Seres Therapeutics represents an important opportunity to advance our understanding of the relationship between the microbiome and the immune system’s ability to respond to cancer therapy,” says Dr. Jean-Charles Soria, a senior vice president at AstraZeneca, the headquarters of which are pictured here.

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science. Our team thrives on new challenges. We truly believe that the best science comes from great minds working together, and we are thrilled to be collaborating with the stellar scientists from Novartis,” adds Lecault.

Under the terms of the agreement with Novartis, AbCellera is eligible to receive technology access, research funding, down-stream milestone payments and royalties on net sales of products. As Lecault explains, “This partnership includes a significant upfront payment for access to the technology and research payments to fund the work. For us, the value is primarily in the downstream payments associated with clinical develop-ment and future commercial success of the programs. Novartis has the option to select up to 10 targets over the term of the agree-ment, which allows them to secure extended access to our platform.”

Over the past three years, AbCellera has successfully completed more than 30 anti-body discovery programs, including deals with seven global pharmaceutical compa-nies and top-tier public and venture-backed biotech companies.

Lecault notes that “[In] general, the types of targets we expect from pharma partners are those where antibody discovery campaigns using other approaches have been tried and have failed. In a single campaign, we can screen millions of B cells. Our throughput is over 100 times higher than other technolo-gies, which means that if antibodies with the desired properties are ultra-rare, it is highly likely we will find them. In addition to our core screening platform, we have many tools to access natural diversity such as immuniza-tion methods, alternative species, repertoire sequencing, machine learning and custom visualization tools. By combining the best technologies at every step of the way, it gives us an edge to crack the toughest problems and generate rich data sets from which the

best therapeutic candidates can be picked.” “In the last two months, AbCellera has

announced multiyear, multitarget deals with Novartis, Denali Therapeutics, and the Bill & Melinda Gates Foundation,” she continues. “These deals mark a transition in AbCellera’s business from single-target projects to multi-year discovery partnerships. We are com-mitted to innovation and continue to invest heavily to build capacity for future partners, extend our capabilities and remain at the forefront of antibody discovery.”

The collaboration with Denali Thera-peutics is intended to discover antibodies as therapies for neurological indications. AbCellera will generate panels of antibod-ies for up to eight drug targets nominated by Denali. This multitarget deal expands the scope of the initial collaboration, announced in June 2018, which successfully produced potent lead candidates now in preclinical development. Under the financial terms of the agreement, AbCellera will receive a technology access fee and research funding, and is eligible for milestone payments and royalties based on the development and com-mercialization of antibodies generated under this collaboration.

“Next-generation antibody drugs hold tremendous potential for the treatment of neurodegenerative and other neurological diseases, one of the great unmet challenges facing our society. Conquering these complex diseases will require that we leave no stone unturned, build strong collaborations and bring together the best in science and tech-nology,” Carl Hansen, president and CEO of AbCellera, said in a news release. “With the vast majority of approved antibodies originat-ing from natural immune systems, the field is recognizing the advantages of immune repertoire screening to maximize chances of success.”

AbCellera has also signed a two-year agree-ment with the Bill & Melinda Gates Foun-dation. The funding provided, which totals $4.8 million, will support a series of scientific

collaborations between AbCellera and Gates Foundation-funded scientists working on the prevention and treatment of high-priority infectious diseases.

The target diseases—including HIV, malaria and tuberculosis—infect hundreds of millions of people annually and dispro-portionately impact developing countries. The collaboration will benefit from AbCel-lera’s new technology capabilities for deep profiling of antibody responses. In August 2018, AbCellera acquired Lineage Biosci-ences, a spinout company that pioneered the use of next-generation sequencing technology (Rep-Seq) to capture the full diversity of antibodies generated by natural immune responses. Rep-Seq complements the unique functional information obtained

from AbCellera’s single-cell discovery plat-form, increasing the diversity of antibodies identified and enabling a more rational vac-cine design.

“We’re thrilled to be working with the Gates Foundation again in such a critical area of global health,” mentioned Dr. Kevin Heyries, head of Business Development at AbCellera. “Because our platform can screen millions of single B cells per day, allowing us to identify rare and highly potent anti-bodies from patient samples, the resulting fully human antibodies can be used for the prevention of deadly diseases for which vac-cine development has proven difficult. It’s a fresh approach to tackling humankind’s old-est infectious adversaries.” nEDITCONNECT: E041905

ABCELLERACONTINUED FROM PAGE 6

In addition to its new deal with Novartis, AbCellera also recently forged one with Denali Therapeutics that expands the scope of an initial collaboration that has successfully produced potent lead candidates, which are now in preclinical development.

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discovery projects across the drug design cycle: from early-stage hit discovery to late-stage lead optimization,” Urbahns says. “At this point in time it has not yet been decided which drug discovery projects will benefit from the technology, except for one project which has already started at lead optimiza-tion stage, where Iktos technology is used to help identify molecules with optimal pro-files for all in-vitro assays (potency, selectivity, ADMET) and which will therefore be likely to have good results in in-vivo testing.”

“We are thrilled that Merck ... is collabo-rating with Iktos to further accelerate its drug discovery capabilities,” commented Yann Gaston-Mathé, president and CEO of Iktos. “In a short space of time, our technology has successfully enabled huge progress, and we are eager to apply the enormous possibilities it holds to help Merck with the successful design of new therapeutic options.”

The agreement with Iktos follows a recent announcement in December of a year-long licensing agreement with Cyclica Inc. for the use of its AI-augmented proteome screening platform, Ligand Express. Merck KGaA was also recently granted a U.S. Patent for a novel combination of artificial intelligence and blockchain technology, aimed at providing a solution for the secure integration of physical products into the digital world.

And in other discovery-related AI news, Elsevier and The Pistoia Alliance recently announced the results of a joint “datathon” for Drug Repurposing for Rare Diseases. The datathon, conducted in partnership with non-profit groups Cures Within Reach and Mission: Cure, involved participants from a range of organizations including life sciences, technology and academia, and has succeeded in identifying drug candidates for repurposing to treat chronic pancreatitis. The full results of the datathon were released at The Pistoia Alli-ance Centre of Excellence for AI/ML in Life Sciences workshop in London on March 12.

Five drug candidates passed the expert review panel and are being actively con-sidered by Mission: Cure with a view to proceeding to patient trials: lacosamide to target cathepsin B; dapsone to target the cystic fibrosis transmembrane conductance regulator; ibuprofen to target the cystic fibro-sis transmembrane conductance regulator; rolipram to target tumor necrosis factor alpha (TNF-α); and prednisolone to target tumor necrosis factor alpha (TNF-α).

“The results of the datathon show that by working in unison, we can achieve break-throughs that will have a real impact on patients’ lives,” said Dr. Steve Arlington, presi-dent, The Pistoia Alliance. “In life sciences today, no one company has the resources to ‘go it alone.’ So the datathon was the perfect oppor-tunity to bring all the relevant experts together and pool our knowledge and resources. The results are very promising, and we look forward to seeing these therapies reach those in need.”

The datathon had participants apply AI, machine learning and statistical techniques to a real-world problem such as drug repur-posing, using Elsevier’s Entellect platform. Participants were able to identify suitable drugs to be repositioned to treat chronic pancreatitis. This involved the use of mul-tiple techniques, including target-based drug discovery, examining the perturbation of a drug on a specific gene known to be disease-modifying and symptomatic-based drug dis-

AICONTINUED FROM PAGE 6

covery — i.e., examining the perturbation of a drug on the body.

“The goal of the datathon was to identify drug candidates for repurposing by using predictive analytics techniques, and we also wanted to explore best practice in the use of data science,” noted Dr. Jabe Wilson, consult-ing director, Text and Data Analytics, Elsevier. “This was the first public trial for our Entel-lect platform, and it’s been a great success on all fronts. I want to thank all our partners and participants for their time and commitment to achieving this positive outcome.” nEDITCONNECT: E041906

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Merck KGaA, Darmstadt, Germany (pictured here) recently signed a deal with Iktos for the use of its generative modeling artificial intelligence technology to facilitate the rapid and cost-effective discovery and design of new compounds.

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SMALL MOLECULES NEED LOVE TOOBY PETER T. KISSINGER

S CIENCE FOLLOWS fashion. Life-sciences research trends in recent decades have sharply moved toward biological solutions to bio-

logical problems. Cells and proteins as therapeutic approaches are in ascendancy. Augmentation via genet-ic editing is at the tip of the spear.

Innovation deserves the excite-ment. After all, these approaches show potential for cures, well beyond reducing disease progression or only treating symptoms. At my age, regenerative medicine appeals. The promise of finally addressing many unmet, or poorly met, needs in human disease is driving the cash as well as the buzz. We have many new tools to drill deeper into the cell. Their cost and performance go up. The excitement for future results drives out some less cutting-edge science that is known to work.

Our patent system modulates the science and the cash. We share ideas with others in trade for a period of exclusivity. That’s fair and it works, although we argue and scheme to extend exclu-sivity. A second bargain involves grandfathering drug approval regulations—not holding older therapies to the new standards of both safety and efficacy. Being exempt from new drug develop-ment standards has the fairness advantage of not requiring, or even encouraging, more work after new tools allow for greater insights. Otherwise, drug approval would become hopelessly chaotic and we would never safely know when our IND-enabling studies were done or our NDA/BLA filings would be complete.

We can argue about process improvements occurring concurrently with development

projects, but we are not going back. Relooking at what could now be done with a drug approved three decades back is not economically feasible. Why not?

We devote little capital when the promise of a return is miniscule vs. alternative uses. Once exclusivity is lost, pricing power has often eroded 90 percent. Oncology, for example, has driven resources away from anti-biotics, depression and hypertension.

What’s wrong with that? I say quite a lot. Older drugs often disappoint in both efficacy and safety. The unknown unknowns in the past have become known unknowns today. Many drugs are ineffec-tive in a high percentage of people for whom they are prescribed at the dose recommended. Let me arbitrarily define high as 20 percent. For some antidepressants it is closer to 70 percent. These patients and their insurance companies do not get their money back. Older drugs interact with each other and with newer compounds in ways that vary person to person.

We learn from qualitative observations (aka bad experiences), but most often we measure absolutely nothing. Older drugs do get some attention from academic toxicologists and ADME folks, but while contributing to knowl-edge, these are not GLP studies. The latter are unfundable.

Why is this important? In the last few years, scripts written for generic drugs passed 90 per-cent of the total. Counting dollars vs. scripts, the percent is much smaller. The cost for a single antibody therapy could pay for a month of antibiotics or antidepressants for the entire population of a small town. Our aging popu-lation experiences more and more unstudied

drug-drug interactions.Furthermore, ethical reasons and science drive

polypharmacy to hedge bets, combining the standard-of-care generic along with the experi-mental drug. For example, 5-fluorouracil might well be used along with an antibody. This highly toxic drug is approaching six decades old and not appearing close to retirement. The exposure varies significantly patient to patient and dos-ing is generally based on mg/m^2 of body surface area. There are multiple API manufacturers and 1,998 clinical studies of 5-FU listed in clinicaltri-als.gov at this writing, and many are studies of drug combinations. While it is well established in the literature that measurement of drug exposure improves efficacy and reduces toxicity with 5-FU, this is all too often not done. Why not?

There are many other examples of grand-fathered (grandpersoned?) drugs that cause trouble, the NSAIDS and acetaminophen being the prototypes. No member of PhRMA will put resources into going backward, and NIH is also far fonder of supporting something new. As a result, very little is being done to optimize dos-ing in individual patients with older drugs, alone or in combination. Pediatrics and geriatrics are special cases, given that neither were considered in trials many decades ago. The possibilities for improvement are clear from papers in the top clinical pharmacology journals. The develop-ment of new measurement tools such as clini-cal mass spectrometry are not quite ready for the world beyond medical schools. Very little of the published science reaches clinical practice. Implementing clinical research is costly, and the profit motive is absent.

In recent years, experts report that repur-posing approved drugs, or drugs that failed

Editor’s focus: Shining light on depression?BY JEFFREY BOULEY

W ITHIN MY CLOSEST CIRCLES, I’ve never really dealt with depression in any significant manner. Yes, I’ve known people with depression, and

there have been the occasional bouts of acute but also very isolated and very brief depres-sive episodes to which I have borne witness up close and personal. And there are many people I interact with or admire from afar in social media who wrestle with depression, sometimes frighteningly.

In my case, it has always been anxiety that has surrounded me in various forms with various loved ones—phobias, panic attacks, obsessive-compulsive behaviors and more.

And those are major issues that have caused many a tear and have been disruptive forces in life, but honestly, depression scares me more. I think of the joy it can drain away in a heart-beat, the way it can undermine a person in such fundamental ways that literally all hope is lost.

Ah, but I said it wasn’t something I had wres-tled with personally or up close, didn’t I?

Well, there was that time my wife had post-

partum depression...There was a beginning and an end to it,

which isn’t the case for people who suffer from the kinds of depression we more often think about. But postpartum depression can be devastating, far more so than what I witnessed and had to help fight against—and believe me, the level of postpartum we struggled with was plenty bad enough, so I feel blessed that I didn’t see any-thing near the worst it could offer. And for those who suffer the worst forms of postpartum depression, it doesn’t matter if it is typically a “phase” rather than a lifelong thing, because in that time that it strikes, people can figuratively and literally be harmed. Or die.

So, it was with keen interest that I read the news recently about the FDA approving Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression in adult women. (Randy Willis also talks a bit about the medication in his special report on neurosci-ence this issue, which focuses on depression and begins on page 16.)

“Postpartum depression is a serious condi-tion that, when severe, can be life-threatening. Women may experience thoughts about harm-ing themselves or harming their child. Postpar-

tum depression can also interfere with the maternal-infant bond. This approval marks the first time a drug has been specifically approved to treat postpartum depression, pro-viding an important new treatment option,” said Dr. Tiffany Farchione, acting director of the Division of Psy-chiatry Products in the FDA’s Center for Drug Evaluation and Research.

It’s not a convenient drug. Zul-resso is administered as a continu-

ous IV infusion over a total of 60 hours, and because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sud-den loss of consciousness and have continuous pulse oximetry monitoring. But it is a start, which I hope can lead to breakthroughs for postpartum depression, as well as other forms of the illness, that will give people back the hope, energy and more that depression steals. n

SMALL CONTINUED ON PAGE 11

Peter T. Kissinger

Jeffrey Bouley, DDNews Chief Editor

www.DDN-News.com

The opinions expressed in guest commentaries do not necessarily represent those of DDNews and/or its owners, editors or other staff.

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COMMENTARY: Targeting α-synuclein and the pathogenesis of Parkinson’s diseaseBY DR. NEIL CASHMAN OF PROMIS NEUROSCIENCES

P ARKINSON’S DISEASE (PD) is a progressive neurodegenerative disorder characterized by the death of dopaminergic neurons in the midbrain (pars compacta area

of the substantia nigra) and the formation of inclusions known as Lewy bodies (hall-mark lesions of PD), which primarily con-tain toxic, aggregated α-synuclein. Symp-toms do not occur in PD until 80 percent or more of the capacity to produce dopamine is lost. PD is the second most common neurodgenerative disease after Alzheimer’s disease, affecting an estimated 10 million people worldwide and ranging in severity from mild to severe.

Carbidopa-levodopa (L-dopa) and dopa-mine agonists are the standard symptom-atic treatments for moderate to severe PD. Administration of L-dopa increases dopamine production by the remaining midbrain neu-rons and usually provides effective relief of motor symptoms for several years. However, treatment with L-dopa has no beneficial effect on the underlying pathogenesis. As neuronal death continues unabated, the effectiveness of ever-higher doses of L-dopa declines, motor symptoms of PD re-emerge and worsen and new, iatrogenic motor symptoms appear, caused by chronic L-dopa therapy. No avail-able treatment has been proven to slow, halt or reverse the progressive neurodegeneration of PD that ultimately leads to death.

Toxic α-synuclein aggregates in the pathogenesis of PDThe cause of the neurodegeneration in PD was not understood until recent years, when specific forms of α-synuclein were found to be toxic to neurons. Strong genetic, neuropatho-logical and preclinical model evidence sug-gests that misfolded α-synuclein aggregates into oligomers, comprising the toxic species that plays a central role in the pathogenesis of PD. α-synuclein oligomers are distinguished from monomers and insoluble fibrils, which are not toxic to neurons.1 Pathogenic mecha-nisms of α-synuclein oligomers include gen-eral cellular toxicity, mitochondrial stress, synaptic dysfunction and compromised cell membrane integrity, among others. Further-more, a large and convincing body of evidence also shows that α-synuclein oligomers act as seeds for the formation of larger aggregates, which acquire the ability to propagate from cell to cell in a prion-like manner, spreading the pathology.

Soon after the discovery of its pivotal role in the pathogenesis of PD and related synucleinopathies, including dementia with

Lewy bodies (DLB) and multiple system atrophy (MSA), α-synuclein aggregation became a lead target for PD therapeutics development. A wide range of development strategies have emerged. Because protein misfolding and formation of α-synuclein aggregates occurs very early in PD, initiating anti-α-synuclein treatment in prodromal or early-stage disease is expected to be advantageous and could prevent the inevitable extensive neurodegeneration.

Early-stage clinical trialsEarly-stage human clinical trials with devel-opmental anti-α-synuclein therapies are underway. Biogen and Prothena Therapeu-tics/Roche are developing immunotherapies based on antibodies aimed at targeting and inactivating misfolded alpha-synuclein. Both programs are in Phase 2 testing in people with early PD. AstraZeneca/Takeda are test-ing an α-synuclein antibody in Phase 1 in healthy volunteers.

Other approaches have reached early-stage clinical testing. Affiris has completed a series of Phase 1 trials, including long-term immunogenicity assessment, with a vaccine designed to stimulate production of α-synuclein antibodies. Neuropore and UCB are developing a small-molecule α-synuclein misfolding inhibitor to inter-fere with propagation of protein aggre-gates and have completed a Phase 1 study in healthy volunteers. Proclara Biosciences is developing a compound that binds to α-synuclein, amyloid-beta and tau and is in Phase 1 in people with mild to moderate probable Alzheimer’s disease. Drugs that are not specific to α-synuclein but proposed to have mechanisms of action that decrease α-synuclein toxicity (e.g., inhibit cell-to-cell transmission, promote autophagic degra-dation) are in early-stage clinical develop-ment, primarily by academic institution sponsors.

Early-stage clinical trials are under-taken, principally, to determine the safety and dosing of developmental compounds. Traditionally, efficacy is not a primary out-come measure until late-stage trials. How-ever, biomarkers for predicting the efficacy of developmental α-synuclein therapeu-tics are currently undergoing evaluation and validation. If successful, they might soon enable drug developers to reach go/no-go decisions based on anticipated effi-cacy before investing in long and costly Phase 3 trials. Which of the current drugs in development, if any, might eventually be approved by FDA will be determined by Phase 3 efficacy trial results, which will not be available for at least several years.

Preserving normal, physiological α-synuclein tetramerDuring the last decade, a novel α-synuclein species designated the helical tetramer was recognized, which is stable and performs an important physiological function by inhibit-ing α-synuclein aggregation.2 More recently, a transgenic mouse model designed to make mice unable to form the physiological tet-ramer resulted in the development of a dis-ease closely resembling human PD.3 These findings have important implications for α-synuclein-based therapeutics development. If the tetramer must be preserved to maintain normal α-synuclein homeostasis, what will be the effects of therapeutics designed to attack all α-synuclein conformations, including the tetramer? Will these drugs be efficacious and without adverse effects (AE)? Or will the inactivation of α-synuclein tetramer compro-mise efficacy or cause AEs?

It is important to understand that protein misfolding, leading to the formation and aggregation of toxic oligomeric conforma-tions and propagation (prion-like, cell-to-cell transmission) of toxic oligomeric aggre-gates, is not unique to PD, DLB and MSA. This pathogenic mechanism is implicated as an underlying cause of most neurode-generative disorders, including PD, DLB and MSA (all three are synucleinopathies), Alzheimer’s disease (AD, aggregation of Aβ and tau are the characteristic proteins), amyotrophic lateral sclerosis (ALS, aggre-gation of TDP43 and SOD1), frontotemporal dementia (FTP; TDP43 and tau aggregation) and others.

In AD, although amyloid beta (Aβ) exists in many different conformations, only spe-cific (low molecular weight) Aβ oligomers (AβO) are toxic.4 The many late clinical-stage failures of developmental anti-Aβ ther-apeutics are directly attributable to targeting non-toxic conformations of the Aβ protein, while failing to target, or ineffectively target-ing, the toxic species, AβO. For α-synuclein oligomers, it is currently unclear which molecular species are toxic. It is presumed that avoidance of α-synuclein physiological tetramers should be avoided, but that other oligomers (including misfolded tetramers and protofibrils) are contributing to the path-ological spread of the α-synucleinopathies. Therefore, the development of an anti-α-synuclein therapeutic with maximal efficacy is expected to require antibodies (or other approaches) that are highly selective for the toxic forms of α-synuclein (oligomers and/or small soluble fibrils), while sparing normal, physiological forms (α-synuclein tetramer) and inert species (monomers) to minimize the likelihood of adverse events.

Discovery of antibodies highly selective for toxic α-synuclein conformationsThe application of classical methods for the discovery of anti-α-synuclein antibod-ies yields pan-α-synuclein antibodies that bind all species of the α-synuclein protein. Discovery research of anti-α-synuclein anti-bodies with highly selective binding profiles for only the toxic forms, while sparing the physiological and inert forms, is challeng-ing. Toxic oligomers contain unstructured regions and are unstable. However, misfold-ing results in the formation of new epitopes in the misfolded α-synuclein aggregates; and, critically, the toxic conformations are preserved during the corruptive protein tem-plating process by which prion propagation and cell-to-cell spread occur. Scientific lit-erature suggests a complex binding profile for such an antibody.

For its part, ProMIS Neurosciences has developed a unique antibody design plat-form to identify an optimal “disease selec-tive” binding profile suggested by the scien-tific literature, “tune” epitopes to generate antibodies with desired binding profiles, and then assess functional performance and comparative binding to select a lead candidate. Application of this discovery platform to α-synuclein and the synucle-inopathies led to the generation and devel-opment of highly selective antibodies that target only the toxic forms of α-synuclein, toxic oligomers and/or small soluble fibrils, while avoiding the targeting of physiological tetramers and inert monomers. These anti-bodies achieved the targeted binding profile for treating PD, demonstrating effective neu-tralization of toxic oligomers and cell-to-cell spread of soluble fibrils, while sparing the physiological forms of α-synuclein such as monomers and helical tetramers. Such anti-bodies would be expected to treat PD and other α-syncleinopathies without adverse effects. n

Neil Cashman, M.D., is chief scientific officer and co-founder of ProMIS Neurosciences Inc.

for efficacy or human toxicity, suggests re-deploying some old molecules and explor-ing them with the new tools. The idea makes sense, just as off-label use makes sense. For approved OMEs (old molecular entities), there is a notion that costly toxicity studies can be avoided as new uses and combinations

are explored. Several “de-risked” repurpos-ing libraries of well-documented candidates have been assembled.

The history of repurposing success is well known, but the few examples were from chance observations and not the deliberate process now ongoing. Here, too, the effort is limited by the patent system. The challenge of safely protecting innovative uses in the face of many generic suppliers is real.

Small molecules are here to stay. They have substantial advantages in safety, manu-facturing cost, stability, delivery to patients and availability in low- to middle-income countries. They are also likely to be partners with their big sisters. Patients could benefit from applying new tools with old drugs, improving efficacy and reducing harm. Physicians could be guided with help from clinical decision support tools in electronic

health records—long discussed, but not yet real. We know what to do but can’t afford to do it while proteins keep vacuuming up so many resources. n

Peter T. Kissinger (who can be reached at kissinger@ddn-news.com) is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia.

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REFERENCES1. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol. 2017;298(Dec, pt B):225-235.

2. Bartels T, Choi JG, Selkoe DJ. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011;477(7362):107-10.

3. Nuber, etal. Abrogating Native a-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease. Neuron 2018;100:75–90.

4. Yang T, Li S, Xu H. Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J Neurosci. 2017;37:152-163.

BRIEFS

RESEARCH & DEVELOPMENT

12 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

New hepatocyte model options

WALKERSVILLE, Md.—Last month saw Lonza announce the addition of Verified for Spheroids Human Hepatocytes to its portfolio, a new offer-ing that is pre-screened for the ability to promote rapid spheroid formation in cell culture. These new primary plateable hepatocytes were debuted at the 58th Society of Toxicology Annual Meeting and ToxExpo in March. Lonza notes that current hepatocyte models face issues of long-term func-tionality, which 2D hepatocyte cultures often lack, and the ability to form spheroids in culture, which not all hepatocyte donor batches are capable of.

“Using spheroids as in-vitro liver model sys-tems requires researchers to carefully select donors and thoroughly examine hepatocyte lots in advance,” commented Erica Chamberlin, tech-nical specialist at Lonza. “With our Verified for Spheroids Human Hepatocytes, we take on this burden on behalf of our customers, enabling them to focus on what matters most—their science.”

A new addition to ApolloMOUNTAIN VIEW, Calif.—DNAnexus Inc. has expanded its DNAnexus Apollo Platform with the addition of a browser for clinico-genomic cohorts that will provide customers with at-scale navigation and exploration of combined genotypic and phenotypic data. The company describes DNAnexus Apollo as “an enhanced platform for data science exploration, analysis and discovery,” adding that this new browser enables rapid inter-rogation of large and complex datasets thanks to a powerful user interface.

“Scientists can bring their data to DNAnexus Apollo and use our cohort browser for easy and rapid exploration, querying potentially thousands of phenotype fields and millions of genetic vari-ants in a matter of seconds … DNAnexus has long been at the forefront of scalable informatics, and we are pleased to offer this novel solution to the research community,” said Richard Daly, DNAnexus CEO.

IN THIS SECTIONBioinformaticsA new addition to Apollo ....................... 12Bioinformatics infrastructure finds funding ........................................... 12

Cell biologyBuilding a new toolbox (TOOLBOX from cover) ............................ 15

OncologyCancer clue in cellular machinery .......... 14Scholar Rock picks SRK-181 ................... 12

Neurology/RaceDementia diagnosis; dementia difference ............................... 12New hepatocyte model options ............. 12

Dementia diagnosis; dementia differenceRace can mean dramatic differences in pathologies, and new research seeks to delve into thatBY ILENE SCHNEIDER

SACRAMENTO, Calif.—According to a new study from the Alzheimer’s Center at the University of California, Davis (UC Davis), there are major differences in the brains of Latinx sub-jects with a dementia diagnosis as compared with those of Caucasian and Black patients.

Published in the Journal of Alzheimer’s Disease, the study analyzed autopsied brains and determined that Latinx people diagnosed with dementia were much more likely to have cere-brovascular disease than either Caucasians or Black individu-als. Researchers also discovered that Latinx and Black patients were more likely to have mixed pathologies; that is, a combina-tion of Alzheimer’s disease and cerebrovascular disease, than is the case with Caucasians.

Also, Caucasians had more pure Alzheimer’s disease (rather than co-morbid disease) than either Latinx or Black individu-als. Researchers hope the findings help to explain the higher rates of dementia among Black and Latinx patients and might

Scholar Rock picks SRK-181Company aims to develop cancer immunotherapy candidate, which is a selective inhibitor of TGFβ1 activationBY MEL J. YEATES

CAMBRIDGE, Mass.—Scholar Rock has announced its selection of SRK-181, a highly specific inhibitor of TGFβ1 activation, as the first product candidate in its TGFβ1 cancer immunotherapy program, based on the strength of its preclinical data and human translational insights. The company has initi-ated manufacturing and is progressing pre-clinical development, with plans to initiate a Phase 1 trial in patients with solid tumors in mid-2020.

“Given that a majority of cancer patients fail to respond to checkpoint blockade thera-pies, we are eager to advance the next prod-uct candidate from our pipeline of growth factor modulators to potentially address a key mechanism of pre-existing resistance,” says Dr. Nagesh Mahanthappa, president and CEO of Scholar Rock. “A growing body of evidence strongly implicates elevated TGFβ1

activity as a cause of immunotherapy failure, and we see tremendous potential for SRK-181 to expand the number of patients who could benefit from checkpoint blockade therapies by potently and selectively inhibiting the activation of TGFβ1.”

SRK-181 is a fully human antibody designed to bind to, and prevent the activation of, latent TGFβ1 with high affinity and high selectivity, with minimal or no binding to latent TGFβ2 and latent TGFβ3 isoforms. Several impor-tant factors led to the decision to advance

SRK-181 as a clinical development product candidate for the treatment of tumors resis-tant to checkpoint blockade therapies (CBTs), such as anti-PD1 antibodies, including the fact that TGFβ signaling has been implicated as a culprit in primary resistance to CBTs in multiple peer-reviewed studies.

According to Mahanthappa, “SRK-181’s mechanism of action is rooted in Scholar Rock’s structural biology insights into the activation of the latent or precursor form

SRK-181 CONTINUED ON PAGE 13

BIOINFORMATICS INFRASTRUCTURE FINDS FUNDINGUKRI has awarded infrastructure funding to support the open data resources provided by EMBL-EBIBY MEL J. YEATES

C A M B R I D G E , U. K . — U K Research and Innovation (UKRI) has awarded £45 million to EMBL’s European Bioinformat-ics Institute (EMBL-EBI) to enhance the institute’s techni-cal and building infrastructure. The funding, from the UKRI’s Strategic Priorities Fund, will support EMBL-EBI’s existing and emerging data resources, includ-ing areas of major interest such

as genomics and bioimaging.EMBL-EBI is a global leader in

the storage, analysis and dissemi-nation of large biological datas-ets. It hosts numerous central-ized data resources, which are critically important for academ-ic and commercial life science research. The volume and diver-sity of life science research data are growing rapidly, partly due to the rise of new technologies such as single-cell sequencing and cryo-electron microscopy. Open, freely available research data is an important driver for new discoveries, but scientific data sharing requires robust data resources.

“EMBL-EBI websites receive over 38 million requests for data

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SRK-181 is a fully human antibody designed to bind to, and prevent the activation of, latent TGFβ1 with high affinity and high selectivity, with minimal or no binding to latent TGFβ2 and latent TGFβ3 isoforms.

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of growth factors such as TGFβ1. Since the mature or active form of members of the same growth fac-tor superfamily share considerable similarities, it is very challenging to achieve selective inhibition of the targeted growth factor with-out also targeting other closely related growth factors and thereby risking unintended side effects. However, the precursor forms of TGFβ superfamily members each present a structurally distinct ‘cage’ that holds what will be the mature growth factor in an inactive state. By targeting the structural dif-ferences in the precursor form of growth factors, Scholar Rock’s platform is designed to discover and develop monoclonal antibodies that have an unprecedented degree of specificity to achieve selective inhibition of growth factor activa-tion and signaling.”

Translational data analyses by Scholar Rock have highlighted the prominent expression of TGFβ1 in many human tumor types, such as bladder cancer, non-small cell lung cancer and melanoma, for which CBTs have either been approved or demonstrated clini-cal activity in trials. Clinical cor-relation and preclinical model data suggest that TGFβ1 excludes effector cell entry into the tumor, limiting immune system access to tumor cells. Preclinical studies in syngeneic mouse tumor models resistant to CBT show that SRK-181-mIgG1 (the murine version of SRK-181), when combined with anti-PD1 antibodies, permit-ted effector T cell infiltration and expansion into the tumor micro-environment, and led to tumor regression or control as well as significant survival benefit.

“In a number of preclinical mod-els of cancer immunotherapy that are otherwise refractory to CBT, we have observed that co-admin-istration of SRK-181-mIgG1, the mouse version of SRK-181, with an anti-PD1 antibody renders these tumor models sensitive to the com-bination treatment. We identified mouse syngeneic tumor models that reflect the primary resistance to CBT observed in human cancers and results from these studies were presented at the SITC annual meet-ing last November,” Mahanthappa notes.

“These models, the MBT-2 blad-der cancer model and the Cloud-man S91 melanoma model, are poorly responsive or unresponsive to single-agent treatment with either anti-PD1 (a CBT agent) or to SRK-181-mIgG1 alone, with lit-tle or no effect on tumor growth. However, the combination of these two agents (anti-PD1 and SRK-181-mIgG1) resulted in either complete responses or tumor control, and led to significant survival benefit. Importantly, a 28-day pilot toxicol-

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ogy study of SRK-181 in adult rats also showed no observed drug-related toxicity up to a weekly dose of 100mg/kg for 4 weeks, with no observed valvulopathy as is com-monly observed with TGFβ inhibi-tors that are not selective to TGFβ1 (i.e. also target TGFβ2 and TGFβ3).”

Detailed preclinical results for SRK-181-mIgG1 (formerly referred to as SRTβ1-Ab3) were presented at the Society for Immunotherapy of Cancer (SITC) 33rd Annual Meet-ing in November. The poster pre-

sented at SITC can be accessed by visiting the Scholar Rock website at http://www.scholarrock.com/platform/publications/. Addi-tional preclinical data for SRK-181-mIgG1 were presented at the 2019 American Association for Cancer Research Annual Meeting in Atlanta.

“While advances in immunother-apy have transformed the treatment of patients with cancer, a majority still fail to respond to CBTs because they have what appears to be a pre-

existing, or primary, resistance to immunotherapy,” adds Mahanthap-pa. “Other patients’ cancers appear to respond initially but subsequent-ly progress. This has led to a deluge of efforts to evaluate these therapies in combination settings in order to overcome tumor resistance.” “Given the growing body of evi-dence that implicates TGFβ1 activity as an important cause of immunotherapy failure, we believe that SRK-181 offers a rational path towards expanding the number of

patients who could benefit from these cancer immunotherapies by potently and selectively inhibiting the activation of TGFβ1. In addi-tion, we believe that SRK-181 has the potential to address unmet medical needs in other oncology indications, and we will endeav-or to maximize the value of this product candidate for patients by exploring its potential in additional oncology indications,” Mahanthap-pa concludes. nEDITCONNECT: E041908

14 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.comRESEARCH & DEVELOPMENT

or analysis every day,” said Ewan Birney, director of EMBL-EBI. “The demand for our data resources has risen dramatically in the last decade and we expect this trend to continue, so we need to be ready for when it happens.”

To meet the increasing demand for open-access data resources, EMBL-EBI plans to use the recently awarded UKRI funding to expand the institute’s technical infrastructure, including the setup of new data storage solutions as well as the scaling up of existing data resources. The funding will also be used to provide secure shared analysis platforms for major research collaborations.

“EMBL-EBI collaborates with academia, industry and governments to develop databases, tools and software that make life science research data available to all,” added Melanie Welham, executive chair of the Biotechnology and Biological Sci-ences Research Council (BBSRC), part of UKRI. “We hope that this funding will enable them to scale up the amazing work they are already doing within the life sci-ence community and beyond.”

In addition to the UKRI funding news, EMBL-EBI also notes that it has combined its knowledge of bacterial genetics and web search algorithms to build a DNA search engine for microbial data. The search engine, described in a paper published in Nature Biotechnology, could enable researchers and public health agencies to use genome sequencing data to monitor the spread of antibiotic resistance genes.

The search engine, called Bitsliced Genomic Signature Index (BIGSI), fulfills a similar purpose to internet search engines like Google. EMBL-EBI pointed out that the amount of sequenced microbial DNA is doubling every two years, and until now there was no practical way to search this data. By making this vast amount of data

discoverable, the search engine could allow researchers to learn more about bacteria and viruses.

“This search engine complements other existing tools and offers a solution that can scale to the vast amounts of data we’re now generating,” noted Phelim Bradley, a bio-informatician at EMBL-EBI. “This means that the search will continue to work as the amount of data keeps growing. In fact, this was one of the biggest challenges we had to overcome. We were able to develop a search engine that can be used by anybody with an internet connection.”

Conventional search engines use natu-ral language processing to search through billions of websites, and take advantage of the fact that human language is relatively unchanging. But microbial DNA shows the imprint of billions of years of evolution, so each new microbial genome can contain new “language” that has never been seen before. The key to making BIGSI work was finding a way to build a search index that could cope with the diversity of microbial DNA.

“We were motivated by the problem of managing infectious diseases and antibi-otic resistance,” explained Zamin Iqbal, research group leader at EMBL-EBI. “We know that bacteria can become resistant to antibiotics either through mutations or with the help of plasmids. We also know that we can use mutations in bacterial DNA as a historical record of bacterial ancestry. This allows us to infer, to some extent, how bacteria might spread across a hospital ward, a country or the world. BIGSI helps us study all of these things at massive scale. For the first time, it allows scientists to ask questions such as ‘has this outbreak strain been seen before?’ or ‘has this drug resis-tance gene spread to a new species?’ Mak-ing genomics data searchable at this point is essential, and it will allow us to learn a huge amount about biology, evolution, the spread of disease, and much more.”

EMBL-EBI also recently launched the

Common Infrastructure for National Cohorts in Europe, Canada and Africa (CINECA), an international project led by EMBL-EBI. A virtual cohort of data from 1.4 million individuals will be made acces-sible to approved researchers around the world through CINECA’s federated cloud-based network. Registered researchers will be able to analyze population-scale genomic and biomolecular data. Com-prised of 18 partner organizations across three continents, CINECA has data from 11 cohorts selected to provide a diverse representation of studies in rare disease, common disease and national cohorts over time (longitudinal).

Federated international sharing of human data presents ethical and techni-cal challenges. To protect patient privacy, access to the federated data cohorts will follow the established structure used by the Global Alliance for Genomics and Health, where researchers must formally apply for data access on an individual basis.

“By enabling access to genetic data from diverse human populations, CINECA will support the development of treatments tai-lored to each individual patient’s genetic profile, the ultimate goal of personalized medicine,” said Thomas Keane, team leader at EMBL-EBI. “Clinicians need to be able to compare a patient’s genome to a large set of healthy people and sick people, in order to understand the underlying genet-ics of the patient. And by large, we mean hundreds of thousands or even millions of other people.”

A key aim of CINECA is to develop tools which allow for rapid data discovery, secure access and authorization within the cloud. Such tools will enable researchers to quickly discover data which are relevant to ongoing research projects, without dupli-cating studies. This raises the potential for novel discoveries into causes of rare and common diseases, such as cancer and diabetes. nEDITCONNECT: E041909

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Cancer clue in cellular machineryFlorida researchers say potential avenue for cancer treatment could be hiding in microscopic ‘molecular machine’BY DDNEWS STAFF

TALLAHASSEE, Fla.—Buried deep within the intricate machinery of the human cell could lie a key to treating a range of deadly cancers, according to a team of scientists at Florida State University (FSU). In a new study, research-ers discovered a critical missing step in the production of proteasomes—tiny structures in a cell that dispose of protein waste—and found that carefully targeted manipulation of this step could prove an effective recourse for the treatment of cancer; their findings were published in the journal Cell Reports.

“Proteasomes are kind of like the cell’s recycling center for proteins,” said study co-author Dr. Robert Tomko, an assistant profes-sor of biomedical sciences in FSU’s College of Medicine. “Typically, proteins inside the cell are produced to fulfill a certain function, and once that function is fulfilled, they are no longer needed and need to be removed.”

In particular, it was the stage of the assem-bly process that involves cellular chaperones’ release of a fully completed proteasome that interested Tomko and his team. Before their study, the signaling mechanisms responsible for triggering the release of assembled pro-teasomes was a mystery, according to FSU, limiting scientists’ understanding of the criti-cal final phase of proteasome assembly.

Tomko’s group found that the answer to this puzzle has to do with a feat of “molecu-lar contortion” in which, once a proteasome is nearly finished assembling, it temporar-ily changes its shape, making room for the chaperone protein as the proteasome’s final building blocks are linked together. When assembly is complete, the proteasome sud-denly snaps back into its original shape, crowding out the chaperone protein and eventually popping it entirely free.

“This finding explains how this seemingly impossible process happens, and important-ly, it suggests that by controlling it, we could regulate proteasome assembly to help treat certain types of cancers,” Tomko noted.

The reason? Cancer cells, just like healthy cells, rely on proteasomes to collect and dis-pense with toxic proteins. Because cancer cells produce large amounts of damaged proteins, they compensate by overproduc-ing proteasome assembly chaperones.

In addition, the specific chaperone protein Tomko and his team studied, called gankyrin, is an oncogene—a piece of genetic material that is present at elevated levels in some tumors and has been shown to promote cancer growth.

Tomko said that if scientists can devise a way of interfering with the “popping off” of gankyrin chaperone proteins from assem-bling proteasomes, they may be able to miti-gate the cancer-causing effects of gankyrin while also condemning harmful cancer cells to death by their own toxic proteins. nEDITCONNECT: E041911

Among other important improvements to its open-access data resources, EMBL-EBI has combined its knowledge of bacterial genetics and web search algorithms to build a DNA search engine for microbial data.

For more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 15RESEARCH & DEVELOPMENT

be able to bring attention to the importance of treating each patient based on their indi-vidual risk factors, including racial ones.

According to Charles DeCarli, director of the Alzheimer’s Disease Center and princi-pal investigator on the study, “It’s a way to tailor our approach to the individual, and it’s something we want to do as early as possible. Our idea was to move from just a clinic-based referral system to then create a community-based recruitment system, where we could broaden the range of people who are being evaluated.”

Recognizing a need to broaden the range of individuals being evaluated by physicians for dementia, DeCarli began the research 15 years ago. He wanted to overcome the poten-tial bias of research based on the statistics for the Caucasian people who have histori-cally sought help for memory problems. If someone is Latinx and diabetic or Black and hypertensive, that person is probably at higher risk for dementia, and these risks should be addressed aggressively, according to DeCarli.

For the recent study, researchers analyzed brain tissue from 423 people who had died after a dementia diagnosis between 2000 and 2017. All of the subjects had been seen at one of the two UC Davis Alzheimer’s Dis-ease Center clinics. There were 360 Cau-casians patients, 35 Black patients and 28 Latinx patients. They discovered a mixed diagnosis of dementia—both Alzheimer’s disease and cerebrovascular disease—in 37 percent of Caucasian subjects and 37 per-cent of Black subjects, but 54 percent of Latinx ones. Only 4 percent of Caucasian people had only cerebrovascular disease, compared with 11 percent of Black peo-ple and 21 percent of Latinx people. Pure Alzheimer’s disease (without cerebrovascu-lar disease) was discovered in 43 percent of Caucasians and 43 percent of Black patients,

but only 14 percent of Latinx ones.According to Dr. Brittany Dugger, an

assistant professor in the UC Davis School of Medicine’s Department of Pathology and Laboratory Medicine who also works in the UC Davis Alzheimer’s Disease Center and was corresponding author on the paper, “Alzheimer’s disease is still the leading cause of dementia. However, many cases may have cerebrovascular disease (a dis-ease that affects the blood vessels of the brain) in addition to Alzheimer’s disease, as our study showed. Having diabetes and/or hypertension can increase both the like-lihood of getting cerebrovascular disease

and Alzheimer’s disease.”As to the next steps in the research, Dug-

ger said, “We hope to do more comprehen-sive analyses of brains, delving deeper into the who, what, where, when, why and how. This research is only the tip of the iceberg. Most brain research on dementia is based on a small subset of volunteers who are typi-cally white; it is imperative to understand the spectrum of disease across individuals from diverse backgrounds and regions as we can have differences in our behaviors and cultures, as well as social and economic factors.” nEDITCONNECT: E041910

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*Weller, MG, Analytical Chemistry Insights:11, 21-27 (2016). Antibodies shown: PD-L1 (A700-016) & Lamin A/C (A303-430A) ©2019 Bethyl Laboratories, Inc. All rights reserved.

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Research at the University of California, Davis, has found significant differences in dementia pathology between patients of different races, with those who are Latinx or Black more likely to have co-morbid conditions. Pictured here is the UC Davis life sciences building.

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most notably, a photoinduced tetrazole-alkene cycloaddition reaction (“pho-toclick chemistry”) and a palladium-mediated cross-coupling reaction, for protein labeling in vitro and in vivo. Our current efforts are geared toward the application of bioorthogonal chem-istry to understand the conformational dynamics of the class B G-protein cou-pled receptors in living cells.”

Recent work includes the develop-ment of tools to study how these cel-lular receptors change shape once activated, and how molecules within the cells respond upon activation. Lin’s lab is engineering fluorescent probes to attach to cellular receptors and monitor change, as well as geneti-cally engineered cellular receptors that can “trap” targeted molecules to shed light on which molecules inside of cells interact with activated receptors on the surface of a cell. Related efforts were detailed in a paper published in November in CHIMIA International Journal for Chemistry titled “Recent Developments of Photo-Cross-Linkers as Tools for Biomedical Research.”

The authors, including Lin, report that “Photo-cross-linkers are invalu-able tools for identifying drug targets and off-targets as well as probing the binding sites in medicinal chemistry and chemical biology. In this review, we summarize recent development of the ligand-based and genetically encoded photo-cross-linkers and their use in biological system. In particular, we highlight our discovery of 2-aryl-5-carboxytetrazole (ACT) as a novel class of photo-cross-linkers and their successful applications in drug target identification as well as identifying transient protein–protein interaction complexes in mammalian cells.”

Within the auspices of the National Institute of General Medical Sciences grant, Lin and his lab are specifically focusing on class B G protein-coupled receptors (GPCRs) that are implicated in diseases such as diabetes, depres-sion and osteoporosis.

“Our tools will enable scientists to monitor what happens inside a cell when a receptor is activated in real time,” Lin said. “This is very valuable, because different molecules can activate the same receptor in different ways and trigger different downstream signaling events within cells, which may produce discrete physiological responses.”

This isn’t the first funding Lin has received for his work from the NIH. Last summer, Transira Therapeutics LLC—a UB spinoff founded by Lin—received a $224,000 Phase 1 Small Business Innovation Research award from the National Institute of Diabetes and Digestive and Kidney Diseases to support the development of a hormone-based drug that could help control blood sugar and support weight loss in patients with type 2 diabetes. The goal is a therapy that could be injected once-weekly, and UB researchers will work in collaboration with the California Institute for Biomedical Research. nEDITCONNECT: E041901

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16 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com16 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

SPECIAL REPORT

Trying to reframe the depression conversationBY RANDALL C WILLIS

L OOK AROUND as you read this arti-cle. Assuming you’re not hidden in a corner somewhere, 7 percent or more of the people you can see have had a major depressive episode within the past year, according to National Insti-tute of Mental Health stats. And more than a third of those people received no treatment for their condition.

An even larger percentage, if not everyone, have had to deal with a loved one or friend who has experienced depression in the past, or does now.

And according to the U.S. Centers for Disease Control and Prevention, at least 80 percent of adults experienc-ing depression will report some difficulty with their work, home or social lives because of the depressive symptoms.

“When you have depression, you also have comorbidity of depres-sion,” says Aptinyx President and CEO Norbert Riedel. “You have sleep disturbance. You have cogni-tive dysfunction.”

And even when a patient’s mood symptoms have been stabilized, a significant proportion of people still struggle with these comorbidi-ties, finding it difficult to get back to work or take care of the kids.

Aggravating this situation fur-ther, according to Roger McIntyre, executive director of the Brain and Cognition Discovery Foundation, is that the longer someone has depression or the more episodes they have, the less reliable treat-ments become.

“Something is happening at the neurobiological level that’s chang-ing the biology of the brain, mak-ing it less cooperative with treat-ments,” he presses. “That is why it is so important for us to have timely early accurate diagnosis and get people on the right treatments.”

Unfortunately, clinicians have not had a lot of options from which to choose.

“When you look back in history, you had tricyclic antidepressants in the 1950s and then the SSRIs [selec-tive serotonin reuptake inhibitors] in the 1980s,” explains Stephen Peroutka, vice president of global product development and neurosci-ence therapeutic lead for PPD Inc.

McIntyre recounts cases he has seen where a patient is put on an antidepressant treatment that is only partially effective, but they are left on that same medication for two, three, four years. As he terms it, the patient’s depression simply smolders along.

“Can you imagine going on a cancer drug that just has a partial effect on your tumor?” he asks. “Your oncologist says ‘just stay on it and in three or four years, we’ll see what happens.’ No one thinks like that outside of psychiatry.”

Alternatively, Riedel offers, the clinician intervenes when the

patient experiences side effects or poor response, but to questionable effect.

“They put you on another one and then a third one, but they are all the same class of molecules,” he com-plains. “I’m not sure what we are gaining by experimenting with dif-ferent molecules of the same class.”

This unfortunate scenario may soon change, however, as the understanding of the pathophysiol-ogy of depression expands and new insights are resulting in a growing pipeline of novel class candidates, some of which recently received blessing from the FDA.

Expanding repertoire“The landscape really has changed and has evolved into a much more comprehensive, much more coher-ent and powerful inflammatory model,” says McIntyre. (See also the table “Drugs in development” on page 18.)

The notion that there is an alteration in your serotonin levels

Neuroscience

Depression in all its various forms is a complex condition, which is why there isn’t simply one “happy pill” or even a few options that work consistently for all people or for extended periods; likewise, the complexity and individuality of depression—along with a lack of truly objective diagnostic parameters—makes the search for biomarkers of depression difficult.

HOLDING OUT HOPE

For more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 17SPECIAL REPORT

SPECIAL REPORT

with these results, and they are a vivid reminder that drug devel-opment is extremely challeng-ing, especially in mental health,” said Allergan’s chief R&D officer, David Nicholson, in an announce-ment. “We will evaluate the impact of these data on the ongo-ing monotherapy MDD program and [Phase 2] suicidality in MDD study. We expect to make a deci-sion on these programs during the course of 2019.”

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has been with us for a long time, he continues, suggesting that most FDA-approved agents for depres-sion are monoamine-based.

“It turns out, however, that a good 30 to 40, maybe 45 percent of people with depression taking Prozac-type drugs do not get bet-ter,” he claims. “So therefore, one can only conclude that there must be some other target that we can look at.”

McIntyre points to the array of preclinical and clinical work show-ing that disturbances in brain neu-rochemistry extend well beyond monoamine, impacting other areas such as glutamate pathways, inflammation and neurosteroids.

“This hangs together because glutamate, among other things, plays a key role in brain plasticity, known to be abnormal in depres-sion,” he explains. “Moreover, inflammation plays multiple roles involved in plasticity, regulating other neurochemistries like dopa-mine and serotonin, and having its own direct effect on brain systems relevant to the symptoms that we see in depression.”

As proof, he points to drugs being developed to target gluta-mate and target inflammation, many of which, he suggests, look very promising.

One such candidate is rapastinel, which was licensed to Allergan as a treatment for depression from what is now Aptinyx. The compound is a partial agonist of the NMDA recep-tor, which is also the target of ket-amine and its derivatives.

“That receptor is very well known to be associated with mem-ory, learning, chronic pain, neuro-degeneration,” explains Riedel. “When that mechanistic approach was applied to MDD [major depres-sive disorder] with rapastinel, we saw very striking recovery in patients in a Phase 2a study, as well as a Phase 2b study. This became the foundation on which Allergan acquired rapastinel.”

These other impacts are why Aptinyx continues to explore the NMDA receptor as a therapeutic target for chronic pain, PTSD and cognitive impairment in Parkin-son’s disease.

Riedel suggests that this allows the company to take a more holistic approach to the various comorbidi-ties that overlap between the many disorders.

“They are always multifactorial diseases,” he says. “None of them are just one thing only.”

The early success of rapastinel hit a bit of a bump in March, how-ever, with an announcement from Allergan, bringing into question rapastinel’s development as adjunc-tive to antidepressant therapy for MDD.

In three acute studies, rapastinel did not differentiate itself from pla-cebo on primary and key secondary endpoints.

“We are deeply disappointed

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“Inflammation plays multiple roles involved in plasticity, regulating other neurochemistries like dopamine and serotonin, and having its own direct effect on brain systems relevant to the symptoms that we see in depression,” notes Roger McIntyre, executive director of the Brain and Cognition Discovery Foundation.

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March was a good month for Sage Therapeutics and Janssen, however, as both companies saw FDA approval of their lead products in depression.

In a Phase 3 program, Janssen’s nasal esketamine formulation (Spravato) was found to be supe-rior to placebo when given on top of an oral antidepressant, provid-ing significant improvement in symptoms of treatment-resistant depression. And in long-term studies, esketamine patients who achieved remission were 51 percent less likely to suffer a relapse than placebo patients.

Because esketamine is a derivative of illicit street drug ketamine, pre-cautions are being taken with dosing such that patients will not take the drug home, but rather self-adminis-ter under clinical supervision.

Like rapastinel, esketamine targets the NMDA receptor, but rather than modulate activity, it completely blocks receptor func-tion. This may help facilitate the rapid efficacy for which the drug has become known, but as Aptinyx’ Riedel explains, it may also bring a lot of safety concerns.

“In oncology,” Riedel continues, “when you have molecule go out of control—like a tyrosine kinase, for example—the goal has to be to shut that molecule down, to block it completely.”

In the brain, however, the NMDA receptor is a very important player in normal brain physiology and is involved in a variety of neu-rological conditions, such as pain, PTSD and cognitive impairment.

“The idea of using a sledgeham-mer to shut that receptor off, in my view, is highly unphysiological,” Riedel offers.

“The right approach is to ask has that receptor gone off-track a little and can you put it back on track by modulating it like a dimmer switch, as opposed to an on-off switch,” he presses. “That, we have shown repeatedly and across multiple indications, gives you a much bet-ter efficacy and a remarkably better safety profile.”

Within two weeks of the esket-amine announcement, the FDA then announced approval of brex-anolone (Zulresso) from Sage Therapeutics for the treatment of postpartum depression, the first and only such treatment.

A derivative of the naturally occurring progesterone metabolite allopregnanolone, brexanolone is an allosteric modulator of both synaptic and extrasynaptic GABAA receptors. In its three clinical tri-als, the drug achieved significant mean reductions in Hamilton Rat-ing Scale for Depression (HAMD) total scores from baseline vs. pla-cebo. Symptom reduction was seen as early as 24 hours, and could be maintained for up to 30 days.

“The potential to rapidly reduce symptoms in this critical disorder is an exciting milestone in women’s mental health,” offered clinical trial lead Samantha Meltzer Brody, director of perinatal psychiatry at UNC’s Center for Women’s Mood Disorders. “[Postpartum depres-sion] is recognized to have sig-nificant and long-term impact on women and their families, but with Zulresso, we may finally have the opportunity to change that.”

As McIntyre suggested above, however, there are numerous other areas being explored to understand depression pathophysiology and treatment, including inflammatory pathways.

Early this year, for example, Lisa Kalynchuk and colleagues at Uni-versity of Victoria and University of Saskatchewan reviewed the evi-dence for antidepressant mecha-nisms of TNF-α antagonists.

“Treatment with proinflamma-tory cytokines, including IL-1, IL-6 or TNF-α, or lipopolysaccharide (LPS), induces sickness behavior and corresponding depression-like behavior on the forced swim test,” they wrote. “Mice that lack cer-tain cytokines or cytokine recep-tors do not display stress-induced depression-like behavior, which suggests that lower levels of cyto-kines confer a protective effect on the development of depression-like behavior.”

The authors then highlighted evidence from several studies of patients being treated for auto-immune disorders with different TNF-α inhibitors.

“Patients with rheumatoid arthritis and plaque psoriasis tak-ing prescribed etanercept, which is a TNF-α antagonist, reported significant reductions in depres-sive symptoms,” they noted. “Simi-larly, patients with Crohn’s disease receiving infusions of infliximab experienced significant reductions in depressive symptoms, and this decrease was associated with corre-sponding reductions in proinflam-matory cytokines. Finally, psoriasis patients with comorbid psychiatric conditions report improvement in mood and overall well-being when taking infliximab.”

Because etanercept does not cross the blood-brain barrier, the authors could not identify the mechanisms by which the anti-TNFs addressed depression, although they speculated that in binding peripheral TNF-α, it may promote activation of microglia, which results in decreased central secretion of TNF-α.

Jumping off findings like these, McIntyre initiated his own stud-ies directly linking anti-TNFs and depression.

“I have a study that’s in-press in JAMA where we gave patients inflix-imab as a treatment of their depres-sion,” he recounts. “We found that people who’ve had depression, who told us that they had trauma

in their history, had a significantly greater improvement on the inflix-imab than they did with placebo.”

Perhaps not surprisingly, even the microbiome is being explored as a possible entry point to under-standing depression and response to treatment.

In January, for example, Tonji Medical Hospital’s Chun Yang and colleagues examined the role of gut microbiota on the antidepres-sant effects of ketamine in an LPS-induced mouse model of depres-sion. They noted that 30 bacterial species were significantly altered in prevalence between mice treated with LPS alone versus those treated with LPS plus ketamine.

In particular, the presence of two bacteria—the phylum Actinobacte-ria and the class Coriobacteriia—correlated with immobility time in a forced swim test, a test of stress meant to parallel depression in

mice. To the authors, this suggested these microbes had potential as bio-markers of ketamine effectiveness.

Working in humans rather than mice, McIntyre looked for bacte-rial signatures or enterotypes in the feces of people with depression that differed from those found in healthy controls. And indeed, he found significant differences, par-ticularly in the microbial diversity.

Thus, he says, “we wonder whether for some people, the altered inflammatory burden that we observe in depression—which, by the way is observed in 35 to 50 percent of patients—may have some type of contribution from the gut biome.”

Despite these extended avenues of exploration, however, many chal-lenges remain in the understanding of depressive pathophysiology and the ability to test new therapeutic candidates in a meaningful way.

Part of that challenge is a lack of quantifiable markers of disease sta-tus and the largely subjective end-points commonly used to diagnose patients and monitor response to treatment.

Begging for biomarkersAccording to PPD’s Peroutka, sub-jective endpoints are problematic, pointing to pain as the simplest example.

“We ask patients, zero to 10, what’s your pain like?” he explains. “And what is a five to me versus you versus another person—we don’t know that they’re the same; there’s no way to check that.”

With depression, that uncertain-ty is amplified dramatically.

“Primary endpoint for HAMD is depressed mood: zero to four scale, how are we, no depression to severe depression,” he says, adding that is just the first of 17 questions.

NEUROCONTINUED FROM PAGE 17 DRUGS IN DEVELOPMENT

COMPOUND TARGET/MECHANISM COMPANY

AGN-241751 NMDAR modulator Allergan

ALKS-5461 (buprenorphine/samidorphan)

Κ-opioid receptor antagonist Alkermes

AV-101 NMDAR antagonist VistaGen Therapeutics

BLI-1005 Norepinephrine reuptake inhibitor BioLite

Brexanolone (SAGE-547) GABAA receptor positive allosteric modulator

Sage Therapeutics

Brilaroxazine (RP-5063) D2/3/4 receptor partial agonist5-HT1A/2A receptor partial agonist

Reviva Pharmaceuticals

BTRX-246040 Κ-opioid receptor antagonist BlackThorn Therapeutics

Cariprazine Dopamine D3 partial agonist5-HT1A partial agonist

Allergan

CERC-301 NMDAR antagonist Cerecor

CERC-501 Κ-opioid receptor antagonist Janssen

Dextromethadone (REL-1017) NMDAR antagonist Relmada Therapeutics

Esketamine NMDAR antagonist Janssen

FKB01MD 5-HT1A/1D receptor agonistSerotonin reuptake inhibitor

Fabre-Kramer

ITI-007 5-HT2A receptor antagonist Intra-Cellular Therapies

MIN-117 5-HT1A/2A receptor antagonistSerotonin/dopamine reuptake inhibitor

Minerva Neurosciences

Minocycline AntibioticAnti-inflammatory?

Nitrous oxide NMDAR antagonist

NRX-100/NRX-101 (ketamine + cycloserine/lurasidone)

NMDAR antagonist (ketamine)NMDAR modulator (cycloserine)5-HT2A receptor antagonist (lurasidone)

NeuroRX

PH 10 Pherine neurosteroid VistaGen Therapeutics

Pimavanserin Selective serotonin inverse agonist Acadia Pharmaceuticals

Rapastinel NMDAR partial agonist Allergan

S-47445 AMPA positive allosteric modulator Servier

SAGE-217 GABAA receptor positive allosteric modulator

Sage Therapeutics

SEARCHING EVERY HAYSTACK: A partial list of some of the drugs and their targets in development for bipolar depression, major depressive disorder, post-partum depression and treatment-resistant depression.

For more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 19SPECIAL REPORT

Feelings of guilt, zero to four, he recounts. Suicidal thoughts, zero to four. Insomnia, early at night…the questions and scales keep coming.

He quickly notes that he is not arguing the tests are spuri-ous—HAMD and its ilk have been validated.

“But along all those different scales, you can see the challenge is that it’s just too subjective,” he says.

And even if you could convince yourself that one patient’s score in one category is every other patient’s score in the same category, there is the broader question of the con-tinuum of scores.

“Is a 15 depression score differ-ent than a 25?” Peroutka asks. “The answer is yes. But in clinical trials, we lump all of them together.”

To get more meaningful data in a clinical trial, he suggests, it might be preferential to narrow the range of subjects as a statistical way of homogenizing the patient population.

A molecular biomarker or panel might clarify some of this uncer-tainty, but finding one has proven elusive.

“I don’t think we have a really good handle on the underlying molecular pathology of defined depressive disorder,” explains Rie-del. “It is a very complex disease and varies as to which pathology matters to which patient or anoth-er—similar, I think, to the example in oncology where not every tumor is the same.”

Efforts have been made to iden-tify biomarkers, he continues, and these efforts have met with limited success, in that researchers have managed to make only modest correlations between a particu-lar biomarker and the disease. He questions, however, whether those correlations have been consistent enough to offer any predictive value.

“There is a prevailing view that if we ever have such a thing,”

McIntyre adds, “it’s going to be exceptionally complicated because of the complexities of the biology.”

“Part of the challenge we have is that because we don’t have a blood test or chest X-ray or CT scan to make the diagnosis, we rely on symptom ratings,” he presses. “We rely on clinician impressions, and they are far from perfect.

“They’re not useless—that’s what we base our whole careers on—but they’re not perfect. And that

introduces, as you might expect, variability.”

That variance makes it very dif-ficult to achieve any consensus, McIntyre adds, because clinicians and researchers can’t even agree on what the phenotype is.

“In cancer, they agree that there’s the tumor,” he offers as an example. “In heart disease, they agree you’ve had a heart attack. This is some-thing we agree on.

“But the challenge is that we just can’t agree on what the lesion looks like in depression, which makes the search for a biomarker to make the diagnosis not believable at this point in time.”

Peroutka sees a strong parallel between today’s analysis of depres-

sion and that of multiple sclerosis 25 years ago.

“MS was defined as two separate neurological lesions or deficits in space and time,” he explains. “So, if I was to ask you has your left or right foot fallen asleep in the last

year, and you’d probably say yes. I’d then ask did your opposite hand or fingers ever fall asleep in the past year, and you’d probably say yes. Technically, you could be diag-nosed 25 years ago with MS.”

Now, with MRI-based brain scans, he says, it really doesn’t mat-ter how the patient answers ques-tions or even why the patient has come in for the scan.

“If you’re scanned for a neck injury, and you have plaques in your

head, then you have MS,” he adds.The desire for and potential of

recognized biomarkers has led to several labs approaching the prob-lem from a multitude of directions.

Earlier this year, for example, Peng Xie and colleagues at Chongq-ing Medical University described their efforts to identify metabolite signatures in the urine of patients experiencing depressive episodes in bipolar disorder (BD).

“A clinical review recommended that the antidepressants should be stopped in period of mania, and the antidepressants should be used with a mood stabilizer in period of depression,” the authors explained. “Given these facts, there is an urgent need to develop objective diagnostic methods for BD patients during different episodes.”

In considering their approach, the researchers suggested that no single methodology would give the wide coverage or meaningful results they would need, so they opted for a dual-platform approach using GC-MS and NMR spectrom-etry to profile urine from young and middle-aged subjects.

Comparing samples from healthy controls and affected patients, the scientists identified 13 differen-tially regulated metabolites, most

of which were involved in carbo-hydrate and energy metabolism. Of these, they defined a biomarker panel of five metabolites that they suggested could be helpful in developing an objective diagnostic method.

“A previous study reported that the brain energy metabolism in BD patients was altered,” they stated, finding their results consistent with others. “Our previous studies have also identified some differen-tial urinary metabolites that were involved in energy metabolism in depressed patients. Meanwhile, we also observed the perturbed energy metabolism in the cerebel-lum of chronic mild stress-treated depressed rats.

“Based on these results, we deduced that the pathogenesis of BD might be associated with the disturbance of energy homeostasis that was caused by the dysfunction-al [hypothalamic-pituitary-adrenal] axis.”

In a similar effort also reported this year, Daihui Peng and col-leagues at Shanghai Jiao Tong Uni-versity & Deakin University used UPLC-3Q-MS to examine blood samples from healthy controls and subjects with MDD or bipolar

NEURO CONTINUED ON PAGE 20

FRUITFUL FEEDBACK. It is possible that for animal models of depression to improve, they must not only feed the clinical experience, but also be fed by it. (Adapted from Söderlund, Lindskog. Int J Neuropsycho. 2018:21;668-676.)

“The idea of using a sledgehammer to shut [the NMDA] receptor off, in my view, is highly unphysiological,” says Norbert Riedel, president and CEO of Aptinyx. “The right approach is to ask has that receptor gone off-track a little and can you put it back on track by modulating it like a dimmer switch, as opposed to an on-off switch. That, we have shown repeatedly and across multiple indications, gives you a much better efficacy and a remarkably better safety profile.”

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disorder. Specifically, they wanted to iden-tify any correlations between metabolites in the kynurenine pathway (KP) and depres-sion presence and severity, as determined with the HAMD-24 survey.

Part of the attraction for KP in particular is a growing understanding of its possible role in a number of neurological disorders, including depression.

“Myint and Kim’s widely accepted ‘KP metabolic imbalance hypothesis’ propos-es that metabolic imbalance is the major mechanism of KP-induced depression,” the authors noted. “In line with this, variations in metabolic factors in the KP and relevant enzymes have been found in MDD, bipolar affective disorder and several neurodegenera-tive diseases.”

The researchers identified several metab-olites that were differentially expressed between healthy controls and depressed subjects, although they noted no significant differences between subjects with MDD or bipolar disorder.

As well, there was an inverse correla-tion between the severity of depression and metabolite levels; for example, lower levels of tryptophan and kynurerine were associated with more severe symptoms. And although not perfect, there was a strong indication that many of these levels could be used for clini-cal diagnosis.

“The associations between HAMD-24 scores and metabolic factors in MDD sug-gest variations in [tryptophan] exert a criti-cal role in disease remission,” the authors concluded. “Most importantly, [kynurenic acid] is a potential biomarker discriminating MDD and healthy controls, offering a novel diagnostic method for clinicians.”

Glen Baker and colleagues at the Univer-sity of Alberta, meanwhile, recently reviewed efforts to understand the roles of D-serine in both schizophrenia and depression. Beyond the compound’s potential as an NMDA receptor co-agonist, the researchers sug-gested it has also shown potential as a predic-tive biomarker for antidepressant response to ketamine.

“Several interesting pharmacodynamic and pharmacokinetic interactions between D-serine and ketamine have been reported, and, interestingly, evidence suggests that low plasma levels of D-serine may predict posi-tive antidepressant response to ketamine,” the authors summarized. “Several animal model and clinical studies also indicate that D-serine may be effective in reducing cogni-tive deficits, but that further study is neces-sary before considering it an effective cog-nitive enhancer for routine use in humans.”

Whether looking at metabolite panels, cytokine levels or protein markers, however, there is still a significant gap between experi-mental correlations and validated, broadly accepted biomarker.

In fact, Riedel is not completely sure that the FDA is ready to immediately accept an objective biomarker that correlates with disease.

“Even if we had [a good biomarker] and we could show that it can be changed with a drug, the FDA would say that’s not good enough, I still need to have patient-reported or physician-reported subjective methods of verification,” he suggests. “The biomarker may be supportive, but it will not become the endpoint upon which you decide the drug

gets regulatory approval. We are a long dis-tance from that.”

And until biomarkers are accepted as objective endpoints, studies of depression will continue to struggle with another major obstacle: the placebo effect.

Because diagnostic panels like HAMD rely on patient-reported feedback—Do I feel bet-ter? Do I feel less depressed?—many clinical studies can suffer from a very strong placebo response, says Riedel.

In part, according to Peroutka, it is the nature of the disorder.

It’s the natural history of the disorder that people get better on their own, he says. Depression is episodic, by definition in the case of bipolar disorder, and so even with-out therapeutic intervention, a percentage of patients in a clinical trial may feel better.

This sets an artificially high bar over which any study treatment must show an effect.

Riedel also offers the example of func-tional unblinding of the study, where patients and clinicians know whether the patient is receiving the study drug vs. placebo because of the associated side effects.

Thus, a positive response may have little to do with drug efficacy but rather the aware-ness of treatment and the belief that it will have a positive impact.

“We probably leave a lot of good com-pounds behind because they really can’t overcome the placebo effect even if they are perfectly active drugs,” Riedel says.

“There may have to be different thinking about how we design and execute trials,” he continues. “Maybe we measure the activity of a drug against the baseline that is known in each of these patients.”

Long before any candidate reaches clini-cal trials, though, the search for effective and safe antidepressants is also challenged by the models on which these drug leads are initially tested.

Middling modelsAnother issue of using subjective, query-based diagnostics criteria such as the HAMD is that unlike molecular biomarkers, which may also be found in model organisms or have analogues, it is difficult to find a rat, mouse or non-human primate that can directly answer questions about how depressed they are feeling.

“In mood disorders like depression, it is hard to measure depression in a rodent,” acknowledges Riedel. “There are ways in which we look at this, but I would say that it is of limited value in predicting a human disease course in a depressive disorder.”

“There is no question that the animal mod-els we have are not just imperfect, but are serving as a major limitation to progress in the field,” McIntyre adds.

In place of the HAMD, researchers are forced to use stress- and anxiety-inducing tests on lab animals, such as the forced swim test mentioned earlier or the tail suspen-sion test. Another commonly used test is a measure of anhedonia—losing the ability to derive pleasure from something that usually produces pleasure. In the case of rodents, this is often measured in the preference for sweetened over unsweetened water.

But how well does the rodent response reflect the human condition?

“I have done that forced swim test [on rodents],” offers Riedel. “Why would you stop swimming? Well, maybe the rat doesn’t know how to swim. Maybe it’s weak. Maybe it did well the day before.”

“But to say that it is because they’re depressed is a stretch,” he adds,

In a recent review, Karolinska Institutet’s Johan Söderlund and Maria Lindskog chose to see these tests in a different light.

“When we compare animal models with clinical conditions, we need to use less well-established clinical descriptions,” they opined. “These conditions are often associ-ated with an increased risk of developing major depression, but are not major depres-sion per se.”

“It becomes clear that the animal models are not diagnostic models, but rather mod-els of risk and vulnerability factors of depres-sion,” they continued. “Importantly, this is not a drawback of the animal models, but again illustrates that the current diagnostic system is neither compatible with neurosci-ence nor is it sufficient to describe the under-lying mechanisms of depression.”

And just as the array of approaches to depression pathophysiology has expanded in human profiling, the pair noted that this is also the case in animal model development, suggesting that we are moving well beyond simply behavioral assays and into more molecular modalities such as gene knock-outs, optogenetic stimulation and neuroin-flammatory models.

McIntyre also sees hope in efforts to model depressive disorders using stem cell approaches.

“If you can take a stem cell from someone who has been affected by depression and induce it into a neuron, what you’ve effec-

tively done is you’ve put into your dish a neuron which presumably is identical to the neuron in the brain,” he says, acknowledging that this is yet a work in progress. “But you can imagine that this is a better methodology than the animal models.”

Indeed, companies like StemonX and Stem Cell Technologies, as well as organiza-tions like the Wyss Institute, have put a lot of effort into the development of brain cell organoids and spheroids, as well as brains-on-a-chip and blood-brain barrier mimics to offer researchers everything from precision medicine approaches to specific patients or simply deeper molecular understandings of cell communication and drug pharmacology.

But if we thought it was difficult to ask a mouse how it felt, we can only imagine the effort to do so with a microwell of cells, no matter how well-organized.

For Söderlund and Lindskog, animal mod-els and human experience can only improve by taking a feedback approach.

“Clinical experience is necessary to develop fruitful animal models, but the animal mod-els are also needed to delineate the complex patterns of different exposures and vulner-ability factors characterizing the clinical situ-ation, indicating the potential mutual benefit between research and clinic,” they concluded.

As the repertoire of possible treatments slowly expands, perhaps a similar feedback loop needs to tighten between patients and clinicians, clinicians and researchers, and patients and communities. nEDITCONNECT: E041931

NEUROCONTINUED FROM PAGE 19 Metabolism and mood

AS RECENT EFFORTS to study the gut-brain axis with microbiomics or correlations between metabolic syndrome and the onset of neurodegen-

erative diseases like Alzheimer’s would indicate, there is a slowly growing aware-ness of links between metabolism and mood disorders like depression.

As the University of Toronto and Uni-versity Health Network’s Roger McIntyre explains, although insulin is prevalent in the brain, it is not being utilized for glucose homeostasis as it is elsewhere in the body.

“The evidence indicates that insulin is a brain peptide that serves a tropic role,” explains McIntyre, who is also executive director of the Brain and Cognition Dis-covery Foundation. “It’s responsible for neurodifferentiation, neuroplasticity and also reducing apoptosis.”

And just as too much or too little insu-lin is problematic in the periphery, so too does the imbalance create problems in the brain.

“If your brain is exposed for a signifi-cant period of time to elevated levels of insulin—which is seen in early type 2 diabetes—that can set in motion, in the short term, something you don’t want,” he continues. “What happens is that the brain begins to deposit amyloid, the pro-tein implicated in Alzheimer’s disease.”

This happens because insulin uses the same degradation pathway as amyloid. Thus, when there is a relative excess of insulin, it is preferentially degraded, leav-ing amyloid to build up and then trigger-ing an inflammatory cascade.

“Diabetics have very high rates of Alzheimer’s disease,” McIntyre adds. “It is now said that 10 to 15 percent of all AD cases are directly due to diabetes.”

But how does this impact depression?According to McIntyre, upward of 30

to 40 percent of people with depression—including those without diabetes—exhib-it impaired insulin-glucose homeostasis.

Thus, he continues, “because people with diabetes and depression have hyper-insulinemia for a long time, the amount of insulin getting into your brain over time begins to diminish. The brain adapts, it decreases the insulin uptake.”

“And the problem with diminishing insulin uptake in response to peripheral hyperinsulinemia is that now you’re losing those key roles that insulin performs in your brain: neurodifferentiation, neuro-plasticity, as well as inhibiting apoptosis,” he says, bringing the discussion full circle.

It’s a double hit, he remarks.“In the short-term, you get this amyloid

deposition. And in the long-term, you lose the tropic support.”

Given this paradigm, McIntyre and colleagues have examined the impact of the GLP-1 receptor agonist liraglutide on non-diabetic subjects experiencing depression. In a pilot study, they found that a four-week regimen was not only safe and well tolerated, but also subjects showed significant improvements in cog-nitive function.

Similar effects have been seen with other diabetes therapies, including met-formin, offering another avenue of anti-depressant exploration. n

BRIEFS

PRECLINICALFor more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 21

Moleculin, WPD ink licensing dealHOUSTON—Moleculin Biotech Inc. has begun a sublicense agreement with WPD Pharmaceuticals that grants the latter exclusive rights, subject to existing license agreements, to develop and mar-ket several of Moleculin’s technologies in speci-fied European countries. In return, Moleculin will receive a minimum of $4 million in development expenditures agreed upon by Moleculin as well as an ongoing royalty on future revenues.

Walter Klemp, Moleculin’s chairman and CEO, said, “We estimate that the territories we are outlicensing represent approximately 10 percent of the worldwide spending on healthcare (as reported by the World Health Organization), and exclude key markets considered important to potential future outlicensing opportunities with ‘Big Pharma’ ... We believe this deal may allow us to pursue new indications for our lead drugs that otherwise would remain unexplored, which may ultimately increase our market opportunities and our chances for earlier drug approval. An added and extremely important benefit of this approach is that Moleculin doesn’t have to invest its own resources in establishing an EU-based infrastruc-ture that would be required to access such grant funding of our own.”

Repositive showcases Cancer Models Scout service

CAMBRIDGE, U.K.—This year’s AACR 2019 featured Repositive demonstrating its Cancer Models Scout service with an interactive app, as well as hosting a roundtable discussion on modeling can-cer metastasis in preclinical drug development. Repositive’s inventory and technology enables researchers to use Cancer Models Scout to access more than 4,500 preclinical cancer mod-els from providers worldwide. Among these are model types such as PDX models, CDX models, syngeneic and humanized mice, cell lines and 3D organoids, and these models can be used for approaches spanning from targeted therapies to immuno-oncology.

IN THIS SECTIONAntibiotics/Infectious diseaseSummit seeks a much-needed superdrug ......................... 21

Business and strategic plansMoleculin, WPD ink licensing deal ........ 21

DermatologySynthetic sebum ..................................... 21

Glaucoma/CannabinoidsGlauconix completes cannabinoid pilot study .......................... 21

OncologyRepositive showcases Cancer Models Scout service ................. 21The point of the spear: Targeting MAGE-A4 ................................................ 23

Glauconix completes cannabinoid pilot studyStudy confirms intraocular pressure-lowering effects, proving promising novel treatment for glaucomaBY MEL J. YEATES

ALBANY, N.Y.—Glauconix Biosciences Inc. revealed in March that the data generated for Nemus Biosciences Inc. validates the mechanism of action of NB1111, Nemus’ proprietary prodrug of tetrahydrocannabinol (THC-valine-hemisuccinate, or THCVHS), in lower-ing intraocular pressure (IOP), a defin-ing symptom of hypertensive glauco-ma. Glauconix is located at the SUNY Polytechnic Institute’s Albany, N.Y.,

Summit seeks a much-needed superdrugCompany explores candidates against antimicrobial-resistant bacteriaBY KRISTEN SMITH

ABINGDON, U.K.—Since acquiring the Discuva Platform in 2017, Summit Thera-peutics has used their new capacity to iden-tify novel-mechanism antibiotics that may revolutionize the treatment of antibiotic-resistant infections. Recent news releases affirm their significant progress in detecting potential new treatment options with razor-sharp specificity to minimize the potential for resistance seen in many of today’s broad-spectrum options. Specifically, Summit has announced successful preclinical testing on drugs to treat Neisseria gonorrhea and the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aerugi-nosa and Enterobacter spp.), all of which have been named as priority targets due to current rates of antimicrobial resistance (AMR).

“AMR is a worldwide problem. We need to see scientific innovation to prevent an era of untreatable infections,” said Dr. David Rob-lin, president of R&D at Summit. “Through

the Discuva Platform, we are using novel science to create targeted, new mechanism antibiotics that are optimized against resis-tance development. Our goal is to develop the most appropriate drug for a specific patient, thereby improving patient outcomes and giving physicians options to address the spread of AMR.”

Researchers can use the Discuva system in three important ways. First, it allows them to identify novel targets, using rapid through-put of mutant pathogens from their in-house library. Secondly, they are able to elucidate the mechanisms of action, by examining the bacteria both upstream and downstream from the insertion point, which allows them to see specifically where the bacteria impacts the genes and how its functionality changes upstream. Lastly, they are able to avoid poten-tial resistance by interrogating surviving bac-teria to narrow the antibiotics’ attack.

According to Roblin, gonorrhea’s growing antibiotic resistance is an emerging public health crisis, making the need for a new treat-

ment for gonorrhea imperative. An estimated 78 million people are currently infected, with infection rates nearing epidemic proportions in Southeast Asia. The current global treat-ment standard is the antibiotic Ceftriaxone, delivered intramuscularly, though there have been numerous reported cases of “super-gonorrhea” completely resistant to known treatments. Dosage once hovered at 250 mg to treat gonorrhea, but now it is routine to administer 1,000 mg because of decreased efficacy. Complicating the issue, Ceftriax-one is also the preferred course of treatment for many other acute conditions, including meningitis, sepsis and pelvic inflammatory disease, making drug resistance potentially lethal.

“We as an industry need to think about what we can do differently,” remarks Rob-lin. “We need to limit our approaches to only advance new mechanisms that work in a pre-cision way, moving away from non-inferiority trials that approve different, but not better

SUMMIT CONTINUED ON PAGE 23

SYNTHETIC SEBUMMouse model mimics human acneBY ILENE SCHNEIDER

SAN DIEGO—“Eighty percent of individuals suffer from acne sometime during their life. Most get it during the teenage years,” according to Dr. George Liu, professor and chief of the Division of Pediatric Infectious Diseases at the University of California, San Diego’s medical school and formerly a faculty member at Cedars-Sinai Medical Center in Los Angeles.

While researchers once thought Propionibacterium acnes (P. acnes) bacteria—

which are plentiful on everyone’s skin—cause acne, not everyone gets it or experiences it to the same degree. Recent genetic sequencing experiments showed that not all P. acnes are the same. There are different strains, some of which are abundant in acne lesions and

some that are never found there.Because researchers had no

animal model that replicates the human condition, acne research and therapeutic development have lagged. Administration of P. acnes to mice does not cause long-

term skin lesions, and the mouse immune system quickly removes the bacteria. Liu and a team of researchers from the UC San

SEBUM CONTINUED ON PAGE 22 GLAUCOMA CONTINUED ON PAGE 22

TOOLS & TECHNOLOGY

Thus far, no animal model has replicated human acne, so research and therapeutic development have lagged, but a new mouse model from researchers in Southern California may change that.

PRECLINICAL22 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

Diego School of Medicine, Cedars-Sinai and the University of California, Los Angeles, have developed a new mouse model that closely resembles human acne by adding one new factor—a synthetic sebum, the waxy skin secretion that increases in human adolescence. The model, described in a paper published in JCI Insight, enabled the researchers to directly compare “good” (health-associated) and “bad” (acne-associated) strains of P. acnes bacteria in a meaningful way.

“Sebum was thought to possibly contribute to either inflammation or P. acnes growth in acne, but published data were not conclusive,” Liu explained. “Our work points to the role of sebum contributing to P. acnes survival, but whether this is direct or indirect is still unclear.”

He added, “Since we know exactly which genes differ between these strains, next we can pinpoint exactly what it is about the acne-associated strains that allows them to cause skin lesions. And that information will help us develop new therapies that specifically block those acne-promoting factors, or tip the balance of a person’s skin chemistry in favor of the healthy strains.”

The team prepared synthetic sebum

by using fatty acid, triglyceride, wax and squalene, a precursor compound to sterols, such as cholesterol and steroid hormones. A previous study described the “recipe” in ratios that resemble human sebum.

According to Liu, “When we started working with these bacteria and checked out the animal models others have been using over the years, we thought: ‘We’ve got to come up with something better than this.’ Acne typically occurs when a person hits their teenage years …What’s the difference between a child’s skin and a teenager’s skin? Increased sebum production. And we were surprised to find how such a simple addition made a big difference in our ability to study acne.”

The researchers injected mice with P. acnes and applied fresh sebum daily. Without the sebum, the mice had minimal lesions, and the bacteria were rapidly cleared from the site of administration. The sebum alone produced no effect on the skin, but applying both sebum and acne-associated strains of P. acnes, produced what appeared to be human acne, and the bacteria lived for weeks. These P. acnes strains also caused inflammation in the skin, as shown by elevated levels of inflammatory cytokine molecules.

When the researchers attempted the same procedure with health-associated strains of P. acnes—strains that are not found in human acne lesions—the results were very different.

The same amount of bacteria was still present on the skin three days post-inoculation, regardless of the strain applied. However, lesions caused by acne-associated P. acnes strains scored about two times higher than lesions caused by health-associated strains in a measure that takes into account a lesion’s size, redness, dryness and degree of skin sloughing.

As Liu explained, “We showed that P. acnes provokes inflammation. P. acnes strains that caused severe acne in mice are more pro-inflammatory. Conversely, P. acnes strains that are associated with mild lesions are less inflammatory.”

Unlike people, the mice in these experiments were all genetically identical. According to Liu, that means that the differences in acne severity were due only to differences between the bacterial strains, not differences in the mice’s innate ability to react to the bacteria.

Next, the team hopes to improve upon its acne mouse model to achieve similar results when the bacteria are applied topically rather than administered by injection under the skin. The researchers also want to study genes unique to acne-associated P. acnes strains and determine how human sebum promotes these strains.

Liu noted that this information could help the team better understand who is at increased risk for acne and how to develop

personalized therapies and vaccines that target the acne-promoting bacterial factors or sebum components. He concluded, “If the type of P. acnes determines if a person is likely to have moderate to severe acne, a personalized therapy would consist of swabbing a patient and determining what type of P. acnes grows on his or her skin. Based on that, the person could be treated topically with the health-associated P. acnes strain.” nEDITCONNECT: E041913

SEBUMCONTINUED FROM PAGE 21

campus, and is a partner in the institution’s Center for Advanced Technology in Nanoma-terials and Nanoelectronics (CATN2).

Glauconix used its 3D human trabecular meshwork model (3D-HTM), which consists of human donor cells containing the ocular tissue responsible for helping to regulate intraocular pressure: the trabecular mesh-work. The studies included a comparison of the activity of tetrahydrocannabinol (THC), the biologically active part of NB1111, in facilitating fluid drainage and lowering lev-els of biomarker molecules associated with inflammation and fibrosis, two processes associated with tissues that are damaged in a disease setting.

“The Glauconix Biosciences’ 3D-HTM technology was designed to help accelerate drug development by using bioengineered human donor 3D tissue models for target identification and validation, high-through-put screening and drug efficacy with physi-ological endpoints, such as fluid outflow,” said Dr. Karen Torrejon, founder and chief scientific officer of Glauconix. “Historically, our technology has exhibited significant pre-dictive value in assessing a drug candidate’s utility and likelihood of clinical success. Nemus’ data helps to provide a rationale for cannabinoid activity in lowering IOP and indicates a potential for the advancement of NB1111 into clinical testing.”

Researchers have previously demonstrated that ocular tissues possess a large number of cannabinoid receptors, especially in areas that help regulate IOP. Given that THC binds both types of cannabinoid receptors, these data point to a unique mechanism of action whereby the ability of THC to bind to can-nabinoid receptors results in a beneficial decline in IOP, due to enhanced fluid drain-age. When IOP is left unchecked there is often damage to the optic nerve, leading to irreversible vision loss.

Additionally, biomarkers associated with

inflammation and fibrosis in tissues affected by glaucoma were significantly decreased, point-ing to anti-inflammatory and antifibrotic activi-ties that are often associated with the cannabi-noid class of molecules in other disease states.

“These studies were significant across a spectrum of findings, and we plan on sub-mitting the data to an upcoming major oph-thalmology meeting. Micro-quantities of cannabinoid delivered directly into the eye could have the dual benefit of a therapeu-tic effect while mitigating risk of systemic adverse events through direct tissue target-ing, an advantage associated with using bio-engineered molecules,” added Dr. Brian Mur-phy, CEO and chief medical officer of Nemus.

In other recent cannabis news, a report from Arcview Market Research (Arcview Group) and BDS Analytics has pointed out the many

ways in which the cannabis industry may potentially disrupt the pharmaceutical indus-try. Entitled “Pharmacies vs. Dispensaries: The Future of Cannabinoids as Medicine,” the report explains that the pharmaceutical indus-try stands to be changed by the populariza-tion of cannabis in two ways: the emergence of cannabis-derived pharmaceutical drugs, and the possible competition between pharmacies and dispensaries as customers begin to trust cannabis to alleviate health issues.

“A slow pace of change is typical of the pharmaceutical industry, but medical can-nabis could change that,” explained Troy Dayton, CEO of the Arcview Group. “It was the medical cannabis industry that initially provided CBD-based relief to children with epileptic seizures, and is currently helping thousands of patients who are suffering

from a vast array of other conditions. Now the pharmaceutical industry is slowly emerg-ing from 80 years of prohibition-induced neglect towards the potential of cannabis-plant medicines.”

The report indicates that cannabinoid pharmaceutical sales are unlikely to take off in the near term, as only five cannabinoid-based pharmaceuticals are in third-stage tri-als and have a chance of getting through the FDA approval process and onto the market before 2022. That said, sales of cannabis-based pharmaceuticals are projected to make up 10 percent of the $31.6-billion legal can-nabis market by 2022. The report also notes that growth in revenue from cannabinoid pharmaceuticals will accelerate in the second half of the decade ahead, as more drugs are approved and fully commercialized.

Tom Adams, editor in chief of Arcview Market Research and managing director of BDS Analytics Industry Intelligence, said, “Epidiolex and the pipeline of pharmaceuti-cals behind it set up a whole new competitive dynamic. For the first time, cannabis dispen-saries will face pharmaceutical competition with its FDA imprimatur and the potential advantage of insurance subsidization … at the same time, the pharmaceutical industry is not used to competing with stores selling effectively the same product it offers at a much lower price.”

The report also noted that 41 percent of BDS Analytics’ consumer surveys respondents report a reduction in the use of OTC medi-cations when using medical cannabis, while 39 percent report a reduction in use of pre-scription medications. According to statistics tracked through the government’s Medicaid programs in states with legal medical mari-juana programs, opioid drug use is reported to have decreased by up to 30 percent. In addi-tion, approximately 770 clinical trials involving cannabis, which include the use of cannabi-noids for treatment of dozens of disorders and diseases, were registered with the U.S. federal government as in process as of January 2019. nEDITCONNECT: E041914

GLAUCOMACONTINUED FROM PAGE 21

Glauconix used its 3D human trabecular meshwork model (3D-HTM), which consists of human donor cells, to facilitate preclinical work on a cannabinoid therapeutic for glaucoma.

Researchers from the University of California, Los Angeles (pictured here) joined with colleagues from the UC San Diego School of Medicine and Cedars-Sinai to help kickstart lagging acne treatment research.

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The point of the spear: Targeting MAGE-A4Adaptimmune presents preclinical data for its next-generation SPEAR T cell

treatment options. We need to find alterna-tives that allow for more rational prescribing, and we need to share our strategies and suc-cesses to attract more research and deeper investments.”

With collaboration from Örebro University in Sweden, Summit has identified SMT-571 as its lead gonorrhea candidate, proving to be more potent against diverse, global gonor-rhea strains from actual patient cases, includ-ing numerous multi- and extensively-drug resistant strains.

“Neisseria gonorrhoeae continues to evolve and acquire resistance to every marketed antibiotic with which it has been challenged. The concern of practitioners is once 5 per-cent resistance to the current standard of care is reached, there will be no new treat-ments available for gonorrhoea,” comment-ed senior author Prof. Magnus Unemo of Örebro University, a WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections. “Antibiotics with a new mechanism of action will be impor-tant in addressing the global health threat of gonorrhea. In the published data, we dem-onstrated that SMT-571, a new mechanism antibiotic, had consistently high potency across hundreds of relevant clinical strains of N. gonorrhoeae, including those that are multi- and extensively-drug resistant. I look forward to the continued development of SMT-571.”

Next up, they will continue to collect and test the most virulent strains, keeping a care-ful eye on any signal of drug resistance in the lab. They are also seeking a treatment that will be effective with just one or two doses, as compliance issues arise in the at-risk popula-tions most affected by AMR. Once they have identified a precise and effective candidate, they intend to amplify their success to drive further investment in R&D and innovation.

Says Roblin: “We must be more success-ful than we’ve been in the last 10 years. We need to have success and share our strategy, to attract the attention of more researchers, and more investors. We need to clearly dem-onstrate the economic benefits of new treat-ments and grab the attention of the payers.” nEDITCONNECT: E041912

SUMMITCONTINUED FROM PAGE 21

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BY DDNEWS STAFF

PHILADELPHIA & OXFORD, U.K.—April 1 saw Adaptimmune Therapeutics plc, which works heavily in the area of T cell therapy to treat cancer, present preclinical data at the annual AACR meeting from its next-gener-ation SPEAR (Specific Peptide Enhanced Affinity Receptor) T cell targeting MAGE-A4. This cell, known as ADP-A2M4CD8, expresses the CD8α co-receptor alongside the engineered TCR that targets the mel-anoma-associated antigen A4 (MAGE-A4) protein.

Co-expression of CD8α is anticipated to broaden the immune response against solid tumors and increase antitumor activity by converting CD4+ helper cells into CD8+ killer or cytotoxic T cells. The preclinical data reportedly demonstrate that the addition of CD8α with the engineered TCR in vitro improved engagement and function in CD4+

T cells that may support clonal expansion of CD8+ T cells, differentiation into effector and memory T cells, as well as engage the wider immune system in antitumor responses.

“Our next-generation programs are designed to enhance our existing SPEAR T cells, to improve their ability to target and kill solid tumors. The preclinical data

we presented at AACR indicate that adding CD8a to our ADP-A2M4 candidate may help broaden the antitumor immune response against additional tumor antigens,” said Rafael Amado, Adaptimmune’s president of R&D. “Further, the CD8α co-receptor may enhance the ability of CD4+ SPEAR T cells to kill cancer cells through the engineered TCR targeting MAGE-A4.”

Adaptimmune is a cl inical-stage biopharmaceutical company focused on the development of novel cancer immunotherapy products. The company is currently conducting clinical trials with SPEAR T cells targeting MAGE-A4, MAGE-A10 and AFP across multiple solid tumor indications. nEDITCONNECT: E041915

BRIEFS

24 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

CLINICAL TRIALSHeading into the clinic

STRASBOURG, France—Last month saw biotech company Transgene announce plans to move its lead candidate, TG4050, into clinical develop-ment and to finalize its collaboration with NEC. Transgene will assume responsibility for TG4050’s clinical development and will launch two clini-cal trials in H2 2019 to evaluate the candidate’s safety and immunogenicity: one in patients with ovarian cancer who have undergone first-line surgery and chemotherapy, and one in patients with head and neck cancer who have under-gone surgery and radiation therapy. Transgene and NEC will co-finance the studies. TG4050 is an individualized immunotherapy designed and manufactured with Transgene’s proprietary myvac platform and integrates neoantigens chosen by NEC’s Neoantigen Prediction System.

Successful Phase 1a has Forendo eyeing Phase 1b

TURKU, Finland—Forendo Pharma announced in March that it had completed its Phase 1a study of FOR-6219, an HSD17B1 inhibitor for treating endometriosis. This first-in-human trial was a ran-domized, double-blind, placebo-controlled study to evaluate the safety, tolerability, food effect and pharmacokinetics of single and multiple ascending oral doses of FOR-6219 in 36 healthy postmenopausal women. The compound can selectively inhibit local estrogen production in the endometrium and endometriotic lesions without impacting systemic estrogen levels. The tested doses were found to be safe and well tolerated, with only grade 1 adverse events reported, and no adverse events that led to study discontinuation. FOR-6219 demonstrated dose-proportionate expo-sure and no significant food effect, and Forendo intends to initiate a Phase 1b trial this summer to demonstrate proof of mechanism.

IN THIS SECTIONHearing lossHear ye, hear ye ..................................... 26

Hormonal disordersStrongbridge shares SONICS study results ............................. 24

Infectious diseaseChallenging Chagas ................................ 24

OncologyHeading into the clinic ........................... 24MorphoSys reports ‘MIND’-bending results .......................... 24

Orphan disease/Metabolic diseaseTransCon hGH scores with superiority (ASCENDIS from cover) .......................... 27

Women’s healthSuccessful Phase 1a has Forendo eyeing Phase 1b ....................... 24

Strongbridge shares SONICS study results Extended evaluation phase meets objective of showing positive long-term benefit-risk profile of RecorlevBY MEL J. YEATES

DUBLIN & TREVOSE, Pa.—Strongbridge Biopharma plc announced in March top-line findings from the extended eval-uation phase of the pivotal Phase 3 SONICS study of Recorlev (levoketoconazole) for the potential treatment of endogenous Cushing’s syndrome. The purpose of the six-month extended evaluation phase was to evaluate the long-term safety, toler-ability and benefit-risk of chronic use of Recorlev.

“We are encouraged by the top-line results from the SONICS extended evaluation phase. Recorlev (levoketoconazole) treat-ment was associated with no new clinically relevant liver-related findings or other new safety signals, while demonstrating long-term efficacy to reduce mean urinary free cortisol, or mUFC, as well as key cardiovascular risk markers such as weight and LDL-cholesterol,” says Dr. Fredric Cohen, chief medical officer of Strongbridge Biopharma. Recorlev was generally well tolerated during the extended evaluation phase, and no new drug-related safety signals were observed. Sixty out of 61 study participants who completed the maintenance phase elected to participate in the extended evaluation phase. Of the 60 patients that entered the extended evaluation phase, 46 patients completed it.

Data were collected twice at three-month intervals, which is

MorphoSys reports ‘MIND’-bending resultsMOR208 clinical trial results promising and drug is on fast track to FDA approval, company says BY LORI LESKO

MUNICH—MorphoSys AG, a clinical-stage biopharmaceutical focused on battling cancer, is on a fast track with its antibody MOR208 toward FDA approval and mar-keting in the United States due to recent updates on L-MIND and B-MIND, its two ongoing clinical trials of the investigational Fc-enhanced anti-CD19 antibody MOR208 in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) who are not eligible for high-dose chemotherapy and autologous stem cell transplantation.

Top-line results of the MOR208 clinical trials are expected to be released at a medi-cal conference in mid-2019. MorphoSys released updates March 6 on its L-MIND and B-MIND trials, and on March 14, the company hosted a conference and webcast for investors on the highlights of 2018 and

its goals into 2019 and beyond. The L-MIND trial, the company’s single-

arm, open-label study investigating MOR208 in combination with lenalidomide, has com-pleted enrollment, and data are currently being analyzed.

The top priority is to bring MOR208 plus lenalidomide in r/r DLBCL to approval as fast as possible.

On the regulatory front, MorphoSys plans to complete the submission of the

MIND CONTINUED ON PAGE 25

CHALLENGING CHAGASBayer’s efforts to advance nifurtimox against Chagas disease bear fruit in successful Phase 3 trialBY KELSEY KAUSTINEN

WHIPPANY, N.J.—Bayer wrapped up the first quarter with encour-aging news, having announced that the CHICO (CHagas disease In Children treated with Nifur-timOx) part of its Phase 3 study of nifurtimox met its primary endpoint. The study evaluated the safety, efficacy and pharma-cokinetics of nifurtimox in 330 pediatric patients with acute or chronic Chagas disease, and was conducted at 25 investigational sites in Argentina, Bolivia and Colombia between 2016 and 2018.

CHICO’s primary endpoint was serological response at one year after the end of treatment,

and 60-day nifurtimox treatment was found to be superior to the historical placebo control. The clinical study was the largest to date of patients with Chagas disease.

“Children are the most vul-nerable patient group suffering from Chagas disease. With the successful completion of the CHICO study, an important milestone in our long-standing commitment to improve the treatment of Chagas has been achieved,” said Dr. Joerg Moeller, member of the executive com-mittee of Bayer AG´s Pharma-ceutical Division and head of research and development.

CHAGAS CONTINUED ON PAGE 26 SONICS CONTINUED ON PAGE 25

MorphoSys has initiated discussions to explore using the L-MIND study as the basis for the submission of a potential marketing authorization application in Europe for MOR208.

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For more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 25CLINICAL TRIALS

Biologics License Application to the U.S. Food and Drug Administration for approval of MOR208 by year’s end. The company is continuing the pivotal Phase 3 B-MIND study, evaluating MOR208 plus bendamus-tine versus rituximab plus bendamustine in r/r DLBCL and conduct a preplanned, event-driven, interim analysis of B-MIND, which is projected to take place in the second half of 2019. Simon Moroney, MorphoSys’ CEO, referred to 2018 as “an outstanding year” for the company, with 2018 revenues “exceeding expectations.”

“Our highest priority has been MOR208, where we have made great progress,” Moron-ey said. “Our goal is to bring MOR208 to market as soon as possible, including plans to commercialize MOR208 in the U.S.”

Malte Peters, chief development officer of MorphoSys, also spoke to investors about the “remarkable progress” of MOR208 and the L-MIND and B-MIND investigational trials. “Our goal is to make MOR208 available to every patient who needs it,” Peters said, with 70 percent of a hospital patient sample on the treatment showing no disease progression in 12 months. MorphoSys has also initiated discussions with the European regulatory authorities to explore the possibility of using the L-MIND study as the basis for the sub-mission of a potential marketing authoriza-

tion application (MAA) in Europe. If the European Medicines Agency agreed

to accept a potential MAA based on L-MIND, submission of an MAA could occur earlier

than originally anticipated, according to the company.

The B-MIND study, which compares MOR208 in combination with bendamustine vs. rituximab plus bendamustine, continues as originally designed, Peters said. Additionally, during the first quarter of 2019 and in agree-ment with the FDA, MorphoSys implemented an amendment of the B-MIND study, with the scientific rationale based on published litera-ture as well as MorphoSys’s own preclinical data, indicating that MOR208 might be par-ticularly active in patients characterized by the presence of a certain biomarker.

Depending on the outcome of the interim analysis of B-MIND, an increase from 330 to 450 patients may be required, in which case an event-driven primary analysis of the study is expected in the first half of 2021.

“The amended B-MIND trial enables us to test the hypothesis that MOR208 shows enhanced activity in patients who can be identified using the biomarker, while allow-ing us to test efficacy in the unselected patient population as originally planned,” Peters added.

Moroney surprised some investors by announcing he would not be renewing his contract as a member of the company’s man-agement board. He will step down as CEO on expiry of his current contract on June 30, 2020, or when a successor is appointed, whichever comes sooner.

After having dedicated 27 years to Morpho-

Sys, Moroney said he wanted the chance “to do something else and explore new oppor-tunities,” adding he has left the company in good shape, declaring, “MorphoSys, today, is stronger than it has ever been.”

MOR208 is an investigational monoclonal antibody directed against the antigen CD19, which is broadly expressed on the surface of B cells. It is therefore considered as an important factor for the treatment of B cell malignan-cies such as non-Hodgkin’s lymphoma, diffuse large B cell lymphoma and chronic lympho-cytic leukemia. nEDITCONNECT: E041916

MINDCONTINUED FROM PAGE 24

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MorphoSys released updates on its L-MIND and B-MIND trials March 6, and plans to complete the submission of the Biologics License Application to the FDA for approval of MOR208 by the end of this year.

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common practice for long-term follow-up of chronic medical therapy for endogenous Cushing’s syndrome. Four patients (6.7 per-cent) discontinued due to adverse events. No patients experienced an increase in either alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal, and there were no reported adverse events of special inter-est related to liver injury or dysfunction.

The most commonly reported (≥5 per-cent) treatment-emergent adverse events in the extended evaluation phase were arthralgia (7 percent), QTc prolongation (7 percent), headache (7 percent), hypo-kalemia (7 percent) and nasopharyngitis (5 percent); QTc prolongation greater than 460 milliseconds was not observed in the extended evaluation phase. Nausea (2 percent) and headache (7 percent) were reported at lower rates compared to the previously reported aggregate rates of 32 percent (nausea) and 28 percent (head-ache) from the dose titration and mainte-nance phases.

“Recorlev (levoketoconazole) is the pure 2S,4R single enantiomer of ketocon-azole, a steroidogenesis inhibitor, which over the years has been used off-label in Cushing’s syndrome based on its believed cortisol control properties. We believe that Recorlev, if approved, may have favorable efficacy, safety and tolerability for patients with endogenous Cushing’s syndrome,” Cohen explains. “The need for a safe and effective next-generation cortisol synthesis inhibitor such as Recorlev in the treatment of Cushing’s syndrome remains substan-tial. Current treatment options either have limited indications or are difficult to dose since they do not reduce cortisol, have significant negative side effects, especially

for women, or are off-label and have never been rigorously studied in Cushing’s.”

“Last year, we announced positive results from the pivotal Phase 3 SONICS study, which evaluated the safety and efficacy of Recorlev in patients with endogenous Cushing’s syndrome. The study met its pri-mary endpoint, with mUFC—a surrogate endpoint that predicts clinical outcomes—confirmed normal among 30 percent of the intent-to-treat population, without a preceding dose increase following six months of maintenance therapy (one-sided P=0.0154). Safety and tolerability findings based upon data collected through the six-month maintenance phase indicate that Recorlev was generally well tolerated,” con-tinues Cohen. “In addition, the exploratory responder analyses indicate that Recorlev provided clinical benefit across the spec-trum of baseline comorbidities in Cushing’s syndrome, including hypercholesterolemia and diabetes. Many markers of cardiovas-cular risk, an important cause of morbidity and mortality in Cushing’s syndrome, also improved significantly.”

In this exploratory evaluation, an observed-case analysis of completers was used to evaluate mUFC respond-ers. At the end of the extended evalua-tion phase, normalization of mUFC was observed in 41 percent of patients, and normalization of or at least 50-percent improvement in mUFC was observed in 68 percent of patients. Clinically mean-ingful improvements in key cardiovascu-lar risk markers (hemoglobin A1c, fasting glucose, total and LDL-cholesterol) were observed throughout the extended evalu-ation phase. Weight loss and reduction in body mass index continued throughout the extended evaluation phase.

“We continue to advance Recorlev, and will be conducting a Type C meeting with FDA in the first quarter of 2019 to

seek guidance on the regulatory path forward to obtain marketing approval for Recorlev for the treatment of endog-enous Cushing’s syndrome,” Cohen points out. “We plan to provide a market update on our FDA meeting outcomes in the second quar-ter, and look for-ward to working with healthcare profes-sionals and patients to raise awareness of Cushing’s syndrome and to potentially provide a new treat-ment option for this disease.”

“ We are most excited about the opportunity to devel-op curative or signifi-cant life-saving treat-ments for patients in areas where there is a tremendous unmet

need, like in Cushing’s syndrome. Our focus on rare diseases—a strategy that wel-comes and nurtures products that may be too large for smaller biotechs, and yet too small for larger firms—allows us to bring research, education and resources to niche communities, which would continue to be largely underserved without our involve-ment,” he adds. “We are excited and proud to continue serving those rare disease com-munities that are often overlooked and underserved in the drug development and commercialization process.” nEDITCONNECT: E041918

SONICSCONTINUED FROM PAGE 24

“We believe that Recorlev, if approved, may have favorable efficacy, safety and tolerability for patients with endogenous Cushing’s syndrome,” says Dr. Fredric Cohen, chief medical officer of Strongbridge Biopharma. “The need for a safe and effective next-generation cortisol synthesis inhibitor such as Recorlev in the treatment of Cushing’s syndrome remains substantial.”

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CLINICAL TRIALS26 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

Chagas is an infectious disease that is caused by the Trypanosoma cruzi para-site and is transmitted to humans by the feces of “kissing bugs,” or triatomines. It is sometimes known as a silent or “forgotten disease” due to being mostly asymptom-atic for years, and even during the acute phase immediately after infection, most patients are unaware they’re infected and only one-third of those infected pres-ent with non-specific symptoms such as fever, fatigue and swollen lymph glands for weeks. Without treatment, Chagas disease moves into a chronic lifelong phase. While this is asymptomatic for most patients, roughly 30 percent develop chronic, irre-versible complications such as cardiomy-opathy or other heart conditions, abnor-mal enlargement of the digestive tract, or even neurological or mixed conditions.

This disease, like others, can be trans-mitted during pregnancy or birth from mother to child, and can also be transmit-ted via blood transfusions or organ trans-plantations. The World Health Organiza-tion estimates that some 8 million people are infected with this disease globally, with Latin America as a key area of high infec-tion. Despite these numbers, less than 1 percent of those infected get treatment, which is attributed both to low disease awareness and limited access to treatment.

At present, Chagas disease is treated with two nitroheterocyclic compounds: nifurtimox and benznidazole. While nifurtimox isn’t approved by the FDA, it is being made available in a 120 mg tablet form exclusively through the U.S. Cen-ters for Disease Control and Prevention under an investigational protocol. In the CHICO trial, Bayer used a newly devel-oped formulation of the drug that can be dissolved in water for easier administra-tion to young patients.

“An adequate dispersable formulation of nifurtimox is a big step forward toward achieving the goal of treating all infected children,” commented Dr. Jaime Altcheh, head of the Department of Parasitology and Chagas disease at the Ricardo Gutier-rez Children’s Hospital in Buenos Aires,

Argentina, and coordinating investigator of the trial. “Early treatment after infec-tion is very important to prevent manifes-tation of the disease in adulthood.”

In other recent and encouraging news for those dealing with Chagas disease, the Drugs for Neglected Disease initiative (DNDi) found that a two-week course of treatment for adults with chronic Chagas disease showed similar efficacy and fewer side effects than the standard twice-daily, eight-week treatment regimen. A Phase 2 trial—the BENDITA study (Benznida-zole New Doses Improved Treatment & Associations)—evaluated benznidazole as a monotherapy and in combination with fosravuconazole, an antifungal agent developed by Eisai Co. Ltd. On the shorter treatment course, patients saw similar results as those who received the eight-week course, with no sign of the parasite in their blood at six and 12 months after completing treatment.

DNDi conducted the trial in collabora-tion with CEADES (Fundacion Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente), ISGlobal, Eisai, Argentinian pharmaceutical com-pany manufacturer of benznidazole Elea and associated non-profit foundation Fun-dación Mundo Sano, among others, and it was funded by the Global Health Innova-tive Technology Fund (GHIT).

More growth and developments are likely on the way for this disease, as well. A report by Coherent Market Insights titled “Chagas Disease Treatment Mar-ket–Global Industry Insights, and Fore-cast till 2025” noted that increased migration from countries where Chagas is endemic is expected to drive growth for the treatment market. Increased R&D in the market and recent and upcoming drug approvals are also expected to boost growth. Coherent Market Insights reports that the Chagas disease treatment market was estimated at $5.67 million in 2016 and is expected to grow at a compound annual growth rate of 7.3 percent from 2017 to 2025. The report also noted that in 2017, benznidazole held approximately 88.63 percent of the market, with nifurit-mox holding the remainder. nEDITCONNECT: E041917

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HEAR YE, HEAR YEAuris Medical announces publication of AM-111 Phase 3 results for inner ear hearing lossBY DDNEWS STAFF

ZUG, Switzerland—Mid-March saw Auris Medical Holding AG, a clinical-stage com-pany dedicated to developing therapeutics that address important unmet medical needs in neurotology and central nervous system disorders, announce the publication of an article that presents and discusses in detail the outcomes from the HEALOS Phase 3 trial with AM-111, Auris Medical’s investigational treatment for acute inner ear hearing loss.

The peer-reviewed article “Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness - A Double-Blind, Randomized, Placebo-Controlled Phase 3 Study” was published in Otology & Neurotology, one of the leading journals in the field of scientific and clinical inner ear research.

While the HEALOS trial did not meet the primary efficacy endpoint in the overall study population, post-hoc analyses revealed a sta-tistically significant hearing improvement with AM-111 from baseline to day 28 in the subpopulation of patients with profound hearing loss (n=98). The AM-111 0.4 mg/mL treatment group showed a mean improve-ment of 42.7 dB vs. 26.8 dB in the placebo group (p=0.0176). AM-111 was well tolerated, and the primary safety endpoint was met.

“The HEALOS trial demonstrated that effective hearing protection is possible with a drug-based approach even in the case of profound acute hearing loss, a condition with very poor prognosis for recovery and high risk for life-long auditory and cognitive dis-ability,” commented Dr. Hinrich Staecker, a professor in the Department of Otolaryngol-ogy Head and Neck Surgery at the University of Kansas Medical Center and lead author on the publication. “In the trial, treatment with a single dose of AM-111 resulted in a clinically meaningful hearing recovery and a

marked reduction in the risk of no improve-ment. These outcomes are very promising, as there are still no effective drug treatments available to protect hearing.”

The HEALOS trial was conducted in sev-eral European and Asian countries as a ran-domized, double-blind, placebo-controlled study evaluating the efficacy, safety and tol-erability of AM-111. It enrolled 256 patients suffering from severe to profound sudden deafness within 72 hours from onset. Patients were randomized in a 1:1:1 ratio to receive a single dose of either AM-111 0.4 mg/mL, AM-111 0.8 mg/m or placebo, administered into the middle ear.

AM-111 is being developed in a biocom-patible gel formulation for the treatment of sudden sensorineural hearing loss with a single-dose administration into the middle ear. Its active substance is brimapitide (also known as D-JNKI-1, D-stereoisomer of c-Jun N-terminal kinase inhibitor 1), a cell-pene-trating peptide which inhibits the JNK stress kinase. JNK is activated following various types of cochlear insults (stress) that cause acute inner ear hearing loss and plays a key role in apoptosis of sensory cells as well as in inflammatory responses. By blocking JNK, AM-111 theoretically protects stress-injured cochlear cells and helps to prevent or reduce chronic hearing loss.

AM-111’s otoprotective effects have been demonstrated in various animal models of cochlear stress, including acute acous-tic trauma, acute labyrinthitis (inflamma-tion), drug ototoxicity (aminoglycosides), bacterial infection, cochlear ischemia and cochlear implantation trauma. AM-111 has Orphan Drug Designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, and it was granted Fast Track status by the FDA. nEDITCONNECT: E041919

In Auris’ HEALOS trial, treatment with a single dose of AM-111 resulted in a clinically meaningful hearing recovery and a marked reduction in the risk of no improvement in patients with profound hearing loss, though it did not meet its primary efficacy endpoint in the overall population.

Bayer recently announced that the CHICO (CHagas disease In Children treated with NifurtimOx) part of its Phase 3 study of nifurtimox met its primary endpoint.

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In the primary analysis of the intent-to-treat population using ANCOVA, TransCon hGH demonstrated an AHV of 11.2 cm/year compared to 10.3 cm/year for the daily hGH. The treatment difference was 0.86 cm/year, with a 95-percent confidence interval of 0.22 to 1.50 cm/year. The AHV for TransCon hGH was significantly greater than the daily hGH (p=0.0088).

The AHV was greater for TransCon hGH than for the daily hGH at each visit, with the treatment difference reaching statistical signif-icance from and including week 26, onward. The incidence of poor responders (AHV < 8.0 cm/year) was 4 percent and 11 percent in the TransCon hGH and daily hGH arms, respec-tively. All sensitivity analyses completed from the trial support the primary outcome, indicat-ing the robustness of these results.

“The heiGHt Trial results ... represent a potential breakthrough for patients and future treatment options for growth hor-mone deficiency,” said Jan Mikkelsen, Ascendis Pharma’s president and CEO. “We believe these results provide a validation of our TransCon technology platform, which forms the basis of our endocrinology pipe-line and has potential application in other therapeutic areas.”

Results from the trial indicate that Trans-Con hGH was generally safe and well toler-ated, with adverse events consistent with the type and frequency observed with daily hGH therapy and comparable between arms of the trial. No serious adverse events related to study drug were observed in either arm. No treatment-emergent adverse events lead-ing to discontinuation of study drug were observed in either arm.

“We are thankful to all those who partici-pated in this important global trial,” noted Dr. Jonathan Leff, Ascendis’ chief medical officer. “Our goal is to alleviate the burden of daily injections so every child has a better opportunity to achieve normal adult height and overall endocrine health—and to look forward to a healthy future.”

These heiGHt Trial data were presented for the first time as an oral presentation on Sunday, March 24, at ENDO 2019 by investi-gator Dr. Paul Thornton, a pediatric endocri-nologist at Cook Children’s Medical Center in Fort Worth, Texas.

“This is exciting news for all of those living with GHD, including our families at Cook Chil-dren’s, because we have shown that a single once-weekly dose of TransCon hGH was just as safe and works as well or better than daily growth hormone,” noted Thornton. “Now, the heiGHt Trial has shown that children with GHD can grow effectively on one shot a week.”

The TransCon hGH Phase 3 program includes the heiGHt, fliGHt and enliGHten Trials. Top-line data for the fliGHt Trial, evaluating TransCon hGH in subjects who switch from daily hGH, are expected in the second quarter of 2019. enliGHten is a long-term extension that provides subjects from the heiGHt and fliGHt Trials with the oppor-tunity to continue once-weekly TransCon hGH treatment.

Ascendis plans a clinical database lock for the TransCon hGH Phase 3 program in the third quarter of 2019. Subsequently, the com-pany intends to submit a Biologics License Application with the U.S. Food and Drug Administration for TransCon hGH to treat pediatric GHD in the first half of 2020.

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According to Canaccord Genuity biotech-nology analyst Michelle Gilson in an investor note related to the trial news: “We previewed the data ... and outlined our expectation for non-inferiority; however, the superiority result is above our expectation and we view as likely to create a competitive moat for programs behind TransCon GH in the clinic. Notably, the superiority result could create a positive dialogue with payers, especially as TransCon GH should be the only long-acting GH option at time of launch.”

“Recombinant (daily) growth hormone market in U.S. is ~$3.5 billion, and we antici-pate it could grow to >$4 billion with a weekly option based on increased compliance and persistence,” Gilson continued. “We estimate ~16,000 treatable pediatric GHD patients in the U.S., and anticipate TransCon GH could move quickly to address next indications where rGH is approved. We anticipate Ascendis will launch TransCon GH beginning in 1H20 in the

U.S. and E.U. shortly following. These superior-ity results may help uptake in E.U., which is a notoriously difficult switch market.”

In other recent news from Ascendis, the company announced in February that the FDA had granted Orphan Drug Designation to TransCon CNP, a long-acting prodrug of C-type natriuretic peptide (CNP) in devel-opment for children with achondroplasia. TransCon CNP is designed to address all aspects of achondroplasia by providing con-tinuous exposure to CNP at safe, therapeutic levels in a single, weekly subcutaneous dose.

“We are pleased to receive Orphan Drug Designation for TransCon CNP in achon-droplasia. Our TransCon CNP candidate is designed to address not only height, but the debilitating comorbidities of the condition,” added Leff. “In our Phase 1 trial in healthy subjects, TransCon CNP delivered continu-ous exposure of CNP at target levels over seven days, supporting once-weekly dosing

with a well-tolerated safety profile. Based on these preliminary results, we expect to initi-ate a Phase 2 trial in children with achon-droplasia in the third quarter of this year. In addition, as part of our commitment to the achondroplasia community, we are currently conducting the ACHieve Study, which we believe will provide important observational insights into the experience of children living with achondroplasia.” nEDITCONNECT: E041902

Ascendis Pharma applies its TransCon technology with the aim to develop best-in-class therapeutics that address significant unmet needs. In addition to its current pipeline of three rare disease endocrinology candidates, the company has established oncology as its second therapeutic area of focus.

Ascendis Pharma’s TransCon technology can be applied to existing drug therapies—including proteins, peptides and small molecules—to create prodrugs that provide for the predictable and sustained release of an unmodified parent drug.

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28 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

American Association of Immunologists Annual Meeting Immunology 2019May 9-13, 2019 n San Diego Convention Center n San Diego, Calif.

The American Association of Immunologists brings its educational and other programming to the West CoastBY JEFFREY BOULEY

SAN DIEGO—Last year, the American Asso-ciation of Immunologists (AAI) went to Austin, Texas, for its annual meeting, and this year we go westward to Southern Cali-fornia—San Diego, specifically—for Immu-nology 2019, which will take place May 9-13 at the San Diego Convention Center.

There is a plethora of programming from the educational (the focus of most profes-sional society annual meetings, naturally) to the social to the business side. For the exten-sive educational offerings, we would point you to the annual meeting website at www.immunology2019.org for details on what the programming currently looks like. (And, of course, some details could change between now and the actual meeting.)

But to give you a little taste of what’s to come in San Diego, we have the DDNews

show preview of Immunology 2019 over the next two pages.

One of the highlights is the annual AAI President’s Program, including the presi-dent’s address itself, which this year features Joanne L. Flynn of the University of Pitts-burgh School of Medicine, the 2018-2019 AAI president, giving a talk titled “At the interface of microbiology and immunology” on May 9 at 5 p.m. The president also leaves her mark on the meeting with the AAI Pres-ident’s Symposium, titled “Interactions of pathogens with the immune system,” which will be held on May 12 at 12:30 p.m. Speakers for that are:

■n Philana Lin of the Children’s Hospital of Pittsburgh: Tuberculosis: exceptions to every rule

■n Karen A. Norris of the University of Georgia: Immunity in the immunocompro-

mised host■n Robert Seder of the National Institute of

Allergy and Infectious Diseases: Intravenous vaccination as an approach for inducing protective tissue resident T cell responses against tuberculosis and malaria

■n Vanja Lazarevic of the National Cancer Institute: Transcriptional regulation of the inflammatory response.

Other notable speakers can be found pre-senting as part of the AAI Distinguished Lec-tures. On Friday, May 10, Andrea J. Tenner of the University of California, Irvine will present “Complement: primitive yet power-ful—New discoveries in immunity and the nervous system.” The next day will see Bruce R. Blazar of the University of Minnesota present “Stem cell transplantation: Restor-ing immune balance.” And then on that Sun-day, Gwendalyn J. Randolph of Washington University in St. Louis will give her lecture, “Clearance of molecules and cells from sites of inflammation.”

About AAIFor over 100 years, AAI has been the world’s leading forum for researchers dedicated to advancing the field of immunology through the elucidation of the basic principles of immune func-tion. AAI is dedicated to fostering the interchange of ideas and information among investigators, and addressing the translation of this information into clinical practice. AAI serves its nearly 8,000 members and the global commu-nity through its annual meeting, summer courses, awards and fellowship pro-grams, career development opportuni-ties, and the publication of The Journal of Immunology and ImmunoHorizons.

Last year it was Austin, Texas, and next year it will be Honolulu, but San Diego (pictured here) is the host for Immunology 2019.

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Immunology 2019 heads to San Diego

For more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 29SHOW

AAI Career AwardsDuring Immunology 2019, as with every annual meeting, the AAI gives out its Career Awards to honor individuals for outstanding research and career achievements. Among the most notable of these awards are the AAI-BioLegend Herzenberg Award, which recog-nizes an individual who has made exemplary research contributions to the field of B cell biology; the AAI Excellence in Mentoring Award, which recognizes an example of someone who significantly influences train-ees’ professional development and careers; the AAI-Thermo Fisher Meritorious Career Award, which recognizes a mid-career scien-tist for outstanding research contributions to the field of immunology; and the AAI-Steinman Award for Human Immunology Research, which recognizes an individual who has made significant contributions to the understanding of immune processes underlying human disease pathogenesis, prevention or therapy.

Here is the full list of 2019 AAI Career Award recipients:

■n AAI Lifetime Achievement Award: Pamela J. Fink, University of Washington

■n AAI Distinguished Service Award: Beth A. Garvy, University of Kentucky Chandler Medical Center

■n AAI Distinguished Service Award: Clinton B. Mathias, Western New England University

■n AAI-Steinman Award for Human Immu-nology Research: Steven A. Rosenberg, National Cancer Institute

■n AAI-Thermo Fisher Meritorious Career Award: Kristin A. Hogquist, University of Minnesota Center for Immunology

■n AAI-BioLegend Herzenberg Award: Frederick W. Alt, HHMI, Boston Children’s Hospital

■n AAI-BD Biosciences Investigator Award: Francisco J. Quintana, Brigham and Women’s Hospital, Harvard Medical School

■n AAI Excellence in Mentoring Award: Harvey Cantor, Dana-Farber Cancer Insti-tute, Harvard Medical School.

They will receive their awards at the meet-ing, and many of the recipients will be there to give lectures as well.

AAI Special EventsAnnual meetings are also social events, as well as a place to receive new knowledge in the field and conduct official business of the society.

One event of Immunology 2019 is the New Member Reception, which is by invitation only and sponsored by the AAI Membership Committee. AAI welcomes new regular, associate and postdoctoral fellow members to meet each other at a relaxed gathering. Members of the AAI Membership Commit-tee, AAI President JoAnne Flynn, fellow council members and chairs from many of the committees will join new members for casual conversation and light refreshments.

On Thursday, May 9, will be the Opening Night Networking Event. Immediately fol-lowing the President’s Address, registrants are invited to toast old friends, make new connections, plan their week and enjoy a picturesque view of San Diego Bay.

On May 12 will be the Immunology 2019 Gala, sponsored by BioLegend and held at the USS Midway Museum, an iconic San Diego destination. On the flight deck, attendees can experience an array of restored naval aircraft, from the workhorse of Vietnam to helicop-ters that picked up Apollo space missions. On deck, a band will perform dance hits surrounded by the 360-degree panoramic view of the San Diego skyline. Below, on the hangar deck, World War II aircraft can be viewed, cockpits sat in, and flight simulators experienced.

Career ServicesImmunology 2019 will also provide a wide range of sessions to support the career devel-opment of students, postdoctoral fellows and faculty. Meeting attendees are invited to attend workshops, roundtables and panel dis-cussions to explore specific career topics and

issues; network with experienced scientists to gain insight into their own career develop-ment; and consult with career experts one-on-one or in small groups for advice specific to their own situations and goals.

One of the career service offerings is the NIH Grant Review and Funding Informa-tion Room. NIH program and review staff will be available in the room for individual conversations and consultations. A schedule will be posted online and on site to show spe-cific times staff members will be available to answer questions about the scientific review process, grant/fellowship opportunities and NIH institute-specific interests. Consulta-tions will be available on a drop-in basis. No appointments are necessary.

In addition, AAI is sponsoring a virtual Jobs Board on the Immunology 2019 website. The Jobs Board service is free to all meeting registrants and exhibitors. Review the online AAI Jobs Board to identify positions that tar-get attendees and reach recruiters directly, as job postings will include e-mail addresses for recruiters’ designated contacts.

There are also lecture-based Career Ses-sions at the meeting, including “How to Convert Your CV into a Résumé” by Derek Haseltine of the Baylor College of Medicine; “Immunology Teaching Interest Group” sponsored by the AAI Education Committee and featuring a panel discussion and break-out sessions; the “Careers Roundtable and Speed Networking Session” sponsored by the AAI Minority Affairs Committee; “Careers in Biotech: Panel Discussion and Networking” sponsored by the AAI Education Committee; “Interviewing for a Job” by Haseltine; the “Careers in Science Roundtable” sponsored by the AAI Education Committee & AAI Committee on the Status of Women; “Secrets for a Successful Postdoctoral Fellowship” by Ryan Wheeler of the Scripps Research Insti-tute; and “International Opportunities in Science” chaired by Winfried F. Pickl, of the Medical University of Vienna in Austria.

There’s more to review in this section aside

from this article, but before we leave you to that, here’s a peek into the future. Looking forward, Immunology 2020 will go for an even more exotic locale, with Honolulu as the host city for the event (to be held May 6-12, 2020). Immunology 2021 and 2022 will be held in notable cities as well—Philadel-phia and Portland, Ore., respectively. nEDITCONNECT: E041932

IMMUNOLOGY 2019

May 9-13, 2019 n San Diego Convention Center n San Diego, Calif.

FRIDAY, MAY 10National Institute of Allergy and Infectious Diseases (NIAID) Symposium: Imaging Tissue-Specific ImmunityCHAIRS: Joseph J. Breen, NIAID & Deborah Fowell, University of RochesterSPEAKERS:

■n Deborah Fowell, University of Rochester: T cell navigation within inflamed skin

■n Garry Nolan, Stanford University: Immune pathology from the molecular scale on up

■n Rodrigo Gonzalez, Harvard University: Microscopy imaging of cellular immune responses in the nasal mucosa

■n Christopher Hunter, University of Pennsylvania: Host-pathogen interactions that leads to T cell priming

SATURDAY, MAY 11 National Institute of Environmental Health Sciences (NIEHS) Symposium: The Missing Link: Our Environment and Immune Mediated DiseasesCHAIRS: Michael C. Humble, NIEHS & Celine Beamer, University of MontanaSPEAKERS:

■n Celine Beamer, University of Montana:

Involvement of ahR in thymic ILC function and regulation

■n Michael Laiosa, University of Wisconsin, Milwaukee: Regulation of cellular energetics by the Aryl hydrocarbon receptor during hematopoiesis

■n Susan McKarns, University of Missouri, Columbia: Aryl hydrocarbon receptor on CD4+ T cell differentiation and autoimmune disease

SUNDAY, MAY 12 National Institute on Aging (NIA) Symposium: Immune Metabolism, Inflammation and AgingCHAIRS: Rebecca A. Fuldner, NIA & Cornelia Weyand, Stanford UniversitySPEAKERS:

■n Cornelia Weyand, Stanford University: Metabolic fitness of T cells in aging and inflammation

■n Christina Camell, Yale University: Tissue resident macrophages drive adipose dysfunction during aging

■n Valter Longo, University of Southern California: Fasting mimicking diets, immunity and cancer

■n Alison Ringel, Harvard University: Immunomodulatory mechanisms in the tumor microenvironment

MONDAY, MAY 13 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Symposium: Single Cell Deconstruction of Rheumatoid Synovium and Lupus Kidney by the RA/SLE Accelerating Medicines Partnership (AMP) NetworkCHAIRS: Jennifer Anolik, University of Rochester & Michael Brenner, Brigham and Women’s HospitalSPEAKERS:

■n Jennifer Anolik, University of Rochester: AMP approach and what we have learned about RA synovial pathotypes

■n Soumya Raychaudhuri, Brigham and Women’s Hospital: The immune landscape in the RA synovium

■n Michael Brenner, Brigham and Women’s Hospital: The stromal cell landscape in the RA synovium from single cell analysis

■n Chaim Putterman, Albert Einstein College of Medicine: New insights into renal resident cells from the AMP Lupus Nephritis cohort

■n Paul Hoover, Broad Institute: The immune cell landscape in lupus nephritis kidneys

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Major symposiaFRIDAY, MAY 10 Major Symposium AInteractions of Innate and Adaptive Immune Cells that Promote Autoimmunity

FRIDAY, MAY 10 Major Symposium BExtrinsic and Intrinsic Immune Aspects of the Tumor Microenvironment

SATURDAY, MAY 11Major Symposium CAcute and Chronic Inflammation

SATURDAY, MAY 11 Major Symposium DStructural and Cellular Aspects of Innate Lymphocytes

SUNDAY, MAY 12Major Symposium EMechanisms of Allergic Immunity

SUNDAY, MAY 12 Major Symposium FFunctional Plasticity of Innate and Adaptive Immune Cells

MONDAY, MAY 13 Major Symposium GImmune Responses to Emerging Viral Infections

MONDAY, MAY 13Major Symposium HRegulating Immune Cell Metabolism to Regulate Immune Responses

The American Association of Immunologists Annual Meeting, also known as Immunology 2019, will take place at the San Diego Convention Center.

BRIEFS

DIAGNOSTICS30 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

A biomarker for CDK4/6 inhibitors

LA JOLLA, Calif.—ActivX Biosciences Inc., a whol-ly owned subsidiary of Kyorin Pharmaceutical Co. Ltd., announced last month that some of its research had been published in Molecular Cancer Therapeutics regarding the molecular mechanism that determines an individual’s sensitivity or resistance to CDK4/6 inhibitors. The work looked at CDK4/6 inhibitors palboci-clib (Ibrance), ribociclib (Kisqali) and abemaciclib (Verzenio), all of which are approved to treat estrogen receptor (ER)-positive, human epider-mal growth factor receptor 2 (HER2)-negative breast cancer. Researchers from ActivX and Vall d’Hebron Institute of Oncology applied the for-mer’s KiNativ platform to demonstrate that high levels of p16/CDKN2A, an endogenous regula-tor of CDK4/6, could function as a biomarker to screen out patients unlikely to respond to CDK4/6 inhibitors.

And one more thing...

TUCSON, Ariz.—HTG Molecular Diagnostics Inc. has amended its second precision diagnostic partnership program with QIAGEN Manchester Ltd. to extend the use of the investigational use only assay previously developed under this program and add certain activities that could be included in future companion diagnostic regu-latory submissions. HTG expects this amend-ment—the fourth for this program—to result in revenues in the low single-digit millions due to the added activities.

“This amendment highlights the expanded utilization of the program assay into additional trials as well as activities getting us closer to a potential companion diagnostic,” Byron Law-son, HTG’s SVP of Pharma Partnerships, said in a press release. “We are very appreciative of the trust our Pharma partner has extended us with this expansion.”

IN THIS SECTIONCompanion diagnosticsAnd one more thing... ............................. 30

CRISPR/GenomicsA ‘Mammoth’ licensing victory .............. 30

OncologyA biomarker for CDK4/6 inhibitors ......... 30A meeting of the minds at multiscale .... 30Biocartis and Bristol-Myers Squibb sign deal ..................................... 32Molecular makeup .................................. 30

A MEETING OF THE MINDS AT MULTISCALEOlympus, USC pair up to leverage a host of technologies to accelerate precision medicine in cancerBY KELSEY KAUSTINEN

WALTHAM, Mass.—Olympus Corp. and the University of South-ern California (USC) are working together in a co-development partnership to advance multiscale research in the prevention, diagnosis and treatment of cancer through precision medicine. This agreement, the USC-Olympus Innovation Partnership in Multiscale Bioimaging, will apply new technologies that unite the workflow of surgical biopsies and primary diagnosis with microscopic cellular and molecular characterization in hopes of advancing cancer research and enabling more precise diagnosis and treatment recommendations.

Olympus will be working with two institutes at USC: the Lawrence J. Ellison Institute for Transformative Medicine and the Translational Imaging Center (TIC), which focus on changing cancer treatment through transdisciplinary, patient-centered research programs and the advancement of biological imaging, respectively. For its part, Olympus specializes in inno-vative imaging technologies and healthcare solutions. Among

A ‘Mammoth’ licensing victoryMammoth Biosciences gains license to Cas14 CRISPR protein, completing its diagnostic toolboxBY KELSEY KAUSTINEN

SAN FRANCISCO—CRISPR is regularly in the news these days as scientists seek to determine the extent—and accuracy—of its gene-editing abilities. But soon enough it could be making headlines not in rela-tion to editing genomes, but rather as a new approach to diagnosis.

Mammoth Biosciences is developing what it says is the world’s first CRISPR-based dis-ease detection platform. Thanks to a recent exclusive licensing deal with the University of California, Berke-ley, Mammoth now has Cas14 to add to that platform. Lucas Har-rington and Jennifer Doudna, co-founders of Mammoth, were part of the UC Berkeley team that dis-covered Cas14, which is the smallest CRISPR protein discovered so far. A paper on Cas14 was published in Science in October under the title “Programmed DNA destruction by miniature CRISPR-Cas14 enzymes.”

Mammoth Biosciences’ goal is to develop an easy, affordable point-of-care diagnos-

tic test that can enable rapid, simultane-ous detection of several conditions in real time. The company is only a year old, having launched in April 2018, and has raised nearly $25 million to date.

Most often, CRISPR is used for genome editing to target select genetic sequences to be removed or altered. Trevor Martin, co-founder and CEO of Mammoth Biosciences, likens the “traditional” approach to using CRISPR as an editor or word processing tool,

while Mammoth sees the system as a “biology search engine.”

“In diagnostics, we program our CRISPR proteins so that they bind to nucleic acid sequences, but in this case, instead of being sequences we want to edit,

they’re sequences that are unique to what-ever we want to detect. So for malaria, tuber-culosis, dengue, Zika or whatever it is, you can bioinformatically say ‘this 20-base pair sequence is unique to this species.’ That’s how you program the protein. So then the

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Molecular makeupResearchers aim to determine likelihood of breast cancer recurrenceBY ILENE SCHNEIDER

CAMBRIDGE, U.K.—Breast can-cer, the most common cancer in the United Kingdom, accounts for 15 percent of all new cancer cases. About 55,000 new cases of invasive breast cancer—roughly 150 per day—are diagnosed in the U.K. each year. Although approximately two-thirds (65 percent) of women diagnosed with breast cancer in England and Wales survive for 20 years or more, the disease still causes about 11,400 deaths annually.

A nonprofit organization thinks it may have an answer to that problem. The METABRIC (Molecular Taxonomy of Breast Cancer International Consor-tium) study stratified breast tumors into 11 different integra-tive clusters based on distinct genomic drivers.

According to a Cancer Research UK-funded study pub-

lished in Nature in March, the genetic and molecular makeup of individual breast tumors pro-vides clues as to how a woman’s disease might progress, including the likelihood of its coming back after treatment and in what time frame. In what they describe as the first study of its kind, scien-tists at the Cancer Research UK Cambridge Institute at the Uni-versity of Cambridge collaborat-ed with Prof. Christina Curtis at Stanford University to examine the patterns of genetic changes

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“Cas14 is the most diverse family of CRISPR enzymes that’s ever been discovered, and that means there’s potential for this family of enzymes to have lots of interesting functions that we haven’t even characterized yet,” says Mammoth Biosciences CEO and co-founder Trevor Martin.

Research driven by Cancer Research UK may one day give healthcare professionals a test to determine the likelihood of breast cancer recurrence.

DIAGNOSTICSFor more information, visit www.DDN-News.com APRIL 2019 | | DDNEWS 31

those leading the partnership are Dr. David Agus, founding director of the Ellison Insti-tute, and Dr. Scott Fraser, director of the TIC.

“Cancer medicine is at a crossroads,” said Agus. “Molecular research has shown that hundreds of genes and proteins are involved, making it difficult to envision how genetic approaches and standard treatments will cure cancer. Because of this, USC and Olympus have assembled a powerful team of translational researchers, clinicians and technologists to advance diagnostic capabilities toward precision medicine.”

“Life happens in 3D, and the USC-Olym-pus Innovation Partnership in Multiscale Bioimaging brings Olympus expertise in 3D imaging and our extensive track record in the GI space together with USC’s multidi-mensional approach to precision medicine,” added Randy Clark, president, Medical Sys-

tems Group, Olympus Corporation of the Americas. “We couldn’t be more excited to be working with such visionaries in the fight against cancer.”

Brendan Brinkman, Olympus’ senior mar-keting manager of its Life Science Micros-copy operation, tells DDNews that in addi-tion to “a collaborative intellectual property element,” Olympus will be loaning specific equipment for this agreement, including the IX83, the VS120 slide scanning system and the FV3000 confocal microscope, which also features NoviSight, a 3D high-content analy-sis software.

“USC approached Olympus initially because we had a demonstrated expertise in both medical endoscopy and scientific microscopy, but it was really an ideal time to approach us since we’d long been having discussions internally about ways to have greater synergy between our medical and scientific divisions,” he says of the origins of this partnership. “And for us at Olym-pus, the expertise and scientific horsepower

at USC are amazing, and looking at their medical, scientific and optical understand-ing made this partnership really attrac-tive. Both at the Ellison Institute and TIC, they’ve really demonstrated a great under-standing of how to approach new methods and new optical technologies, and bring a significant multi-layered set of expertise to the partnership.”

Brinkman notes that the initial agreement is slated to run three years, but that there is a possibility to expand it. He adds that the work is all for research use only.

“Cancer is a very heterogeneous disease, varying from patient to patient and cancer type. The term multiscale in the central con-text of this partnership really refers to under-standing the totality of contributors to cancer and its treatment, from the whole patient down to the cellular, molecular and genetic levels, and the ability to engage in precision medicine for an individual patient using all of the tools at our disposal,” he explains. “In our case, that involves the use and develop-

ment of optical tools including microscopy to examine patient samples from the macro scale to micro scale. So we can, for instance, examine the effect of anti-cancer drugs on patient-derived tumor organoids, or better understand the margins of a tumor biopsy, or compare whole-slide visual pathology images across many patients and to really link the microscopic variability in tissues to the more coarse-grained predictors of cancer progres-sion and metastasis.

“There are a lot of different ways of looking at cancer, and by viewing things in a multi-tude of ways and applying new optical tech-nologies to better visualize physiologically relevant samples like tumor organoids and computational technology like artificial intel-ligence and true 3D analysis of these kinds of patient-derived samples, we can look at an array of data, and we believe—both us and USC—that we can provide a more precise set of information to help treat a specific patient’s cancer.” nEDITCONNECT: E041922

CRISPR protein will go and bind to that sequence,” Martin explains.

“Then what happens is that we have these special proteins that are not Cas9, because Cas9 really can only just cut the sequence that you tell it to bind to, and that’s not terribly useful for diagnostics. Our proteins do what Cas9 does, but they do something else—they have this addi-tional second functionality, which is con-ditional on having bound and successfully cut their target,” he continues. “When the CRISPR system successfully binds to that nucleic acid, it’ll cut that, and what hap-pens that’s really useful for diagnostics is these proteins have a switch that’s activat-ed. They flip this switch where they become these prolific collateral cutters—they start cutting everything in the solution. And that allows us to put these little reporter mol-ecules in that light up when they’re cut, so that way we can breed out the signal, [and] the solution starts lighting up on successful activation.”

With this latest addition, Mammoth holds exclusive commercialization rights to Cas12, Cas13 and Cas14, which have applications for double-stranded DNA, single-stranded RNA recognition and sin-gle-stranded DNA, respectively.

“[Cas14] actually has a bunch of proper-

ties that make it a very unique and applica-tion-enabling protein. One of the key fea-tures on the diagnostic side that’s exciting is it targets the ‘untargetable,’” Martin tells DDNews. “CRISPR proteins are these pro-grammable enzymes that, when you give them what’s called a guide RNA, they then bind to the complement of that guide RNA, and that’s how you tell it to bind to this nucleic acid that’s for malaria, or this other nucleic acid that is representative of tuber-culosis. And it’s programmable, but there are some caveats with proteins like Cas9 or Cas12 where there’s a bit of restraint on what types of nucleic acid you can target—maybe they need a GTAC sequence, or an AT sequence, so there are some rules basi-cally that constrain what you can have these proteins bind to.

“The exciting thing about Cas14 is that it doesn’t have these rules, and that’s exciting because it means that especially in applica-tions where you need to get it exactly in the right spot, like in oncology—maybe you’re detecting a single snip, and you’re trying to see what the genotype is for that snip; you can’t just put it anywhere in a hundred base pair region.”

The addition of Cas14 is a huge boon for the company for other reasons, accord-ing to Martin. With it, the company can target “any nucleic acid you want, at any location,” he remarks, adding that “Cas14 is

the most diverse family of CRISPR enzymes that’s ever been discovered, and that means there’s potential for this family of enzymes to have lots of interesting functions that we haven’t even characterized yet.”

And the enthusiasm for this newly com-pleted toolbox extends beyond Mammoth, as Martin tells DDNews that the company has been approached by several companies that are hoping to explore the potential of

CRISPR-based diagnostics.“We’ve had many companies reach out,

and we’ve actually signed our first round of partnerships with really exciting partners. I can’t reveal the names, but we’re definitely excited to work with them on the system, and we’re still open to partners that are excited by the potential of this system and what it can do,” he adds. nEDITCONNECT: E041920

MAMMOTHCONTINUED FROM PAGE 30

Two institutes at the University of Southern California (the campus of which is pictured here) will work with Olympus Corp. to apply new technologies that unite the workflow of surgical biopsies and primary diagnosis with microscopic cellular and molecular characterization.

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Mammoth Biosciences, a biotech developing a CRISPR-based diagnostic platform, recently licensed a new CRISPR protein from UC Berkeley. Pictured here are the founders of Mammoth, from left to right: Lucas Harrington, Trevor Martin, Ashley Tehranchi, Jennifer Doudna and Janice Chen.

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DIAGNOSTICS32 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.com

in tumors from nearly 2,000 women with breast cancer.

Following disease progress for more than 20 years, including whether their cancer returned, the researchers used the infor-mation to create a statistical tool to predict whether and when a woman’s breast cancer could come back. The team is working on a routine test designed to give doctors that information. The researchers hope to help doctors to tailor treatments and follow up to individuals, improving their chances of survival.

As Prof. Carlos Caldas, lead researcher at the Cancer Research UK Cambridge Insti-tute, explained, “Treatments for breast can-cer have improved dramatically in recent years, but unfortunately for some women, their breast cancer returns and spreads, becoming incurable. For some, this can be many years later, but it’s been impossible to accurately predict who is at risk of recur-rence and who is all clear. In this study, we’ve delved deeper into breast cancer molecular subtypes so we can more accurately identify who might be at risk of relapsing and uncover new ways of treating them.”

Previous results from this group of researchers showed that breast cancer is not just one disease. Instead, it could be classified into one of 11 molecular subgroups. Recent research showed how these molecular sub-types have distinct clinical trajectories that cannot be predicted by looking at commonly used characteristics, such as size, stage, estro-gen receptor (ER) or HER2 status, alone.

Clinical trajectories vary considerably, even between tumors that seem similar. Among women with triple-negative breast cancer, there was a distinct subgroup whose outlook is initially poor, but for whom the disease is unlikely to come back in those who survived five years.

The researchers also identified subgroups

of women with estrogen receptor-positive (ER+) tumors, who were at a higher risk of their cancer coming back as much as 20 years after they were first diagnosed. As many as 12,300 women in the UK may belong to one of these late relapse subgroups and might benefit from longer courses of treat-ments such as tamoxifen, or more frequent check-ups.

The research also showed how molecular subgroups could behave very differently if a patient’s cancer comes back. Recurring can-cers commonly spread to different parts of the body and some are more aggressive than others, affecting how much time women sur-vive for following a relapse.

In addition to developing an affordable test for future use in hospitals, the research

team is investigating personalized treatment options for different subtypes of breast can-cer. The next step for the researchers will be to recruit patients into different clinical trials depending on the molecular makeup of their tumor.

Dr. Oscar Rueda, first author of the paper and senior research associate at the Cancer Research UK Cambridge Institute, sum-marized, “We’ve shown that the molecular nature of a woman’s breast cancer deter-mines how her disease could progress, not just for the first five years, but also later, even if it comes back. We hope that our research tool can be turned into a test that doctors can easily use to guide treatment recommenda-tions.” nEDITCONNECT: E041922

BREASTCONTINUED FROM PAGE 30 Biocartis and

Bristol-Myers Squibb sign dealCollaboration will focus on MSI testing related to immuno-oncology therapiesBY DDNEWS STAFF

MECHELEN, Belgium—On March 12, Biocartis Group NV, a molecular diagnostics company, announced the signing of a collaboration agreement with Bristol-Myers Squibb Co. that is aimed at the use of the Idylla MSI test—and its potential registration as a companion diagnostic—in connec-tion with immuno-oncology therapies.

MSI (microsatellite instability) is the result of inactivation of the body’s so-called DNA mismatch repair (MMR) system. Consequently, errors that spontaneously occur during the normal process of DNA replication are no longer corrected, contributing to tumor growth and evolution. Under-standing a person’s MSI status may therefore be important for patient care.

MSI-High status is found in various types of tumors, including approxi-mately 15 percent of colorectal (CRC) tumors. In addition to applications for CRC, MSI is believed to be an indepen-dent factor that may predict a patient’s response to certain immunotherapies.

Bristol-Myers Squibb’s Opdivo (nivolumab) plus low-dose Yervoy (ipilimumab) is the first immuno-oncology combination treatment approved by the U.S. Food and Drug Administration for MSI-High or mis-match repair-deficient metastatic colorectal cancer that has progressed following treatment with certain chemotherapies.

The fully automated Idylla MSI test, which received CE-IVD marking in the European Union on Feb. 28, 2019, pro-vides information on the MSI status of CRC tumors within approximately 150 minutes from just one slice of FFPE (formalin-fixed paraffin-embedded) tumor tissue, without the need for a reference sample. nEDITCONNECT: E041923

slaseurope2019 CONFERENCE

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t: +32 (0) 497 85 18 38e: GTurkmen@slas.org

Bristol-Myers Squibb Co. (pictured here) recently signed a deal with Biocartis for a companion test in connection with immuno-oncology treatments.C

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According to a Cancer Research UK-funded study, the genetic and molecular makeup of individual breast tumors provide clues as to how a woman’s disease might progress, including the likelihood of its coming back after treatment and in what time frame.

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CONTRACT SERVICESDelaware company to

open new locationWILMINGTON, Del.—The theme of Q1 2019 for Wilmington PharmaTech is growth, as the con-tract research/manufacturing organization has announced plans to expand its Delaware footprint by hiring up to 139 new employees and invest-ing $18 million to build a state-of-the-science research and manufacturing facility in Newark.

“This marks the next wave of growth, posi-tioning Wilmington PharmaTech as the leader in new drug manufacturing in the US,” said com-pany president and CEO Dr. Hui-Yin Harry Li. “This expansion scales up operations and significantly enhances offerings to our clients in API manufac-turing and related services. It also expands our portfolio of research, development and potential commercial API services. PharmaTech’s expansion plans fulfill the commitment to growth and its hallmark reputation for excellence for our employ-ees, customers, partners and our community in the state of Delaware.”

Cancer immunotherapy market on the rise

DUBLIN—According to a recent report from Research and Markets, the global cancer immu-notherapy drug discovery outsourcing market is expected to reach $1.7 billion by 2025, growing at a compound annual growth rate of 13.5 per-cent between 2018 and 2025. Key drivers for this growth are rising cancer prevalence and mortality, as well as accelerated development within the area of cancer immunotherapy. Pharmaceutical companies spend 2.5 percent more than other high-tech industries on in-house research and development, the report notes, which is a lead-ing cause of the transition to outsourcing drug discovery. In addition, established tax credits provide companies with the opportunity to out-source to CROs and “therefore, receive benefits and reduce problems associated with taxation authorities or other bodies administering such incentive programs.”

IN THIS SECTIONe-Clinical servicesAxiom awarded multiple contracts ........ 33

New service offerings/ ExpansionDelaware company to open new location .................................. 33Launch time ............................................ 33

OncologyA match made in the cloud .................... 33Cancer immunotherapy market on the rise .................................. 33

Research modelsCrowning the rodents (CROWN from cover) .............................. 34

Axiom awarded multiple contracts Studies will use Fusion eClinical Suite’s IWRS ModuleBY DDNEWS STAFF

TORONTO—Axiom Real-Time Metrics, a provider of unified eClinical solutions and services, has been awarded three new stud-ies using its Fusion eClinical Suite’s IWRS Module.

As one of the core modules of Axiom’s Fusion eClinical Suite, the IWRS module boasts many key features, including the abil-ity to manage drug supply across an entire group of studies, plus a range of real-time dashboards to track drug supply, pending shipments and upcoming site needs.

“Fusion eClinical Suite empowers orga-nizations to manage every aspect of their clinical trials. This truly unified product platform offering is unique in the indus-try with every component built by Axiom engineers, allowing sponsors to benefit from our agile development, intuitive design and feature-rich technology that is highly con-figurable and end user-focused to all key

stakeholders in the process,” said Andrew Schachter, Axiom’s CEO and founder. “We are thrilled to be working with small to mid-sized biotech and medical device companies to solve their IWRS/RTSM [interactive web response systems/randomization and trial supply management] challenges, and look forward to supporting our clients on these new studies.”

Added Heather Di Fruscia, associate direc-tor of IWRS/RTSM: “Fusion’s capacity for automated predictive resupply via AI tech-nology that analyzes all site data and deter-mines overall site needs allows our clients to focus on other important study details instead of worrying about sufficient inven-tory for upcoming subject visits. Overall, our strategic, study specific approach to plan-ning, design and implementation ensures that our clients and their inventory are well taken care of.” nEDITCONNECT: E041926

A match made in the cloudNew alliance seeks to change and improve patient recruitment and trial participationBY JENNIFER CLIFFORD

MORRISVILLE, N.C. & COLUMBUS, Ohio—Worldwide Clinical Trials Inc. and Deep Lens recently announced a new strategic alliance in oncology with the intent to support a new ecosystem for sponsors, researchers and care teams to accelerate cancer diagnoses and present clearer treatment and clinical trial options earlier in the process.

Currently, patient recruitment is a time-intensive, costly barrier to the execution of drug development programs. While more than 14,000 oncology clinical trials are actively recruiting patients, it is estimated that actual participation rates are as low as 3 percent of potential trial candidates. The new alliance will address this challenge by first collaborating to design a pilot study to marry innovative clinical trial designs and operational acumen with the VIPER plat-form in hopes of improving trial recruitment through real-time diagnosis and alerting to

enhance coordination between research teams, care teams and patients.

What does this entail? To start with, it means accelerated oncology patient recruit-

ment for clinical trials and an increase in clinical research as a care option (CRAACO), where the critical conversation with a patient

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LAUNCH TIMEA roundup of recent new offerings from contract services organizationsBY MEL J. YEATES

I N THE LATEST from contract ser v ices companies this month, we lead with Enviro’s launching of the PATHWAY safety assessment solution.

From Medsource comes a new business unit, MedSource Staffing Solutions, which will focus on staff-ing sourcing and recruitment. And PPD and HLT have co-created a ser-vice designed to enhance research capabilities and access to China’s evolving drug development mar-ket for the Chinese pharmaceutical industry.

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Worldwide Clinical Trials and Deep Lens seek to marry innovative clinical trial designs and operational acumen with the VIPER platform in hopes of improving trial recruitment.

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is able to occur as soon as possible. The alli-ance aims to create trusted networks of preci-sion diagnosis and clinical research options in order to provide pharmaceutical clients with a new platform for basket and umbrella study designs that can quickly process diagnosis and tumor response in real time. Lastly, the companies hope to support pre-competitive research into better clinical trial approaches by organizing “data clubs” (disease-specific consortia) of industry stakeholders.

Each company brings a wide range of expertise and industry experience to the alli-ance. Worldwide Clinical Trials is an award-winning, full-service, midsize, global con-tract research organization (CRO) boasting a network of more than 1,600 professionals in 60 countries in North and South Ameri-ca, Eastern and Western Europe, Russia and Asia. Founded by physicians committed to advancing medical science, Worldwide seeks to change the CRO experience from early phase and bioanalytical sciences through late phase, post-approval and real-world evidence, by providing “world-class, full-service drug development services with predictable, suc-cessful studies with operational excellence across a range of therapeutic areas, includ-

ing central nervous system, cardiovascular, metabolic, immune-mediated inflammatory disorders, oncology and rare diseases.”

Deep Lens supports Worldwide’s mission by offering a modernized, artificial intelligence-driven approach to pathology, expanding one of the world’s first digital pathology cloud platforms, VIPER, to include artificial intel-ligence, enhanced pathology workflow sup-port and collaboration capabilities. In addition to providing essential workflow support to pathology teams, Deep Lens says it offers the most precise and timely source for identifying sites and patients for sponsored clinical trials.

“Cancer research is advancing at an incredible pace. We need to up our game as pathologists and CROs to deliver increased precision, speed and communication to find patients with particular disease subtypes or biomarkers,” said Dave Billiter, co-founder and CEO of Deep Lens. “With the global reach and scientific and operations exper-tise of Worldwide, we believe we can stream-line clinical trial recruitment. And, just as importantly, oncologists can inform patients and their caregivers about clinical research options from day one.”

By working with Deep Lens on clinical trial recruitment, Worldwide believes it can reach upstream from the oncologist to the pathologist to identify eligible patients at the

time of their diagnosis, which is much sooner than current methods.

The companies’ plans are to develop advances in digital pathology, deep learning and workflow for interventional and observa-tional research in oncology; accelerate char-acterization of complex oncology sub-types and stages in real time; and engage study teams and care teams in meaningful patient conversations about treatment options.

In an interview with DDNews, Dave Bil-liter said that with the release of VIPER 3.0 the industry has an unprecedented ability to seamlessly adopt a free, cloud-based, AI-driven platform, transforming pathology labs worldwide and strengthening their role in the clinical trial process. The hope is that this will allow these studies to be completed on time, or even early and under budget.

Since VIPER is set up directly in pathology labs, it is reportedly easier to identify, notify and track candidates at the time of diagnosis. Once a trial site is verified and onboarded to the VIPER database, the patient’s pathol-ogy images are analyzed and and patients are matched to available trials. The trial coor-dinator at the site is alerted to a possible match, then the inclusion/exclusion criteria are analyzed for potential recruitment before commencing any other course of treatment. nEDITCONNECT: E041924

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Envigo launches PATHWAYEAST MILLSTONE, N.J.—Envigo recently debuted PATHWAY, an integrated solution that optimizes non-clinical safety assess-ment programs to enable first-in-human clinical trials. PATHWAY is designed to manage the complexity of the entire safety assessment process on behalf of Envigo’s pharmaceutical and biotechnology custom-ers by integrating safety assessment study types and bioanalytical support with sci-entific and regulatory consulting, program design, and project management.

Envigo developed the PATHWAY solu-tion to help its customers navigate the increased scientific and regulatory com-plexity facing advanced therapies going through safety assessment. The intricacy of design and management of these criti-cal non-clinical programs, and the level of interaction with regulatory bodies required, raises the risk of introducing delays and costs to development programs. PATHWAY has been designed to use Envigo’s capacity, capabilities and experience in the field to optimize safety assessment programs and deliver translational biology insights for first-in-human clinical trials.

“Our deep expertise in the complex fields of biologics and advanced therapies adds particular value to our customers with drug development programs in these growing categories. On our customers’ behalf, we frequently work with regulators to deter-mine the most appropriate interpretation of regulatory guidance as it applies to a spe-cific therapeutic,” said Lee Coney, Envigo’s chief scientific officer.

MedSource creates Staffing Solutions divisionHOUSTON—MedSource has expanded with the offering of a new business unit, MedSource Staffing Solutions. The comple-mentary sourcing division of MedSource will

continue the dedication to drug development by providing clinical, technical and executive professionals to life-science organizations.

MedSource has recognized the industry’s demand for an innovative clinical staffing provider. The formal launch of MedSource Staffing Solutions allows MedSource to bet-ter deliver solutions for the multitude of resource constraints encountered during the life cycle of biotechnology, pharmaceu-tical and life-science companies.

“Our tagline, ‘Taking Relationships as Seriously as Science,’ is not simply an empty catchphrase, but a standard exemplified by everyone within our organization. With the launch of our staffing solutions division, now more than ever we can continue to focus on identifying passionate people to join our deep network of industry profes-sionals,” mentioned MedSource president and CEO Eric Lund.

MedSource Staffing Solutions is led by MedSource’s current director of Cli-ent Services, Billy Howell, who has been MedSource’s head of recruitment for over three years.

“I am excited to apply my previous expe-rience to leading the growth of MedSource Staffing Solutions,” noted Howell. “Over the past 20 years, MedSource has contin-ued to build a strong recruitment engine in addition to our wide experience as a clini-cal research organization. The skilled team we’ve constructed for this new division has the expertise to deliver staffing solu-tions from clinical to executive, support-ing clients from early clinical development through commercialization.”

HLT and PPD pair upWILMINGTON, N.C. & BEIJING—Pharma-ceutical Product Development LLC (PPD) and Happy Life Tech (HLT) of China have signed an exclusive agreement to develop a distinctive service offering for the China drug development market, delivering data science-driven clinical trials and real-world evidence of drug products’ effectiveness,

safety and value.The strategic collaboration is designed

to enhance global pharmaceutical compa-nies’ access to China’s evolving drug devel-opment and post-marketing ecosystem to address unmet clinical needs in China, while enhancing research capabilities for the Chinese pharmaceutical industry in the global market. The combined service offerings are powered by HLT’s artificial intelligence and data technology, and PPD’s global expertise in clinical trial manage-ment and evidence generation.

“Our collaboration with HLT will pro-vide PPD’s clients with exciting new oppor-tunities in China,” said David Simmons, chairman and CEO of PPD. “Our focus on sites with access to eligible patients is designed to speed patient recruitment at high-performing sites, and to more effec-tively incorporate Chinese patients into global trials. We will help clients adapt study protocols to the China market, while helping sites enhance quality, drive perfor-mance and lead global multicenter trials. In addition, we will intelligently leverage real-world data in China to recruit patients with a high potential for participation in our clients’ studies and to generate real-world insights needed for market access and product uptake.”

“I am very excited about this collabora-tion. We believe a joint effort between PPD and HLT will empower our clients with unique solutions, significantly increase trial efficiency, reduce costs and ultimately benefit patients in China and around the world,” explained Rujing Gong, founder of HLT. “We’ll also help the Chinese pharma industry be more competitive in the global market through a better registration strat-egy. China’s research capability has been developing quickly and will play an impor-tant role in the global clinical develop-ment market in the future. We have strong interest in being involved and in driving the process.” nEDITCONNECT: E041925

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and CrownBio says it more closely mimics human disease development.

Proprietary to CrownBio, the ZDSD rat was developed by crossing the ZDF rat (Lean +/+) with the CD (SD) rat and selectively inbred for obesity and diabetes traits for more than 35 generations. It has also been charac-terized as a novel model of diabetic nephropathy.

“The ZDSD rat has proven to be a leading translational model for obesi-ty, diabetes and metabolic disease with complications. I am confident that this exciting agreement with Charles River will extend the reach of this model,” said Dr. Jim Wang, senior vice presi-dent of CrownBio’s Cardiovascular and Metabolic Disease division.

In the same general therapeutic

area, the exclusive agreement with JAX aims to utilize its world-class dis-tribution channels to make the FATZO mouse model available to researchers globally. As CrownBio’s exclusive dis-tributor of the FATZO model, JAX—an independent, nonprofit biomedical research organization—will utilize its expertise in the breeding, production and delivery of high-quality mouse models to increase worldwide access with immediate effect. As part of the agreement, JAX will provide a priori-tized model supply to support Crown-Bio’s global service platform in obesity, diabetes and associated indications.

A unique and proprietary model to CrownBio, the FATZO model, is a translationally relevant, inbred poly-genic mouse model said to be ideal for the study of obesity, metabolic syndrome and diabetes, as well as for drug development in those areas. The model is sensitive to developing obe-sity and metabolic syndrome under the influence of a high-fat diet, which has been demonstrated to be a signifi-cant factor in the human development of these conditions. The model also exhibits human-like disease progres-sion, making it an ideal candidate for modeling human metabolic syndrome.

“I am excited that our ongoing rela-tionship with The Jackson Laboratory has resulted in this agreement and will enable easier access to FATZO, thereby accelerating discovery in obe-sity, diabetes and NAFLD/NASH,” said Wang. nEDITCONNECT: E041903

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“The ZDSD rat has proven to be a leading translational model for obesity, diabetes, and metabolic disease with complications. I am confident that this exciting agreement with Charles River will extend the reach of this model.”Dr. Jim Wang, a senior vice president at CrownBio

BUSINESS & GOVERNMENT POLICY

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Q&A: Modeling the microenvironmentA newly developed tumor model could offer better accuracyBY KELSEY KAUSTINEN

M ORE ACCURATE disease modeling is becom-ing one of the biggest points of interest in the industry of late as

companies explore 3D models and lab-on-a-chip technology. In addition to giving new insights into the nature and development of diseases, disease model-ing also enables early screening of drug candidates at a time when drug develop-ment costs are measured in the billions and unforeseen toxicity is the leading cause of clinical failure. And for a complex disease like cancer, a more accurate look at how a tumor grows and interacts with its surroundings is pivotal.

In hopes of answering this need, HemoShear Therapeutics recently announced the publication of research data regarding a multicellular 3D model of the tumor microenvironment

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Biogen to offload Danish subsidiary

CAMBRIDGE, Mass.—Biogen and Fujifilm Corp. have struck a share purchase agreement under which the latter will acquire all shares of Biogen’s subsidiary for up to $890 million in cash, subject to minimum purchase commitment guarantees and other terms. The subsidiary, which houses Biogen’s biologics manufacturing operations in Hillerød, Denmark, employees roughly 800 indi-viduals, who are expected to remain once Fujif-ilm assumes ownership. In conjunction with the transaction, Biogen will enter into manufacturing services agreements with Fujifilm, while Fujifilm will leverage the subsidiary’s abilities to pro-duce commercial products for Biogen, as well as third-party products. Biogen is predicting a total after-tax loss in Q1 2019 of roughly $130 million to $150 million related to the subsidiary agree-ment, which includes an estimated $120 million associated with guarantees of future minimum purchase commitments.

Growth abounds for RoosterBioFREDERICK, Md.—RoosterBio Inc. is spreading its wings with recently announced plans to expand its Frederick, Md.-based facility. Last February, RoosterBio opened the doors to a 14,000-square-foot facility meant to support increased mesenchymal cell manufacturing, research and development, and this January, the company announced it had grown to more than 40 employees, with plans to double that in the next 18 to 24 months. RoosterBio also forecasts six new product launches for 2019.

“Hundreds of researchers and scientists around the world have used RoosterBio’s adult human mesenchymal stem/stromal cell products to streamline their product development efforts in the regenerative medicine field, resulting in strong growth for our company,” said RoosterBio CEO Margot S. Connor. “The additional expansion space in the building we already occupy at The Offices at Westview will better accommodate our growing staff and support our company’s vision.”

IN THIS SECTIONBusiness deals/ExpansionBiogen to offload Danish subsidiary ...... 35Growth abounds for RoosterBio ............. 35

Drug manufacturingA ‘continuous’ need ................................ 35

M&A activity/Gene therapyBiogen buys into ophthalmology ............ 35

M&A activity/Pain managementNo pain and a gain ................................. 36

Q&A/OncologyModeling the microenvironment ............ 35

Biogen buys into ophthalmologyCompany announces agreement to acquire Nightstar Therapeutics BY MEL J. YEATES

CAMBRIDGE, Mass.—Biogen recently announced an agreement to acquire London-based Nightstar Therapeutics, a clinical-stage gene therapy company focused on adeno-associated virus (AAV) treatments for inher-ited retinal disorders. Under the terms of the proposed acquisition, Biogen will pay $25.50 in cash for each Nightstar share.

“Biogen continues its diversification strat-egy through the acquisition of Nightstar Therapeutics. The deal will allow Biogen to catapult itself into the ophthalmology mar-ket, a new segment which the company had been chasing to enter in the past already. Although the deal will not have an immediate impact on Biogen’s bottom line, as Nightstar is a clinical-stage company, it will inherit its pipeline of rare inherited retinal diseases,” explained Maura Musciacco, director of neurology and ophthalmology at data and analysis firm GlobalData. “Notably, this deal comes only one week after Roche’s acquisi-tion of Spark Therapeutics, another gene therapy specialist, and less than a year ago,

BIOGEN CONTINUED ON PAGE 37

A ‘continuous’ needContinuous manufacturing embraced by FDA and researchersBY KRISTEN SMITH

SILVER SPRING, Md.—The U.S. Food and Drug Administration (FDA) has issued a challenge that scientists and academics are racing to fulfill: to success-

fully transform batch-based drug manufacturing processes to the more efficient, higher-quality and higher-yield method known as continuous manu-

CM CONTINUED ON PAGE 36

Dr. Brian Wamhoff, co-founder of HemoShear

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Zinia Jaman, a Purdue University doctoral student in chemistry, prepares a reactor system as part of the process for making generic lomustine using a continuous manufacturing method. The FDA wants the pharmaceutical industry to switch to continuous manufacturing and move away from the traditional batch method.

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“Ophthalmology is an emerging growth area for Biogen, and we are excited about the opportunity to work with the talented employees at Nightstar to advance potentially transformative gene therapy programs for rare retinal diseases,” says Michel Vounatsos, CEO of Biogen (which is pictured here).

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facturing (CM). In response to the FDA’s directive, backed by agency grants and DARFA’s deep pockets, researchers are seek-ing prime candidates for com-mercialization of a CM success story. A research team at Purdue University’s Center for Cancer Research has reported initial suc-cess in the continuous manufac-ture of lomustine, a cancer drug indicated in the treatment of Hodgkin lymphoma and certain brain cancers.

“There are many factors that must be balanced to achieve an efficient continuous manufactur-ing process for production of a target drug molecule,” according to Purdue’s David H. Thompson, a professor in Chemistry and a member of the Center for Can-cer Research. “Each step must be evaluated in a multistep drug synthesis to determine those transformations that are best done in flow verses those that are best performed in a conventional reactor.”

Traditional batch processing involves adding all of the raw material(s) into the system at the beginning of the process, with the product being discharged all at once some time later, within a closed system—no more ingre-dients go in, and nothing comes out until the finished product is attained. In CM, material(s) and product are continuously charged into and discharged from the system, respectively, throughout the duration of the process, with outputs from each process step continuously mov-ing to the next step for further processing. Each processing step needs to reliably produce an intermediate material or product

with acceptable characteristics, according to a consistent and predictable timeline. Within six months, Thompson’s team devel-oped a method to make lomus-tine at a rate equivalent to one dose every two hours using con-tinuous manufacture.

“We first examined the steps that had been published for this compound and selected the routes that seemed most direct and efficient. We then used a high-throughput experimenta-tion (HTE) method to identify the set of preferred conditions for the reactions to make lomus-tine. Next, we used those condi-tions identified by HTE to opti-mize the individual reactions in flow. The final step was ‘telescop-ing’ the reactions, such that the output from the first reactor was fed into a continuous extractor and then into the second reac-tor. The lomustine product was collected and then recrystallized in a batch process to produce highly pure lomustine,” details Thompson. “We were success-ful ... because the pathway was short (two steps) and we were able to balance the needs of the two reactions and integral liquid-liquid separation step.”

The FDA is financially and philosophically committed to advancing CM, as it promises to revolutionize the availability of certain critical treatments. According to an FDA statement issued in February, CM is “a key step towards promoting drug quality and improving the effi-ciency of pharmaceutical manu-facturing. [We are] committed to helping more companies advance these CM platforms, owing to the public health benefits of these more modern approaches. We support the early adopters that are embracing this innovative

technology and we look forward to working with other interested companies.”

Starting with just four inex-pensive commercially available initial materials, the Purdue team prepared lomustine in just nine minutes using a linear sequence of two chemical reac-tions performed separately in two telescoped flow reactors, allowing for rapid manufacture of lomustine while avoiding some of the needed steps for batch processing, thereby sig-nificantly increasing the purity and yield of the active agent. The ability to reduce production costs has the potential to allow for more agile and cost-effective production of many life-saving medicines. The shared goal for CM is to improve manufactur-ing flexibility, enhance quality and uniformity, and reduce costs for patients. CM shows particu-lar promise in personalized and regenerative products aimed at very small patient populations, groups too small to warrant large-scale, batch-processed drug development.

The Purdue researchers, the FDA and others working on drug discovery are heartened by CM’s promise, not just with lomustine, but many other potential prod-ucts. Says Thompson: “One of the most exciting aspects of our combined HTE and continuous synthesis capability is the chance we have to both devote it to the preparation of new lead com-pounds at Purdue, and democra-tize the capabilities of the system to other members of the Purdue synthetic chemistry community. Expansion of these tools to a larger set of users will also teach us the strengths and limitations of these tools.” nEDITCONNECT: E041928

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No pain and a gainPacira acquires MyoScience and its non-opioid pain therapy ioveraºBY KELSEY KAUSTINEN

PARSIPPANY, N.J. & FREMONT, Calif.—Pacira Pharmaceuticals Inc. is moving to expand its port-folio and its foothold in the pain alleviation market with the recent announcement of its pending acquisition of medical technol-ogy company MyoScience Inc. Following the completion of the deal, Pacira will change its name to Pacira BioSciences to represent its more diversified focus, while MyoScience will become a whol-ly owned subsidiary and will be renamed Pacira CryoTech Inc.

Per the agreement, Pacira will pay $120 million in an initial pay-ment, and MyoScience’s sharehold-ers stand to receive up to an addi-tional $100 million in contingent payments if specified regulatory and commercial milestones are met. Pacira expects the transaction to close this April—subject to expi-ration or termination of the Hart-Scott-Rodino Act and other cus-tomary closing conditions—and to be accretive to net income starting in the first half of 2020 and increas-ingly accretive from then on.

“Like Pacira, MyoScience is committed to fighting our nation’s opioid crisis through innovative, opioid-free pain treatments,” David Stack, chairman and CEO of Pacira, said in a conference call about the deal. “We have a strong sense of purpose for our combined assets as we address the opioid epidemic, the public health emergency and we ful-fill the mandate from Governor Christie’s opioid commission and the Health and Human Services taskforce that non-opioid options be available to all patients—in-patients and out-patients—for acute pain.”

The main draw for Pacira in this deal is MyoScience’s ioveraº system, which is a non-opioid treatment that uses cryoanalgesia—intensely focused cold therapy targeted at a specific nerve to block its ability to transmit pain signals—to alleviate pain. Relief is immediate, accord-ing to a press release, and can last up to three months or longer while the nerve regenerates.

“The ioveraº precise cold treat-ment delivers a reversible nerve block through a process called Wal-lerian degeneration. Importantly, the degeneration only involves the nerve axon and its surrounding myelin sheath,” Ron Ellis, senior vice president of strategy and cor-porate development, explained in a conference call. “The endoneurium and other surrounding tissue are

unaffected by the ioveraº focused cold therapy. The results are safe, effective pain relief for three or more months as the signal is not able to conduct along the sensory nerves until the nerve axon is regen-erated, which occurs at a rate of 1 to 2 millimeters per day. So we have a predictable indicator of when nerve function will be restored.”

MyoScience has tested ioveraº in more than 20,000 procedures, and in cases of osteoarthritis of the knee or knee replacement surgery, it has provided decreased knee pain and stiffness, improved physical function, fewer opioid prescrip-tions and faster recovery.

Pacira has its own pain relief product in EXPAREL (bupivacaine liposome injectable suspension), which uses its proprietary Depo-Foam to deliver drugs. DepoFoam encapsulates drugs without affect-ing their molecular structure and releases them over a period of time.

“We are pleased to enter into this transaction and are confident that Pacira is the ideal fit to build the ioveraº franchise, given their commitment to and proven track record of expanding patient access to non-opioid options,” remarked Timothy Still, president and CEO of MyoScience. “This acquisition comes at a time when opioid abuse and addiction has reached epi-demic proportions and alternative approaches to pain management are being mandated. We believe adding ioveraº to EXPAREL-based opioid-sparing protocols will help create an opioid-free perioperative and postoperative experience for many patients.”

On the analyst side of things, some feel that while the deal itself is logical, the price might not be.

“We believe Pacira’s acquisition of Myoscience makes sense, given the opportunity to synergize Iovera and Exparel in the post-surgical pain market while leveraging exist-ing commercial infrastructure,” commented Dewey Steadman, Canaccord Genuity pharma ana-lyst. “That said, we’re a bit disap-pointed the company didn’t provide many financial details to justify the purchase price, but we think over time the acquisition could shift investor focus away from Exparel and the looming threat of competi-tion later this year … Overall, we think there’s a lot of potential for Iovera in postoperative settings and beyond, but given the lack of financial details we are taking a wait-and-see approach to this trans-action.” nEDITCONNECT: E041930

“There are many factors that must be balanced to achieve an efficient continuous manufacturing process for production of a target drug molecule,” according to David H. Thompson of Purdue University’s Center for Cancer Research. “Each step must be evaluated in a multistep drug synthesis to determine those transformations that are best done in flow verses those that are best performed in a conventional reactor.”

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Novartis also showed interest in building its gene therapy portfolio through its acquisition of AveXis. Despite being a field typically asso-ciated with small specialist players, the recent news is a strong sign that big pharma is ready to splash the cash and pay significant premiums to expand its rare disease offering.”

The offer represents a total trans-action value of approximately $800 million, after taking into account expected transaction expenses and anticipated cash at closing. The acquisition of Nightstar is planned to be funded through available cash and accounted for as an acquisition of a business. Biogen expects to complete the acquisition by mid-year 2019.

“Ophthalmology is an emerging growth area for Biogen, and we are excited about the opportunity to work with the talented employ-ees at Nightstar to advance poten-

tially transformative gene therapy programs for rare retinal diseases,” said Michel Vounatsos, CEO of Bio-gen. “With this proposed acquisi-tion, we are continuing to bolster our pipeline and further execute on our strategy to develop and expand a multi-franchise neuroscience pipeline across complementary modalities. Nightstar would accel-erate our entry into ophthalmology by contributing two mid- to late-stage gene therapy assets, with the potential to create long-term share-holder value.”

Nightstar’s lead asset is NSR-REP1 for the treatment of choroi-deremia (CHM), a rare degenera-tive X-linked inherited retinal dis-order which primarily affects males and is caused by loss of function in the CHM gene which encodes the Rab escort protein-1 (REP-1). The REP-1 protein plays a role in intra-cellular protein trafficking, and loss of function in the CHM gene leads to abnormal intracellular protein trafficking and impaired elimina-

tion of waste products from the retinal pigment epithelium and photoreceptors. Initially patients with CHM experience poor night vision, and over time progres-sive visual loss leads to complete blindness.

NSR-REP1 is an AAV vector administered by subretinal injec-tion which provides a functioning CHM gene and expression of the REP-1 protein to restore membrane trafficking and slow, stop or poten-tially reverse the decline in vision. Data from the Phase 1/2 trial of NSR-REP1 demonstrated potential-ly meaningful slowing of decline in visual acuity as compared to natural history, as well as signs of improved visual acuity in some patients. NSR-REP1 is currently being evaluated in the ongoing Phase 3 STAR trial, with data expected in the second half of 2020.

“Both of the lead clinical pro-grams for NITE are intending to treat serious inherited blinding diseases of the eye and both have

established initial proof of concept, but are still two to four years away from commercialization. The most advanced of these programs could launch by 2022, assuming clinical development and regulatory time-lines are maintained. The final profile and potential of these pro-grams will depend on the results of their pivotal trials,” noted a report by SVB Leerink. “We believe the inherent difficulties in patient identification in choroideremia and XLRS, as well as the logistical constraints associated with a sub-retinal injection, may dampen the commercial opportunity for such transformative medicines.”

Nightstar’s second clinical pro-gram is NSR-RPGR for the treat-ment of X-linked retinitis pigmen-tosa (XLRP), also a rare inherited retinal disease primarily affecting males. XLRP is characterized by mutations in the retinitis pigmen-tosa GTPase regulator (RPGR) gene, and a lack of active protein transport in photoreceptors. This

leads to loss of photoreceptor cells, resulting in retinal dysfunction by adolescence and early adulthood, and progressing to legal blindness when patients reach their 40s.

NSR-RPGR is also a subretinal injection of an AAV vector, which provides a functioning RPGR gene and expression of the RPGR protein. The restoration of photo-receptor function is intended to slow, stop or potentially reverse the decline in vision. Phase 1/2 data from the dose escalation por-tion of the XIRIUS trial for NSR-RPGR demonstrated an increase in central retinal sensitivity. The Phase 2/3 dose expansion portion of the XIRIUS trial is currently ongoing.

Nightstar’s preclinical pipeline includes NSR-ABCA4 for Stargardt disease, and potential programs targeting Best vitelliform macular dystrophy (Best disease) and other genetic forms of retinitis pigmen-tosa. nEDITCONNECT: E041928

BIOGENCONTINUED FROM PAGE 35

for pancreatic cancer. This new model was created with the use of HemoShear’s REVEAL-Tx platform and the expertise of co-author Dr. Daniel Gioeli, associate professor of Microbiology, Immunology, and Cancer Biology at the University of Virginia. Dr. Brian Wamhoff, co-founder and head of innovation at HemoShear, took the time to give DDNews a more in-depth look at the work and where it could lead.DDNews: Can you briefly describe the nature of this model, which was described in Lab on a Chip as “a human triculture 3D in-vitro tumor microenvironment system”?Wamhoff: Our research published in the Royal Society of Chemistry’s Lab on a Chip journal focused on our multi-cellular three-dimensional model of the tumor microenviron-ment for pancreatic cancer. This human triculture 3D in-vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemo-dynamics and biological transport with co-cultured human micro-vascular endothelial cells, pancre-atic ductal adenocarcinoma and pancreatic stellate cells. In our research, we demonstrate that sig-nificant tumor cell transcriptomic changes occur in the TMES that correlate with the in-vivo xenograft and patient transcriptome. Treat-ment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients’ clinical responses. Thus, this model provides a unique platform to rigor-ously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.DDNews: How did HemoShear’s

REVEAL-Tx human biology plat-form enable this work?Wamhoff: What is important to note about the HemoShear’s proprietary REVEAL-Tx platform is that this “technology” not only allows us to create a tumor microenviron-ment—the platform combines both biological and computational mod-els of human disease to accelerate discovery of novel targets and suc-cessful new drug treatments. This merging of computational science with meaningful human biological data is a powerful capability.

More specifically in this research, working with our REVEAL-Tx human biology plat-form, we developed the tumor model, which uniquely incorpo-rates multiple human tumor cell types, including endothelial cells, stromal fibroblasts and patient-derived tumor cells that are exposed to mechanical shear forces derived from tumor blood flow to restore the tumor’s physiological environment. Of major signifi-cance, we demonstrated that treat-ment with therapeutically relevant doses of chemotherapeutics in the pancreatic tumor model yields responses paralleling the patients’ clinical responses, which is rarely the case in traditional cell culture and mouse cancer models. DDNews: What are some of the dif-ferences in accuracy between this new model and existing 3D tumor models?Wamhoff: This model appears to more closely replicate the patient transcriptome than either PDXs [patient-derived xenografts] or 2D cultures. The model also pro-vides responses to drugs at con-centrations equivalent to patient doses that reflect patient outcome, which is not possible with PDXs or 2D cultures. However, more research is required to accurately

confirm these differences.DDNews: It was noted that you are adapting the model to explore its potential in immuno-oncology; are there certain types of immune cells in particular that you’re look-ing to integrate first?Wamhoff: In the immuno-oncology area, we are working in collabora-tion with Dr. Dan Gioeli, UVA, School of Medicine Cancer Cen-ter, focusing on CAR T-cells. We have also explored the addition of myeloid-derived cells.

More broadly, there are a breadth of applications for our human tumor platform that uses human primary tumor cells, spanning from target validation to creating patient avatars for efficacy dos-ing, to developing a de-novo tumor microenvironment. For instance, the tumor platform can be part-

nered in multiple ways with mul-tiple partners because there are so many solid tumor cancers. All that to say that we can adapt the model to explore other disease areas and solid tumor cancers that our part-ners and potential partners wish to collaborate on. DDNews: Are there any cancer types that have been particularly difficult to model in the lab so far that you’re hoping will be success-fully recreated with this approach?Wamhoff: To date, we have success-fully validated builds for pancreatic and non-small cell lung cancer. We also have preliminary results with prostate cancer. We have focused on solid tumors, which across the board generally lack predictive in-vitro models. We are optimis-tic that the TMES can be applied to any solid tumor types. In fact,

we have conceptualized using the system for hematologic malignan-cies. And we look forward to forg-ing partnerships with companies who want to apply our platform to accelerate successful cancer drug discovery and ultimately develop more effective treatments for patients. nEDITCONNECT: E041929

Brian Wamhoff, Ph.D., is co-inventor of HemoShear’s technology and was pivotal in the launch of the company’s drug discovery programs in rare metabolic diseases. His efforts have also led to partnerships with Takeda, Horizon Discovery and Carnot Biosciences. In addition to co-founding HemoShear, Wamhoff has also co-founded a number of medical device and therapeutics companies.

Q&ACONTINUED FROM PAGE 35

For a complex disease like cancer, a more accurate look at how a tumor grows and interacts with its surroundings is pivotal. In hopes of answering this need, HemoShear recently announced the publication of research data regarding a multicellular 3D model of the pancreatic tumor microenvironment.

38 DDNEWS | | APRIL 2019 For more information, visit www.DDN-News.comLATE-BREAKING NEWS

Late-Breaking NewsHERE ARE SOME NEWS ITEMS THAT ARRIVED TOWARD THE TAIL END OF THIS ISSUE’S PLANNING AND PRODUCTION PROCESS

Splicing complex on surface of NHL cells provides potential antitumor targetIRVING, Texas—Caris Life Scienc-es, a molecular science innovator focused on “fulfilling the promise of precision medicine,” on March 28 announced the publication of new data in Cell Chemical Biology in a paper titled “Translocation of a Cell Surface Spliceosomal Complex Induces Alternative Splicing Events and Lymphoma Cell Necrosis” that may offer a novel pathway to treat non-Hodgkin’s lymphoma (NHL).

Specifically, the published find-ings show for the first time the identification of a spliceosomal complex on the surface of cancer cells that has potential as a unique antitumor drug target. This com-plex, comprised of proteins typi-cally found in the nucleus or cyto-plasm of cells, was unexpectedly

localized to the surface of the can-cer cell.

The complex was discovered using an NHL-specific single-stranded DNA aptamer, C10.36. The aptamer was discovered by Caris Life Sciences collabora-tors Günter Mayer and Michael Famulok at the Life & Medical Sciences Institute at University of Bonn. Target identification was performed using Caris’ proprietary ADAPT Biotargeting System previ-ously described by Domenyuk et al. in Scientific Reports and Nature Communications.

The results show that when the C10.36 aptamer binds to its target on the cell surface, the complex is translocated into the cell, causing global changes in RNA splicing

(“splicing chaos”) and necrotic cell death. This reportedly represents the first time a spliceosomal com-plex has been identified on the cell surface.

“To our knowledge, this study demonstrates that the C10.36 aptamer specifically recognizes a unique spatial arrangement of a large spliceosomal complex on the surface of NHL cells,” said Dr. Heather A. O’Neill, a senior research scientist at Caris Life Sci-ences and co-lead author of the paper. “We believe that the mis-localization of the complex on the surface of the cell may play a role in driving and/or maintaining the malignant state. For the first time, we have identified a spliceosomal complex on the surface of cancer

cells that may be pursued as a novel drug target.”

“The ability of the aptamer to cause cell necrosis and the pres-ence of the complex on various NHL cells opens two interesting paths of further fundamental and translational research. On the one hand, our findings motivate studies to unravel the biological function of the surface spliceosomal complexes and its role in cancer, but also to investigate the aptamer’s poten-tial as a therapeutic agent,” added Dr. Günter Mayer of the Center of Aptamer Research and Develop-ment at the University of Bonn.

The ADAPT Biotargeting Sys-tem is Caris’ proprietary profiling platform that uses a broad library of synthetically manufactured

molecules (aptamers) that bind to a wide range of biological targets and characterize complex biologi-cal systems in their native state, enabling them to profile biological samples at a systems-wide scale.

“This paper further demon-strates the power of our proprie-tary ADAPT Biotargeting System, which is capable of identifying novel drug targets for therapeutic and diagnostic applications,” said Dr. David Spetzler, president and chief scientific officer of Caris Life Sciences. “Our work with the Uni-versity of Bonn is a prime example of how our use of ADAPT can assist researchers by identifying unique molecular targets for deeper understanding and exploring new approaches to cancer therapy.” n

Beckman Coulter International .........................23 www.beckmancoulter.comBethyl Laboratories, Inc. .....................................15 www.bethyl.comBioIVT ......................................................................25 www.bioIVT.comBMG LABTECH GmbH ......................................1, 40 www.bmglabtech.comCharles River Laboratories, Inc. ..........................2 www.criver.comEssen Bioscience, Inc.,

formerly IntelliCyt Corporation ...................13 www.intellicyt.comEurofins DiscoverX Corporation ..........................7 www.eurofinsus.comHorizon Discovery Ltd ..........................................17 www.horizondiscovery.comISSCR 2019 ..............................................................27 www.isscr2019.orgQuanterix Corporation .........................................39 www.quanterix.comR&D Systems, Inc. .........................................Cover www.RnDSystems.comSLASEurope2019 ...................................................32 www.SLASEurope2019.orgSony Biotechnology, Inc. ......................................9 www.sonybiotechnology.comThermo Fisher Scientific .......................................5 www.thermofisher.com

A D V E R T I S E R ’ S I N D E X

related damage, the researchers say.“One of the issues with aging is

organ dysfunction, accompanied by a decline in the activity of the stem cells that nurture and replenish that organ, so this is a potentially very useful intervention point to either slow or reverse aging,” noted Leonard Guarente, the Novartis Professor of Biology at MIT.

Guarente and Toshimasa Yamau-chi, a professor at the University of Tokyo, are the senior authors of the study, which appeared online in the journal Aging Cell on March 28. The lead author of the paper is Masaki Igarashi, a former MIT postdoc who is now at the University of Tokyo.

Guarente’s lab has long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimu-lated by calorie restriction.

In a paper published in 2016, Guarente and Igarashi found that in mice, low-calorie diets activate sir-tuins in intestinal stem cells, help-ing the cells to proliferate. In their new study, they set out to investi-gate whether aging contributes to a decline in stem cell populations,

and whether that decline could be reversed.

They explored a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had nor-mal levels of intestinal stem cells, and these cells were able to gener-ate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health ben-efits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this

compound in older animals.“That has real implications for

health because just having more stem cells is all well and good, but it might not equate to anything in the real world,” Guarente said. “Knowing that the guts are actually more stress-resistant if they’re NR-supplemented is pretty interesting.”

Guarente says he believes that NR is likely acting through a path-way that his lab previously identi-fied, in which boosting NAD turns on not only SIRT1 but another gene called mTORC1, which stimulates protein synthesis in cells and helps them to proliferate. n

Article edited from the original written by Anne Trafton of the MIT News Office.

Findings suggest that a compound able to boost stem cells in the gut could help protect recipients from age-related intestinal damage.

Study suggests that stimulating stem cells may protect the GI tract from age-related disease.CAMBRIDGE, Mass.—Cells that line the intestinal tract are replaced every few days, a high rate of turn-over that relies on a healthy popula-tion of intestinal stem cells. Mas-sachusetts Institute of Technology (MIT) and University of Tokyo biol-

ogists have now found that aging takes a toll on intestinal stem cells and may contribute to increased susceptibility to disorders of the gastrointestinal tract.

The researchers also showed that they could reverse this effect in aged mice by treating them with a compound that helps boost the population of intestinal stem cells. The findings suggest that this com-pound, which appears to stimulate a pathway that involves longevity-linked proteins known as sirtuins, could help protect the gut from age-

Biologists boost intestinal stem cell populations

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