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01.18JANUARY 2018 : VOLUME 14 : NUMBER 1
CONTRACT SERVICES 31
AI aids efforts in ALSIBM’s Watson validates discovery of five new genes linked to the neurodegenerative diseaseBY LORI LESKO
PHOENIX—Researchers at Barrow Neurological Institute have validated an earlier study, using the artificial intelligence (AI) of IBM’s Watson to verify the discovery of five new genes linked to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.
The latest study results, validated through five different methods, were published in November 2017 in Acta Neuropathologica, in an online manuscript entitled, “Artificial intelligence in neurodegenerative disease research: Use of IBM Watson to identify additional RNAbinding proteins altered in amyotrophic lateral sclerosis.”
“The significance of our work is that it demonstrates that the use of artificial intelligence methodologies for scientific discovery can greatly accelerate the more traditional
laboratorybased research approach,” says Robert Bowser, a professor of neuroscience at Barrow Neurological Institute.
Watson uses machine learning, natural
language processing and other cognitive reasoning technologies and was trained about proteins that researchers already knew were
Novartis eyes nAMDResults from Phase 3 studies support brolucizumab’s less-frequent dosing scheduleBY MEL J. YEATES
EAST HANOVER, N.J.—In late 2017, Novartis announced positive results from two Phase 3 studies of brolucizumab (RTH258) vs. aflibercept. The results of the headtohead trials, HAWK and HARRIER, were presented at the American Academy of Ophthalmology 2017 Annual Meeting. Results showed noninferiority in the primary endpoint, superiority in key retinal health outcomes and longlasting effect in patients with neovascular agerelated macular degeneration (nAMD), a leading cause of blindness.
HAWK and HARRIER are 96week randomized, doublemasked, multicenter studies with more than 1,800 patients across 400 centers worldwide. The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 6 mg and 3 mg versus aflibercept 2 mg in patients with nAMD. The primary efficacy objective of HAWK and HARRIER trials was to confirm that brolucizumab is noninferior to aflibercept in mean change in BCVA from baseline
to week 48. Secondary endpoints include average mean change in BCVA from baseline over the period week 36 to 48, the proportion of patients on a 12week interval at week 48 and anatomical parameters.
Frequent injections into the eye, a standard requirement for nAMD therapies, can be a significant hardship for patients. Brolucizumab is the first and only antivascular endothelial growth factor treatment for nAMD to demonstrate robust visual gains with a majority of patients maintained on a lessfrequent 12week
BARROW CONTINUED ON PAGE 9
NOVARTIS CONTINUED ON PAGE 27
A GalXC far, far awayCollaboration to explore RNA interference therapeutics for liver diseaseBY JIM CIRIGLIANO
INGELHEIM, Germany & CAMBRIDGE, Mass.—Global researchdriven pharmaceutical company Boehringer Ingelheim (BI) has announced a research collaboration and license agreement with Dicerna Pharmaceuticals, a developer of investigational RNA interference (RNAi) therapeutics and inventor of the GalXC technology platform. The partnership will allow a joint effort to develop novel GalXC RNAi therapeutics for the treatment of chronic liver diseases, with an initial focus on nonalcoholic steatohepatitis (NASH).
The collaboration combines BI’s capabilities in drug discovery, expertise in the cardiometabolic space and proven commercial experience with Dicerna’s GalXC technology
Telemetry device advances metabolic disease research .............................................18More trials, more data sources, more problems ..........26On the cutting edge.............................................................33
SHOW PREVIEW:
SLAS 2018Society for Laboratory Automation and Screening heads to San Diego for annual meeting
20
WHAT’S INSIDEDISCOVERY 6
TOOLS & TECHNOLOGY
PRECLINICAL 16
RESEARCH & DEVELOPMENT 12
CLINICAL TRIALS 24
DIAGNOSTICS 28
BUSINESS & GOVERNMENT POLICY 33
MARKET NEWS 3EDITORIAL/COMMENTARY 10AWARDS & HONORS 36ONLINE 37PEOPLE & PROMOTIONS 37 LATE-BREAKING NEWS 38
THE HUNT FOR BIOMARKERS HAS NO PEER
See the back cover.
GALXC CONTINUED ON PAGE 15
Chronic liver disease will be the focus of a therapeutic collaboration between Boehringer Ingelheim and Dicerna Pharmaceuticals, a developer of investigational RNA interference therapeutics and inventor of the GalXC technology platform.
“While the primary endpoint of the trial was non-inferiority ... superiority was shown in three secondary endpoints that are considered key markers of nAMD disease,” according to a Novartis spokesperson speaking about a trial of brolucizumab vs. aflibercept.
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“The significance of our work is that it demonstrates that the use of artificial intelligence methodologies for scientific discovery can greatly accelerate the more traditional laboratory-based research approach,” says Robert Bowser, a professor of neuroscience at Barrow Neurological Institute.
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For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 3MARKET NEWS
LONDON—Data and analytics company Glo-balData has commented in recent months on paradigm shifts in a few therapeutic markets, most recently noting that Amgen’s erenumab is poised to become the first calcitonin gene-related peptide (CGRP) on the market for preventing migraine.
It made that observation in the wake of the biopharma company publishing the results from its Phase 3 trial STRIVE, which evalu-ated the efficacy of the drug erenumab in the treatment of episodic migraine. Data showed that the CGRP monoclonal antibody (mAb) delivered significant differences vs. the pla-cebo in all endpoints.
“A large proportion of migraines are inade-quately treated, this represents one of the larg-est unmet needs in the market. Erenumab is targeting this unmet need,” commented Rhael Maladwala, a GlobalData healthcare analyst.
Those receiving the 140 mg dose of the drug experienced a 50 percent reduction in the number of migraine days, compared to 26.6 percent reduction in the placebo group. Patients also reported significant improve-ments when assessing the impact of migraine on their lives when receiving erenumab.
According to GlobalData, key opinion leaders have expressed the huge potential for this class of drugs, and the analytics firm pre-dicts that after an initially slow uptake, this CGRP mAb will generate combined sales of $4 billion for the migraine market by 2026—which would make Amgen a major driver of growth in the migraine space.
However, the cost of CGRPs, which are estimated to be $8,000 to $9,000 per year,
might prevent their uptake as they may not be reimbursed by insurance companies.
“Once approved, the CGRP mAbs would initially be reserved for the most severe cases. With more time and physician experience, CGRPs would however be prescribed to a higher number of patients,” said Maladwala.
C. difficile vaccineIn slightly earlier prognostic news from GlobalData, the issue was not of a single market mover but of one company’s loss being others’ gain—specifically, the discontinuation of Sanofi’s Clostridium difficile vaccine program presents an opportunity for Pfizer and Valneva, observed GlobalData.
On Dec. 1, 2017, Sanofi Pasteur announced
its intention to discontinue the Phase 3 development program for its C. difficile vaccine. The vaccine had been on track to become the first option available globally for the prevention of C. difficile, which GlobalData estimated could reach peak annual sales of around $400 million.
As GlobalData noted, “Sanofi’s decision to cancel the vaccines development program will be interesting news to Pfizer and Valneva, who both have their own vaccines in late-stage clinical development.”
Sanofi’s C. difficile vaccine was set to be the first prophylactic option to be approved for the prevention of CDIs. But with the cancellation of Sanofi’s vaccine program, Pfizer’s vaccine, PF-06425090, is now set
to be the first prophylactic option for CDIs. PF-06425090 is currently being investigated in a 16,000 participant Phase 3 trial, which has a primary completion date of September 2020.
Thomas Moore, a healthcare analyst at GlobalData, noted: “The majority of major global healthcare markets have seen a gradual increase in the incidence of CDIs over the last 20 years, increasing the burden of the disease, and driving a high need for prophylactic options to reduce the risk of infection in vulnerable patients. If the Phase 3 efficacy endpoints for PF-06425090 are met, GlobalData expects strong uptake for this product, driven by Pfizer’s previous experience manufacturing and distributing vaccines.”
French firm Valneva also has a vaccine in clinical-stage development for CDIs, known as VLA84. From a developmental standpoint, VLA84 sits behind Pfizer’s vaccine, but its contrasting mechanism of action could give it an advantage when it comes to successfully meeting Phase 3 trial endpoints.
However, Moore noted: “The size and experience of Valneva make it unlikely that the company could effectively market this product on its own, making its success heav-ily reliant on securing a licensing deal with big pharma.”
Key opinion leaders interviewed by GlobalData believed that a vaccine for CDIs would be well received by physicians due to the high levels of unmet need for products to lower the incidence of this infection. However, they did have some concerns over
Therapies and companies making major moves in various segments
Mergers and acquisitions may be set for an upswingLONDON, BOSTON, TOKYO & SAN FRAN-CISCO—In early December, EP Vantage, the editorial arm of Evaluate Ltd., noted that the upward momentum seen in the pharma and biotech sectors during 2017 looks set to continue into 2018, with more novel medicines set to hit the market and investor support for the industry remain-ing strong.
According to EP Vantage, “[The] cur-rent business-friendly stance at the FDA is unlikely to change next year, while merg-ers and acquisitions (M&As) could see an uptick, driven by big pharma and big biotech’s need to re-stock pipelines and U.S. tax reforms.”
The coming year will also test the com-mercial expectations that have been hung on novel therapies like CAR-T and gene therapy, which are being launched into increasingly into cost-sensitive markets. Important clinical readouts from the field of immuno-oncology, where asset values remain very high, will be closely watched, all of which will help set the tone for investors throughout the year, according to EP Vantage.
“Venture capital funds are very well stocked going into 2018, and both public and private investors look set to remain supportive of innovative, early-stage drug developers,” says Amy Brown, author of the “Pharma & Biotech 2018 Preview” report from which these opinions stem. “However there is evidence that expec-tations have got ahead of themselves in certain areas, particularly in immuno-oncology. To keep investors on side next year the industry needs to deliver some big pipeline wins, and important new drug launches need to perform.”
Some highlights of the report:■■ M&A activity expected to climb after
a slow 2017—U.S. tax reform could be a deciding factor for big deals
■■ Another big year is predicted for ven-ture financing, as crossover funds return and push 2017 toward a record
■■ The initial public offering window is expected to remain open to cash-up pri-vate companies
■■ Gilead’s new HIV triplet is the biggest potential new drug launch of 2018, with 2022 sales seen reaching $5 billion
■■ Abbvie’s Humira will be biggest sell-ing drug in 2018, with global sales topping $20 billion
■■ Merck’s Keytruda will add the most new sales next year, for $2.3 billion
■■ Another strong year is expected for licensing transactions in 2018, with a pickup in activity in 2017 set to continue
■■ The focus on immuno-oncology set to continue with new checkpoint targets moving through the clinic
■■ Drug pricing debates in the United States are expected to ease, but people keep an eye on trends at the state level
Evaluate Ltd. is a provider of commercial intelligence, including product sales and consensus forecasts, for commercial teams and their advisors within the global life-sciences industry. Given the EP Vantage take on M&As, it is worth noting some thoughts from Mergermarket, an Acuris company, which released in
November its global M&A roundup report for the pharma, medical and biotech (PMB) sector for the third quarter of 2017. A few key findings included:
■■ Global PMB M&A totaled $207.6 billion across 1,040 deals for the first three quarters of 2017, falling 9.9 percent in value with 106 fewer deals compared to that seen during the same period last year
■■ Despite the slight dip in activity, the sector still commanded a healthy 9.4-per-cent market share of global M&A values
■■ Gilead’s $10.2-billion takeover of Kite Pharma was the largest deal of the third quarter, and its CAR-T treatment, Axi-cel—recently approved by the FDA—means that that Gilead stands as the only manufacturer of the complex treat-ment, possibly giving it a similar pricing power that it found itself having after its $11-billion acquisition of Pharmasset five years ago when it came into possession of hepatitis C drug Solvadi. ■
To obtain the EP Vantage report, go to www.evaluategroup.com/PharmaBiotech2018Preview
Merger and acquisition activity is expected to climb after a slow 2017—U.S. tax reform could be a deciding factor for big deals.
MOVES CONTINUED ON PAGE 4
Amgen’s erenumab could become a game-changer and a market-mover in the area of migraine, as it is poised to become the first calcitonin gene-related peptide on the market for preventing migraine.
MARKET NEWS4 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
how easy it would be to identify appropriate patient groups to receive vaccination, and they did not envision a blanket vaccination program for all patients above a certain age.
Non-insulin diabetes treatmentsIn fall of 2017, GlobalData also commented on the changing face of the diabetes market, saying that new diabetes therapeutics are set to steal ground from insulin therapies.
The company pointed out that the inci-dence of diabetes mellitus (DM)—and most notably type 2 diabetes mellitus (T2DM)— which accounts for 90 to 95 percent of all DM cases, is growing rapidly on a global scale.
DM is a generalized term used to define multiple diseases with different etiologies characterized by chronic hyperglycemia resulting from insufficient synthesis, secretion or signaling of insulin. The main role of insulin is to facilitate the absorption of glucose into skeletal muscle and fat cells following food digestion, which provides these cells with a source of energy for metabolism, and also reduces the concentration of glucose in the blood. Insulin signaling also has important roles in many processes including growth, development and controlling inflammation.
As GlobalData notes, the DM market has undergone a dynamic shift over the past decade, primarily due to the entry of three new non-insulin drug classes for T2DM: glucagon-like peptide-1 (GLP-1) receptor ago-nists, dipeptidyl peptidase 4 (DPP-4) inhibi-tors and sodium-glucose linked transporter 2
(SGLT-2) inhibitors. Increased market diver-sification is expected to continue throughout the forecast period due to patent expiries for major insulin products and increased uptake of non-insulin drugs.
“In 2016, the top five products, all of which are insulin products, commanded 47 percent of the market by sales. By 2023 the top 10 products are expected to occupy 42 percent market share, many of which will be non-insulin products,” said Oliver Mundell, a healthcare analyst at GBI Research, which is a GlobalData firm.
Alongside rising prevalence, market diversi-fication will be a key driver of growth, with the DM market projected to increase from $97.4 billion in 2016 to $158.8 billion in 2023, at a compound annual growth rate of 7.2 percent.
“Competition will intensify over the fore-cast period as more companies enter the DM market space. However, Novo Nordisk, which is currently the leading player in terms of market share, is expected to maintain its position throughout the forecast period,” Mundell maintained.
Despite declining revenues for high-grossing products such as Levemir (insulin detemir), more recent market additions such as Tresiba (insulin degludec), as well as the upcoming pipeline products semaglutide and oral semaglutide, are expected to more than compensate.
Mundell added: “The development of extremely long release insulin products and a fully artificial pancreas using both insulin and glucagon will shape the future of the DM market beyond the forecast period as ease of administration and safety is increased.” ■
NGS informatics market worth 1.3 billion by 2022LONDON—In late November, the report “NGS Informatics Market- Global Opportu-nity Analysis And Industry Forecast (2017-2022)” from Meticulous Research stated that the global next-generation sequencing (NGS) informatics market will grow at a compound annual growth rate of 22.1 percent during the forecast period to reach more than $1.3 billion by 2022.
The NGS informatics market is driven by the reduced cost of DNA sequencing with the use of NGS informatics; various government initiatives and rising clinical applications; substitution of microarray technology by NGS; continuous innovation and developments in technology; and increasing investments and funding for life-sciences, pharmaceutical and biotechnology research.
Moreover, growing investments in personalized medicine and increasing initiative from governments to promote use of NGS informatics is also propelling the growth of the market globally. However, lack of accuracy and standardization of technology, ethical challenges and reduced grants and funding from government in various countries are expected to inhibit the growth of NGS informatics market to some extent.
North America held the major share in the global NGS informatics market, followed by Asia-Pacific and Europe. Increasing demand for clinical information technology, various government initiatives and availability of funds and promotion of NGS by research laboratories and academicians are the major factors fueling the growth of NGS informatics market in North America. In addition, the presence of many bioinformatics players in this market improves the product accessibility which further propels the growth of the market.
The key players in the global NGS infor-matics market are Illumina Inc. (U.S.), Thermo Fisher Scientific Inc.(U.S.), Qiagen N.V. (The Netherlands), Bina Technologies (U.S.), PerkinElmer Inc. (U.S.), BIOVIA (U.S.), Amazon Web Services LLC (U.S.), IBM Corp. (U.S.), GENEWIZ Inc.(U.S.), Bei-jing Genomics Institute (China), BioTeam Inc. (U.S.), Biomatters Ltd. (New Zealand), DNAnexus Inc. (U.S.), DNASTAR Inc. (U.S.), Eagle Genomics (U.K.), Edge Biosystems (U.S.), Genomatix AG (Germany), Partek Inc.d (U.S.), PierianDx Inc. (U.S.), Real Time Genomics Inc. (New Zealand), SoftGenetics LLC (U.S.) and Sapio Sciences (U.S.). ■
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Series A to help finance new class of immune cell therapiesCAMBRIDGE, Mass.—In mid-November, Torque, an immuno-oncology company devel-oping its Deep Primed brand of cell therapies for evoking immune responses in the tumor microenvironment, announced the launch of its technology platform to create a new class of immune cell therapeutics to treat cancer. This was financed with $25 million in Series A capital by Flagship Pioneering. The Torque platform reportedly makes it possible to anchor powerful stimulatory cytokines, antibodies and small molecules directly to immune cells to direct their activity and increase their efficacy and durability in the “hostile” tumor microenvironment, without systemic exposure.
“The tumor microenvironment shuts down immune cells, protecting tumors from their attack,” said Dr. Doug Cole, lead director of Torque and managing partner of Flagship Pioneering. “Torque is engineering immune cells with the tools to fight back to overcome this immunosuppression. This directed, precisely controlled approach goes far beyond what can be achieved using either gene editing or genetic engineer-ing alone.” ■
Funds advance PhaseBio orphan cardiovascular pipelineMALVERN, Pa.—Late November saw Phase-Bio Pharmaceuticals, Inc. a clinical-stage biopharmaceutical company developing therapies for the treatment of orphan dis-eases, announce that it had secured $15.6 million in funds to support the clinical advancement of its expanded pipeline.
PhaseBio entered into a $7.5 million term loan facility with Silicon Valley Bank, subject to funding in up to three tranches. PhaseBio received the initial tranche of $3.5 million upon execution of the loan agreement. The remaining fund-ing under the term loan may be drawn, at PhaseBio’s option, in $2 million incre-ments subject to certain milestones. In addition, PhaseBio has drawn down the remaining $8.1 million second tranche
of an existing convertible note financing agreement entered into in January 2017.
“In addition to the commitment from our current investors, this new loan facil-ity strengthens our financial position in support of recently reported milestones, including the dosing of our lead therapy PB1046 in an exploratory study for pul-monary arterial hypertension and the diversification of our pipeline with the in-licensing of PB2452, a reversal agent for ticagrelor,” said John Sharp, chief finan-cial officer of PhaseBio. “[We] anticipate that this extended runway will enable us to further deliver on our goals, by support-ing the initiation of a Phase 2 study for PB1046 and a Phase 1 study for PB2452, both planned for 2018.” ■
MOVESCONTINUED FROM PAGE 3
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DISCOVERY6 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
METTL3 tagged as new AML target
CAMBRIDGE, U.K.—The journal Nature recently published data from STORM Therapeutics that links an essential RNA-modifying enzyme to acute myeloid leukemia (AML). The study identified the METTL3 gene as a new drug target for the dis-ease. Inhibition of this gene was found to destroy mouse and human AML cells without damaging healthy blood cells, and METTL3 is necessary for AML cell survival and also regulates other leukemia genes. The results came from research STORM conducted together with Wellcome Trust Sanger Institute, The Gurdon Institute and Depart-ment of Pathology at the University of Cambridge and Cold Spring Harbor Laboratory.
Keith Blundy, CEO of STORM Therapeutics, said: “STORM leads the field of harnessing the power of RNA epigenetics as a new area of impor-tant biology. Our ambition is to become a world leading therapeutics company tackling diseases through modulating RNA modifying enzymes. Pub-lication of these data, in such a prestigious journal as Nature, is validation of the world class science on which the Company was founded.”
A new ‘template’ for collaborationPLZEN, Czech Republic & AUSTIN, Texas—AbCheck s.r.o. and Molecular Templates Inc. have teamed up in a strategic collaboration, under which AbCheck will leverage its proprietary AbSieve discovery platform to deliver antibodies against oncology targets chosen by Molecular Templates. In particular, AbCheck will initially bring to bear its expertise in phage/yeast display through the AbSieve platform. Financial details were not released.
“Molecular Templates has one of the most exciting platforms in immuno-oncology, with the capabilities to deliver toxins to cancer cells in a way that has not previously been possible. We are pleased to enter into this new collabo-ration to support lead discovery for Molecular Templates’ next-generation Engineered Toxin Bodies,” Dr. Volker Lang, managing director of AbCheck, said in a press release.
IN THIS SECTIONNeurologyAI aids efforts in ALS (BARROW from cover) .............................. 9
OncologyA new friend in AMIGO2? ........................ 6A new ‘template’ for collaboration .......... 6Compugen and JHU chart a new course ................................... 6METTL3 tagged as new AML target ........ 6
Solubility/ Development issuesSubstance solubility ................................. 6
A new friend in AMIGO2?Mount Sinai details the potential of transmembrane gene for halting melanoma growthBY KELSEY KAUSTINEN
NEW YORK—While melanoma is not the most common form of cancer—that distinction belongs to breast or lung cancer—it remains one of the most aggressive and deadly forms of skin cancer. Melanoma accounts for just 1 percent of skin cancers, according to the American Cancer Society, but incidence
SUBSTANCE SOLUBILITYSPA could expedite drug developmentBY ILENE SCHNEIDER
HELSINKI, Finland—Drug discovery is a slow and costly process—at present, discovering and developing a new drug can cost more than $1 billion and take 13.5 years on average. At the early stages of drug discovery, there are thousands of molecules to be studied, but only small amounts of the substances available.
Information about the solubility of the substance is a critical success factor for drug development. After potency, solubility is one of the most important properties of a drug. Solubility is crucial because a substance that does not dissolve will not enter the bloodstream and cannot be effective in the body. In the absence of measuring the solubility of small amounts, the early stages of drug discovery have been focusing on the pharmacological and toxicological effects of the drug candidate.
Researchers at the University of Helsinki say that they have developed a new method to determine the solubility of pharmaceutical substances with samples 1,000 times smaller
than ever before. The technique could have a great impact at the beginning of the drug development processes, providing more
HELSINKI CONTINUED ON PAGE 7
Compugen and JHU chart a new courseCollaboration researches first-in-class cancer therapyBY JENNIFER CLIFFORD
HOLON, Israe l—Recent ly, Compugen Ltd. disclosed new data demonstrating the potential of CGEN-15032 as a target for the development of first-in-class cancer therapy, as well as the extension of its multi-year immuno-oncology research collaboration with Johns Hopkins University (JHU) School of Medicine. The data were the subject of both an oral and a poster presentation at the 3rd Annual CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, in Mainz/Frankfurt, Germany.
The data generated as part of this collaboration under the
direction of Dr. Drew Pardoll, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns
COURSE CONTINUED ON PAGE 8 MELANOMA CONTINUED ON PAGE 8
Researchers at the University of Helsinki say that they have developed a new method to determine the solubility of pharmaceutical compounds with samples 1,000 times smaller than ever before.
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Compugen recently shared data about the potential of CGEN-15032 as a first-in-class cancer therapy, as well as the extension of its multiyear immuno-oncology research collaboration with Johns Hopkins University School of Medicine.
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While melanoma is not the most common form of cancer, it remains one of the most aggressive and deadly forms of skin cancer.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 7DISCOVERY
information with smaller samples and enabling faster development of new drugs.
“Single Particle Analysis, SPA, is the world’s first method for accu-rately measuring solubility from very small amounts of a substance,” according to a news release. “It is both significantly more precise and significantly faster than cur-rent technologies used in drug development. While other current methods measure how much of the substance has been dissolved in the liquid, this method turns the pro-cess around: a computer program analyzes microscope images to see how much the solid dissolving par-ticle has diminished.”
Postdoctoral researcher Sami Svanbäck developed the innovation in his doctoral dissertation in Prof. Jouko Yliruusi’s research group at the University of Helsinki’s Faculty of Pharmacy. The idea originally arose from theoretical musing and the hypothesis that the dissolution of a substance could be determined by means of machine vision, from individual particles. This led to the development of the method and the instrument.
“SPA is a unique method based on optical shape recognition, and therefore requires no complicated chemical analyses or understanding of the chemical structure of the substance,” Svanbäck explained. “SPA uses machine vision and optical shape recognition to operate on particles that are invisible to the human eye. SPA focuses on the physical size. As a particle diminishes, we can determine how fast it dissolves. And best of all, SPA is appropriate for most substances, not just pharmaceuticals.”
The SPA method enables the determination of a drug’s solubility in the drug discovery process. It examines very small amounts of substance to help find the most viable candidate for further development. SPA is a multidisciplinary combination of physical chemistry, optics, fluidics, machine vision, engineering and software design.
Svanbäck believes that SPA is at the “cutting edge of personalized medicine,” noting that “In the near future, all patients will receive the medication and dosage specifically tailored to them. For this reason, it must also be possible to predict and change the solubility and release of each drug in the body of the individual. Here, SPA could help by providing extensive solubility data quickly and precisely.”
After successful proof-of-concept studies with some of the largest pharmaceutical companies in the world, Yliruusi’s team is ready to launch its start-up company in January 2018. The patent application is currently in
HELSINKICONTINUED FROM PAGE 6
Bioscience Solutions
©2017 Lonza. All trademarks belong to Lonza or its affiliates. The information contained herein is believed to be correct. No warranty is made, either expressed or implied.
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the international stage.The other founders of the
start-up include Yliruusi from the Faculty of Pharmacy, who has extensive experience in drug discovery, having participated in bringing more than 200 pharmaceutical products to market, and Kari Jussila, business world and technology professional. Start-up investor Harry Santamäki and product development guru Ville Voipio will be serving as advisers.
Svanbäck summarized, “Single
particle analysis offers a completely new way to address the central chal-lenges of drug discovery: expense and duration. SPA can significantly speed up early-stage decision-mak-ing by providing crucial—and pre-viously unattainable—information about substances in development, making SPA the missing link of drug discovery. SPA thus enables holistic drug development based on both pharmacology and physi-cal chemistry.” nEDITCONNECT: E011804
“Single particle analysis offers a completely new way to address the central challenges of drug discovery: expense and duration. SPA can significantly speed up early-stage decision-making by providing crucial—and previously unattainable—information about substances in development, making SPA the missing link of drug discovery.”Sami Svanbäck of the University of Helsinki
DISCOVERY8 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
rates have been on the rise for the past 30 years. The society reports that 87,110 new melanoma cases were expected to be diagnosed in 2017, with 9,730 deaths attributed to this cancer type.
Though a variety of treatment options exist, from resection surgery to chemotherapy, melanoma’s tendency to metastasize and spread rapidly means that there is always room for new and more effective therapies.
A study led by Mount Sinai scientists might have a new target for such thera-pies—or rather, two targets: a gene called AMIGO2 and its partner gene, PTK7. Prior to this study, little was known about the role either gene plays in cancer, but
now it has been discovered that both are required for melanoma cells to grow and spread. The study in question was pub-lished in Molecular Cell.
“Melanoma is the most aggressive form of skin cancer, affecting more and more patients,” said Dr. Emily Bernstein, senior author of the study and associate professor of oncological sciences and dermatology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “While immunotherapy and targeted therapies have significantly improved the outcome for some metastatic melanoma patients, they have had success in a small subset of patients and can cause significant toxic side effects. Thus, their limitations underscore the need for new therapies, highlighting the importance of this research’s discovery of novel targets.”
AMIGO2 is “a member of the Amphoterin-induced gene and ORF family,” the Molecular Cell paper notes. Additionally, the gene was recently reported to be “a pro-survival factor in endothelial cells subjected to hypoxia, thus playing a key role in the vasculature.” As cancer cells exist in hypoxic environments and often trigger angiogenesis to bring more blood flow to tumors, a target linked to hypoxia is promising for cancer treatment.
This revelation came about thanks to the team’s study of bromodomain and extraterminal (BET) proteins, which regulate AMIGO2 and gene expression in cancer. As reported in the paper, “Our groups and others reported that BRD2 and BRD4 [members of the BET family] are overexpressed in melanoma tissues and are essential for tumor maintenance. Silencing of BRD2 and BRD4, as well as BET inhibition, impairs melanoma
growth, suggesting that BETs regulate pro-proliferative and/or survival genes.”
Based on these results, the team performed a loss-of-function screen in a subset of genes “that are significantly upregulated relative to normal human melanocytes, in order to identify melanoma pro-tumorigenic factors,” the authors noted in the paper. That led them to discovering AMIGO2 and its upregulation in melanoma cells, while mass spectrometry let them identify PTK7 as also being necessary for melanoma survival.
As melanoma develops, AMIGO2 lev-els increase; by silencing the function of AMIGO2, cancer growth is notably slowed. As AMIGO2 regulates PTK7 function, which also plays a role in melanoma cells’ growth and survival, inhibiting AMIGO2 has double the impact in inhibiting cancer
growth, so to speak. Both genes are located on the membrane of melanoma cells.
“We assessed AMIGO2 expression by qRT-PCR in a panel of melanoma cell lines and [normal human melanocytes] and found that AMIGO2 is higher in more melanomas irrespective of geno-type. AMIGO2 is also upregulated at the mRNA and protein levels in patient-derived melanoma short-term cultures,” the authors wrote.
“Our data indicate that AMIGO2 is sensitive to [BET inhibitors], displays increased expression in melanoma tissues and acquires BET-regulated [super-enhancers] in melanoma … Our study further illustrates the value of leveraging the BETi-associated transcriptome as an effective strategy to identify pro-tumorigenic genes and therapeutic targets in melanoma,” they continued.
Fortunately, some work has already been done in exploring PTK7 as a drug target: therapies against this gene—specifically, antibody-drug conjugates (ADC)—have already undergone successful Phase 1 testing in clinical trials of solid tumors. The results were reported in a Science Translational Medicine paper published in January 2017, titled “A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.” When testing their PTK7-targeted ADC against patient-derived xenografts, mouse models of triple-negative breast cancer, ovarian cancer and non-small cell lung cancer, the ADC “induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of [tumor-initiating cells].” nEDITCONNECT: E011806
Hopkins and chairman of Compugen’s scientific advisory board, demonstrate the target’s immunomodulatory effect and its effect on tumor growth. The collaboration was initially announced in December 2014, and it will be expanded to include new additional targets discovered by Compugen that have the potential to serve as a basis for the development of cancer immunotherapy treatments.
Dr. Anat Cohen-Dayag, president and CEO of Compugen, said, “The data we achieved with CGEN-15032, together with JHU, exemplifies the tremendous value of our collaboration, providing us with access to world-class immuno-oncology knowledge and expertise to successfully develop our immuno-oncology programs and accelerate their path towards future human testing.”
While antibody blockade of CTLA4 and PD-1 immune checkpoints has emerged as a successful treatment option for cancer patients, most do not experience sustained benefits, pinpointing a need for additional immune checkpoints. CGEN-15032, a novel myeloid and epithelial immuno-oncology target which may serve as an immuno-sup-pressive target within the tumor microenvi-
ronment was discovered by the company’s immune checkpoint discovery platform, which also served as the cornerstone for the identification of TIGIT and PVRIG, two novel immune checkpoints which are currently in preclinical development by Compugen.
Data gathered from research on both human and mice in in-vitro experimental systems suggest that CGEN-15032 may serve as an immuno-suppressive component of the tumor microenvironment, and that drugs inhibiting CGEN-15032 either alone or in combination with checkpoint inhibitors may activate anticancer immune responses. Ectopically expressed CGEN-15032 dampened anti-melanoma activity of tumor-infiltrating lymphocytes, derived from melanoma patients. In line with the effect observed in human system, overexpression of murine CGEN-15032 in artificial antigen-presenting cells resulted in reduced activity of TCR-transgenic DO11.10 T cells. These functional data, in
conjunction with the expression of 15032 on myeloid and tumor cells, suggest that 15032 is a ligand and part of a novel pathway that inhibits T cell function.
To study the immuno-modulatory function of CGEN-15032 and its role in anticancer immunity, researchers generated CGEN-15032 knock-out mice. MC38 tumors grew slower in these relative to wild-type mice. Furthermore, a combinatorial treatment of CGEN-15032-deficient mice with anti-PDL1 antibody resulted in tumor growth inhibition compared with anti-PDL1-treated wild-type mice.
The next step, according to Dr. Yona Geffen, Compugen’s vice president of research and validation, is to “Perform mechanistic studies in order to shed more light on the biological significance and the mechanism of action. These studies are being conducted under the multiyear collaboration with Prof. Drew Pardoll’s lab at the Johns Hopkins University and Dr. Miriam Merad’s lab at the Icahn School of Medicine at Mount Sinai in New York. Mainly, these studies will be focused on in-vivo studies and expression in clinical samples.”
The Mount Sinai collaboration in question is a multiyear cancer immunotherapy research agreement under Merad’s direction.
Geffen tells DDNews: “This collaboration focuses on the research and target validation of selected myeloid candidates discovered by Compugen for their potential to serve as a basis for cancer immunotherapy treatments, including the validation of their role in innate immunity and involvement in tumor biology.”
“Myeloids are a newly rising field in cancer immuno-therapy that is receiving growing interest and investment from both established pharma and biotech companies,” she continues. “These myeloid target pro-grams affect T cell immunity through vari-ous immunosuppressive mechanisms, and therefore have the potential to serve as the basis for the next wave of cancer immuno-therapies. These targets may offer a compli-mentary strategy to that of checkpoint inhibi-tors, and may provide treatment solutions for non-responsive or relapsing patients. A limited number of known myeloid targets are currently pursued in clinical trials, with only initial efficacy results presented to date.” nEDITCONNECT: E011805
COURSECONTINUED FROM PAGE 6MELANOMA
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Pictured here is the Mount Sinai Medical Center. A Mount Sinai team recently identified two genes that play a role in the growth and spread of melanoma cells.
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Compugen and Johns Hopkins University are building on the momentum of positive data regarding CGEN-15032 in cancer with the extension of their research collaboration. Pictured here is a Compugen scientist.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 9DISCOVERY
The results were “groundbreaking,” according to Bowser.
“Further validating and expanding on our earlier findings has been exciting because in research of this nature, time is of the essence,” Bowser tells DDNews. “We could have individually looked at the 1,500 pro-teins and genes, but it would have taken us much longer to do so. These findings inspire hope that, with this technology, we may someday identify new and more effective treatments for ALS.”
In 2011, IBM Watson showed off its skills by competing against human contestants on Jeopardy—and won. Watson for Drug Discovery launched in August 2016, work-ing with clients and partners on a variety of research centered on neurodegenerative diseases such as ALS, Parkinson’s disease, Alzheimer’s disease and more. On Dec. 14, 2016, Barrow announced that Watson had performed a “revolutionary study” which identified new genes linked to ALS discov-ery, giving researchers new insights. This
study was validated the following November.A fatal neurological disorder affecting
more than 220,000 patients worldwide, ALS has no cure and few treatments. It is a progressive and degenerative disease in which the cells that control voluntary mus-cle movements die, leading to paralysis and ultimately, death, Bowser explains. Scientists don’t yet know what causes ALS, and there is just one FDA-approved medication for the disease that is only marginally effective. Most individuals die from ALS within three to five years from the onset of symptoms, and approximately 6,000 people are diagnosed with ALS every year.
More than 30 genes have been linked to ALS, and mutations in the 11 genes that encode RNA binding proteins cause familial forms of ALS. These RNA binding proteins play a critical role in how genes encoded within the DNA in every cell are converted to the proteins that perform all the functions within a cell.
“We are currently performing additional
laboratory research studies to explore how the top genes/proteins identified by Watson contribute to motor neuron degeneration,” Bowser comments. “In addition, we are exploring whether any genetic alterations of the Watson identified RNA binding proteins occur in the ALS patient population.
“The goal is to use our new knowledge to define specific molecular mechanisms that can be targeted for drug development.”
The Barrow laboratory studied whether IBM Watson could accelerate the identification of additional RNA binding proteins (RBPs) linked to ALS by helping scientists focus research efforts on the proteins that Watson ranked high and predicted to be altered in ALS.
“Overall, we successfully used IBM Watson to help identify additional RBPs altered in ALS, highlighting the use of artificial intelligence tools to accelerate scientific discovery in ALS and possibly other complex neurological disorders,” the authors of the Acta Neuropathologica manuscript conclude. nEDITCONNECT: E011801
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related to the disease using data, as well as all published research information surround-ing ALS.
“The identification of additional genes/proteins for ALS can take years since we don’t know where to focus our research efforts,” Bowser says. “And the use of Watson for Drug Discovery quickly provided insight into which genes/proteins to further explore and validate.”
Considered one of the nation’s top ALS researchers, Bowser, along with his team, provided a list of 11 RNA binding proteins with known mutations that cause ALS. Wat-son used the list of proteins and cross-ref-erenced medical literature from 28 million MEDLINE abstracts to rank order all other 1,500 RNA binding proteins encoded by the genome to attempt to identify new RNA binding proteins linked to ALS.
The research team validated the top 10 RNA binding proteins using five different methods that included use of patient tissue samples and patient-derived stem cells dif-ferentiated into motor neurons. Researchers also examined a smaller set of RNA binding proteins near the bottom of the list to demon-strate that any changes detected in the top 10 were not observed for those at the bottom of the list, demonstrating the ability of Watson to correctly predict RNA binding proteins linked to ALS.
BARROWCONTINUED FROM PAGE 1
“Overall, we successfully used IBM Watson to help identify additional RBPs altered in ALS, highlighting the use of artificial intelligence tools to accelerate scientific discovery in ALS and possibly other complex neurological disorders.”Authors of “Artificial intelli-gence in neurodegenerative disease research” in Acta Neuropathologica
The artificial intelligence powers of IBM’s Watson went to work on the discovery of five new genes linked to amyotrophic lateral sclerosis in research work by the Barrow Neurological Institute.
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“The identification of additional genes/proteins for ALS can take years since we don’t know where to focus our research efforts,” says Robert Bowser, a professor of neuroscience at Barrow Neurological Institute. “And the use of Watson for Drug Discovery quickly provided insight into which genes/proteins to further explore and validate.”
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EDITORIAL10 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.comEDITORIAL10 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
Out of order: We are our storiesBY RANDALL C WILLIS
A S YOU DISCOVERED back in Novem-ber, I have a variety of creative out-lets in my life aside from writing for DDNews. And although most of those outlets involve writing, rarely
do they intersect; until this past autumn, that is.In late October, I attended the Austin Film
Festival and its wonderful screenwriters’ conference. One session that caught my eye was entitled Science Fiction vs. Science Fact, which highlighted the fundamental need for actual science as the underpinning of good science fiction.
I like science fiction—and agree wholeheartedly
with this premise—but what made this panel particularly interesting to me was that it included not only three screenwriters, but also two scientists from the National Academy of Science (NAS) and the Jet Propulsion Laboratory. It was their input that had the greatest impact for me.
The panel, I discovered, was part of a broader NAS initiative to reach out to the artistic community and improve the way science was communicated to the lay public. Hollywood having the influ-ence it does on society, in particular, the NAS
saw an opportunity in connecting screenwriters and filmmakers directly with scientists, even instituting a hot-line—the Science & Entertainment Exchange—to address writers’ ques-tions (844-NEED-SCI).
What struck Eric Heisserer, screenwriter of the movie Arrival, however, was that beyond getting the story factually accurate, he found that when he checked his
ideas or plot points with scientists, they were liable to come up with new perspectives that
Editor’s focus: What looks like outrage might be necessityBY JEFFREY BOULEY
O NCE OR TWICE A YEAR usually, Public Citizen is good for spurring my idea for this editorial column that I write 11 times each year (nod to my publishers for pen-
ning that twelfth one). As I’ve noted at some point in the past, I have experience working with advocacy groups on editorial/communica-tions issues, so I do have affection for them. At the same time, I recognize that they have agen-das—as do the corporate or government targets of their ire—and so I give them the same critical eye I do everyone else (that pesky skepticism of the old-school journalist).
Sometimes I’m on the side of Public Citizen, but most of the time I honestly feel like they assume more evil intent in the pharma and bio-tech world (and the regulatory world) than actu-ally exists there.
And so it is with one of their latest news releases, titled, “$850,000 Charge for Gene Therapy Is an Outrage.”
I’ll give them the first word so that I can have the last one; it’s the advantage of this being my column, after all.
Anyway, as they worded their outrage:“Spark Therapeutics has announced it will
charge $850,000 per person for Luxturna, a gene therapy for retinal dystrophy, which causes reduced or deteriorating vision in both eyes. Spark’s development of Luxturna has benefited from tax breaks, favorable U.S. Food and Drug Administration designations and public research investments. Public Citizen sent Spark CEO Jef-frey Marrazzo a letter insisting that Spark dis-close its Luxturna-related research and develop-ment (R&D) costs. Commenting on early specu-lation from some analysts that Spark may charge $1 million, Marrazzo told The Washington Post, ‘A more affordable, pragmatic solution wouldn’t be that we took all the value, but took a reasonable amount of it. We thought there was a middle ground between addressing the affordability con-cerns of payers with the value of the treatment.’
Spark has set a new bar for corporate avarice and insensitivity to the national burden of ris-ing healthcare costs. Spark’s near-million-dollar
charge for Luxturna is an outrage that will hurt struggling families and raise premiums for all of us.
The consequences are both immediate and long-term. When we fail to hold accountable a corporation that sets a new standard for greed, others will follow suit, ultimately making unaf-fordable the treatments each of us and our fami-lies need.
Consumers, doctors, patients, payers and fami-lies need to unite and ask, ‘How much is enough?’ Medical corporations charge more for each new treatment—to morally indefensible levels few people would have imagined possible even a few years ago.
Spark CEO Jeffrey Marrazzo’s comments, implying that $850,000 represents something other than greed, are absurd and obscene. Per-haps it’s affordable for a pharma exec—but the inevitable result of Spark’s greed will be treat-ment rationing, preventable suffering and high-er premiums. Our healthcare system is crack-ing under the strain. Congress and the Trump administration must establish basic disciplines for medicine affordability.
Spark must disclose its R&D costs for Luxtur-na so that analysts, payers and the public have a basis to assess Spark’s decision. The public deserves to know what return we can expect on our taxpayer support for Luxturna.”
In all fairness, I thought that posting their entire statement verbatim is more important than me paraphrasing and abridging and possibly skewing things. So, my feelings?
I agree—only with the idea that it would probably be a very good idea for Spark to release thorough information on R&D costs.
Frankly, I wish all biotech and pharma companies did so, but most especially the Big Pharmas and those that don’t quite make that classification but have expensive and/or blockbuster therapies in their hands.
The assumption among many people, as with
Public Citizen, is that corporations are greedy and heartless at their core. And this seems to be especially true with respect to pharma and biotech, which people seem to routinely accuse of jacking up prices just to get rich or hiding the cure to cancer (or Alzheimer’s or whatever) so they can keep providing long-term treatments for better profits.
And while many of you readers are bench-level scientists at pharmas and biotechs (or their supervisors) and probably realize what goes into R&D for potential therapeutics, it might be rash to assume that just because you take a paycheck you know the inside workings. After all, I’ve never known the full budgets or expenses of any place I’ve worked at, despite being upper-level management for much of the past 20 years.
So, while I cannot comment on Spark specifically, let me remind everyone (Public Citizen included) of what the Tufts Center for the Study of Drug Development noted in 2014: Developing a new prescription medicine that gains marketing approval was estimated at that time to be running just under $2.6 billion—not to mention that it often takes around a decade, and sometimes 13 to 15 years, to get from discovery to commercialization.
Note also that this 2014 study followed a similar one by Tufts in 2003. In the intervening years, the cost of getting a drug to market had increased by 145 percent. And considering the most recent information from Tufts is now a little over three years old, does anyone really think costs haven’t continued to rise for pharma and biotech?
Now, this doesn’t mean I assume the $850,000 price tag from Spark is fair. But what I do know is that gene therapy is still very new and very tricky, and so I expect it would be very costly. This isn’t just another pill going after a GPCR target, which is expensive enough—this is a whole new world.
So, yes, Spark should be transparent about its expenses and, if they are being greedy, they should scale back to something saner and apol-ogize. But at the same time, folks like Public Citizen need to be prepared to find out that the only way to do these very advanced therapeutics right now might be to charge a very high price for them. n
ORDER CONTINUED ON PAGE 11
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For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 11EDITORIAL
were vastly more interesting than anything he could have imagined.
Nature and the universe, he and his screenwriting panelist colleagues suggested, was quite literally stranger than fiction. None of this would ever have been known, however, without that simple conversation between writer and scientist, without scientists telling stories about their work and their fields of study.
Now that would simply have been a fascinating panel and informed my own screenwriting, had I not also attended Neuroscience 2017 in Washington, D.C., a couple of weeks later. There, I happened upon another panel discussion: Science of Storytelling and Storytelling in Science.
Thinking more of hospitals than Hollywood, this panel examined the concept of relating the humanity of science through storytelling, gently attempting to burst the myth of dispassionate inquiry and highlighting the passion behind the quest.
Science is so much more than sterile statistics and bar graphs, so much more than supposedly objective reasoning. And ultimately, to present it in those terms is to meet with indifference and antipathy, if only because no one understands why they should
care, let alone why it matters.As Liz Neeley, marine biologist and
executive director of The Story Collider, explained, stories are evolutionary tools that help us understand what happened versus what we expected to happen. And because science typically challenges expectation, there is an inherent challenge in communicating it.
For science journalist Ed Yong, rather than focusing on the facts and figures, science communication should focus on the people who care about and/or are impacted by the meaning of those facts and figures. Perhaps it is no surprise, given the way I typically approach the DDNews Special Reports and particularly their openings, that I completely agree with this sentiment.
In the absence of a human context, science becomes an academic exercise in the most derogatory sense of that phrase. And I mean “a human,” a single or concrete group of humans, rather than a mathematical abstraction (e.g., a statistically defined population).
Scientists have a passion for their work and the communities in which they work. Clinicians have a passion for their work, their communities and their patients/study subjects. In many respects, there is too little reward in these pursuits not to love it.
I hear that passion in the many interviews
I lead each year. These aren’t people simply trying to make their quarterly sales objectives or complete enough experiments to get that grant extension—although both are vital to their continued pursuits and should not be viewed as venal or necessary evils.
By and large, these are people who are driven by a passion for the work they do, the subjects they are trying to understand, the adrenaline of new discovery, the hope of what lies around the next corner.
And it is that—the humanity of the undertaking—that makes them and their pursuits relatable to the least educated, least experienced, least knowing of us.
Yes, these are specialists working in highly specialized fields of endeavor, fields filled with jargon and statistics and minutiae.
They are also humans, experiencing human emotions, suffering human expectations and frailties, and relating to other humans. And that is the thing that makes science relatable.
We are our stories.Rather than shy away from that as a betrayal
of science, let us embrace it as the one thing that makes science possible and worthy.
May we all have a happy, healthy and story-filled 2018. n
Randall C Willis can be reached by email at [email protected]
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THE POLITICIZATION OF SCIENCE
I N A cover feature titled “The Politicization of Scientific Issues” in the Skeptical Inquirer, the thought is put forward that politicization of scientific issues
may actually be a danger to democracy.As the publication notes, in the
national debates over contentious sci-entific issues such as climate change, vaccines and evolution, political and cultural identification have become a determining factor as to whether one accepts the facts of science. In its Sep-tember/October issue last year, Skepti-cal Inquirer—published by the Center for Inquiry, a nonprofit educational, advocacy and research organization headquartered in Amherst, N.Y.—traced the roots of the politicization of scientific issues and how these anti-scientific attitudes might threat-en the very foundations of American democracy.
“There are striking similarities of Galileo’s world with ours today in the twenty-first century,” writes Jeanne Goldberg, formerly of the American Cancer Society, in the issue’s cover feature, showing that today, as then, political and ideological concerns are being held above evidence and scien-tific consensus.
Goldberg explains that science can be alienating to the general public, as its complexities can only be grasped by “experts,” distant elites located in coast-al urban areas with little connection to the beliefs and culture of a population who feel their self-sufficiency threat-ened in a changing world.
At the same time, many urban elites have also come to reject science “almost in a tribal fashion,” falling for anti-vaccination misinformation or spending exorbitant amounts of money on pseudoscientific “alterna-tive” medicines in what Goldberg sees as a “distrust of the Enlightenment principle of rationality.”
The implications for society as a whole are dire, says Goldberg. “There is no doubt that a threat to our democ-racy exists when there is scientific illit-eracy, complacency or extreme polar-ization regarding scientific issues,” she writes, as powerful interests work to suppress scientific truths that threat-en their positions. “This constitutes a form of authoritarianism that can be used to impede scientific progress and, in the long run, cause a government to fail.” n
“There is no doubt that a threat to our democracy exists when there is scientific illiteracy, complacency or extreme polarization regarding scientific issues.”Jeanne Goldberg for the Skeptical Inquirer
Expert insight: How pharma can extract greater value from population-scale studies
AT THE OXFORD GLOBAL Pharma-ceutical IT congress held Sept. 27-28 in London, Genestack CEO Dr. Misha Kapushesky discussed empowering discovery, noting that the cost and complexity of organizing genomics research data are challenges shared by larg-
er global pharma and growing biotech alike. Kapushesky believes the availability of
large-scale population studies will intensi-fy this pinch-point, and at the Oxford Glob-al Pharmaceutical IT conference he used real-world case-studies to describe how effective data management can empower discovery.
No matter who he talks to across the industry, Kapushesky says he has found that a major issue is managing research data across organizational and geographical borders.
“Today, you rarely come across an organization that believes it can generate all the data it needs to make deductive discovery and development, so more data is being created through collaborations,” he notes. “This can be between academic partners and a therapeutic area, or between several therapeutic areas in the same organization. There are also opportunities to put private data into a wider context with public data emerging from large population studies.
“You don’t have to look very far for exam-ples, like the collaboration between Astra-Zeneca and HLI, or GSK and the UK Bio-
bank. Organizations in this R&D space are getting access to practically population size multi-omics datasets. However, this comes with challenges.”
First, he asks, “[How] do you find relevant data both internally and in public reposito-ries and keep track of the provenance of the data that has been captured and processed? There needs to be a complete audit trail of the data so that computations are reproducible.
“Secondly, how do you provide rapid access for scientists and improve collaboration? You
need to build an IT infrastructure so that they can find the data they need, wherever it is held, with simple searches such as ‘find patients that are over 30, female, nonsmokers, without a mutation in a particular gene for whom I also have transcription data’? The ability to get fast answers to these queries is critical.”
Finally, he notes, “[In] discovery, we want to be able to reuse and repurpose data, so how do you stop it residing in silos? For instance, ontologies are needed to struc-ture data in existing databases and allow the infrastructure to scale as more information is generated. Distributed storage, compute and federated queries are tough technologies to harness. Being able to address these chal-lenges effectively will free bioinformaticians from the routine work and make the scien-tists more productive.” n
“Distributed storage, compute and federated queries are tough technologies to harness. Being able to address these challenges effectively will free bioinformaticians from the routine work and make the scientists more productive.”Dr. Misha Kapushesky, CEO of Genestack
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12 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
More robust analysis with new Geneious Biologics release
SAN DIEGO—A December announcement from Geneious Biologics shared word of a new release that will significantly improve analysis of large-scale next-generation sequencing datasets, in order to better equip researchers to analyze antibody sequences to speed the identification of antibody candidates. The release was announced at the Antibody Engineering & Therapeutics Conference in San Diego.
Jannick Bendtsen, vice president of technology services for biomatters at Geneious, said “This is a big milestone for Geneious Biologics and a huge step forward on our development roadmap. High-throughput antibody sequencing technolo-gies are revolutionizing the biologic drug discov-ery industry. However, dealing with huge volumes of associated data remains a challenge. Geneious Biologics now offers a real solution.”
New updates to SIMCA and SIMCA-online
GOETTINGEN, Germany & MALMO, Sweden—New ver-sions of SIMCA and SIMCA-online are now avail-able, Sartorius Stedim Biotech (SSB) announced in early December. The data analytical solutions are offered by the company’s subsidiary, Sarto-rius Stedim Data Analytics. SIMCA, part of SSB’s Umetrics Suite, is an advanced data analytics and visualization program that enables users to combine and analyze data, with a multivariate data analysis engine to aid in identifying depar-tures from normal operating conditions. SIMCA now offers an intuitive graphical interface, the flexibility to handle more complex data and the option of uploading projects directly to an avail-able SIMCA-online server. SIMCA-online is a real-time monitoring and prediction system that offers constant process monitoring. New features include a self-service analytics capability and new notification system, as well as a new web client.
IN THIS SECTIONAAV vectors/Gene therapyOxford Genetics and MeiraGTx tackle AAVs ........................... 12
Analysis/SequencingCulturing the unculturable ...................... 14More robust analysis with new Geneious Biologics release ............ 12New updates to SIMCA and SIMCA-online .................................. 12
HemophiliaProud partnership ................................... 12
Liver disease/NASHA GalXC far, far away (GALXC from cover) ................................ 15
OncologyMicroRNAs and cancer .......................... 12
Oxford Genetics and MeiraGTx tackle AAVsThe partners hope to develop a new production system that offers better yields and robustnessBY MEL J. YEATES
OXFORD, U.K.—At the beginning of December, Oxford Genetics, a synthetic biology company, announced a new agreement with clinical-stage gene therapy company MeiraGTx. The collaboration will enable Oxford Genetics and MeiraGTx to develop novel adeno-associated virus (AAV) vectors, as well as packaging and producer cell lines. The companies aim to create a fully scalable AAV production system that can satisfy the requirements for increased viral vector yields, process robustness and product efficacy.
“We are delighted to be working alongside the MeiraGTx team on such an exciting project, which will take us another step forward in our vision to deliver breakthrough technologies to the biotherapeu-tic industry,” said Dr. Ryan Cawood, CEO at Oxford Genetics. “By creating advanced AAV production systems, we aim to power the expansion of gene therapy as it moves towards addressing the more common disease indications that present technologies cannot satisfy.”
Dr. Paul Brooks, chief commercial officer at Oxford Genetics, adds, “The agreement further demonstrates that our business model for early access to our technologies is resonating with the biotherapeutic industry. Through such partnerships we will ultimately deliver real
MicroRNAs and cancerSalk Institute research illustrates how tumors outsmart immune response BY RACHEL FLEHINGER
LA JOLLA, Calif.—The immune system automatically destroys dysfunctional cells such as cancer cells, but cancerous tumors often survive nonetheless. A new study by Salk Institute scientists shows one method by which fast-growing tumors evade anti-tumor immunity.
According to a recent paper in Nature Cell Biology, Salk researchers have discovered a pair of gene-regulating molecules that can change cell signaling in tumor cells to sur-vive and evade the immune system’s normal response.
Tumors often grow so rapidly that they deplete their available blood supply, which results in hypoxia, or a low-oxygen environ-ment. While hypoxia typically causes cells to self-destruct, the tumor microenvironment can help protect the tumor.
“The immunological pressure occurring during tumor progression might be harmful for the tumor to prosper,” Salk Prof. Juan Carlos Izpisua Belmonte, senior author of the work and holder of the Roger Guillemin Chair, said in a press release. “However,
the cancer cells find a way to evade such a condition by restraining the antitumor immune response.”
“Our findings actually indicate how cancer cells respond to a changing microenvironment and suppress antitumor immunity through intrinsic signaling,” he
added.Those findings hinge on microRNAs. These
noncoding RNA molecules, which regulate genes by silencing RNA, are gaining attention as research elucidates the roles they play in tumor survival and progression. The Salk
SALK CONTINUED ON PAGE 13
Proud partnershipCollaboration between Shire and Rani will evaluate approach to oral delivery of factor therapy for patients with hemophiliaBY ILENE SCHNEIDER
CAMBRIDGE, Mass. & SAN JOSE, Calif.—Hemophilia is a chal-lenging chronic disease that causes longer-than-normal bleed-ing due to absent or deficient clotting factor in the blood. Fac-tor replacement therapy attempts to make bleeding subside when enough clotting factor has reached the source of the bleed, but no oral therapies currently exist for the treatment
HEMOPHILIA CONTINUED ON PAGE 14 AAV CONTINUED ON PAGE 15
Shire and Rani Therapeutics are teaming up to research the use of the Rani Pill technology for the oral delivery of factor VIII therapy for patients with hemophilia A.
“To boost cancer immunotherapy, we’d like to find ways to block the Lkb1 pathway,” says Min-Zu Wu, formerly of the Salk Institute. “The outcome of this inhibition would be an increased immune response from other types of T cells, which would help them to destroy tumors.”
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 13RESEARCH & DEVELOPMENTWhile these results are promising,
and the discovery of a new potential target is always encouraging, the sci-entists caution that directly target-ing microRNAs is often difficult, and a simpler route might consist of targeting the other links in the cell signaling chain between miR25 and miR93 and cGAS.
Wu reported in a news release that in the wake of these results, the team is now looking into “the different immune cells that can contribute to cancer antitumor immunity.”
This work complements other immune response research at Salk. In another recent study, scientists found a specific protein that influences the survival and function of regulatory T cells, known as Tregs, that show potential in cancer immunotherapy and therapies for autoimmune diseases like rheumatoid arthritis and type 1 diabetes.
The protein in question is the Lkb1 protein (for liver kinase B1). This kinase was previously known to have a role in cell metabolism, but until now, it wasn’t known that
it also controls the functions in the immune response of Tregs. In the case of cancer, Tregs are hijacked by tumors to prevent other types of T cells from eliminating cancer cells. The Lkb1 pathway, the team found, “is responsible for supplying Tregs with energy. Without it, Tregs don’t have enough fuel to function,” said Ye Zheng, an associate professor in Salk’s Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis.
“To boost cancer immunotherapy, we’d like to find ways to block the
Lkb1 pathway,” he added. “The out-come of this inhibition would be an increased immune response from other types of T cells, which would help them to destroy tumors.”
As with miR25 and miR93, Lkb1 represents a difficult molecule to target directly, but the team has identified other molecules further downstream in its signaling pathway that are viable, druggable targets. Their work going forward will include developing drugs against those targets. nEDITCONNECT: E011808
team screened a variety of tumor types for altered microRNA levels and identified two microRNAs—miR25 and miR93— whose levels were higher in hypoxic tumors. A series of articles published in 2016 linked miR25 to liver cancer, pancreatic and other gastric cancers, osteosarcoma, glioblastoma and even melanoma, while miR93 has a strong correlation with breast cancer.
The researchers measured levels of miR25 and miR93 in the tumors of 148 cancer patients and found that tumors presenting with high levels of those microRNAs resulted in a worse prognosis when compared to tumors with lower levels. The reverse was true for a molecule known as cGAS—they found that a patient’s prognosis
worsened the lower the level of cGAS their tumor had.
Indeed, cGAS has been found to serve as an alarm for the immune system. It detects mitochondrial DNA floating around the cell—which is a sign of tissue damage—and activate the body’s immune response accordingly.
“Given these results, we wondered if these two microRNA molecules, miR25 and miR93, could be lower-ing cGAS levels to create a protec-tive immunity shield for the tumor,” noted Min-Zu (Michael) Wu, first author of the paper. Wu was former-ly a research associate in the Gene Expression Laboratory at Salk, and now works at Amgen.
It turned out they were right. When they tested their hypothesis in mouse models and tissue samples, the team discovered that a hypoxic state triggered miR25 and miR93 to kick off a chain of cell signaling that lowered cGAS levels. When miR25 and miR93 were inhibited in tumor cells, cGAS levels stayed high. Beyond that, inhibition of miR25 and miR93 enabled the Salk researchers to slow tumor growth as well. However, this effect was dimin-ished in immune-deficient mice.
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“The immunological pressure occurring during tumor progression might be harmful for the tumor to prosper. However, the cancer cells find a way to evade such a condition by restraining the antitumor immune response.”Juan Carlos Izpisua Belmonte of the Salk Institute
14 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.comRESEARCH & DEVELOPMENT
of hemophilia. According to a recent research report, the global hemophilia treatment drug market is expected to be worth $25.1 billion in 2024, up from $15.8 billion in 2015.
Shire plc, a biotechnology company specializing in rare diseases, and Rani Therapeutics, an InCube Labs company involved in multi-disciplinary life-sciences R&D, have formed a collaboration to conduct research on the use of the Rani Pill technology for the oral delivery of factor VIII (FVIII) therapy for patients with hemophilia A. According to the collaboration agreement, Shire has acquired an exclusive option to negotiate a license to develop and commercialize the technology for delivery of FVIII therapy after completing feasibility studies.
“Rani Therapeutics was founded in 2012 with the mission of converting injectable drugs into pills and thereby radically improving patient outcomes,” explained its CEO, Mir Imran. “The Rani Oral Delivery Platform (ODP) is suitable for a wide range of molecules and across therapeutics areas including inflammatory disease, diabetes and hemophilia, to name a few.”
With its platform, the company has demonstrated absorption similar to sub-cutaneous injections in preclinical stud-
ies, and it has established partnerships with several pharmaceutical companies, including Novartis and AstraZeneca, according to Imran. Most recently Shire, a leader in hemophilia, was interested in exploring Rani’s technology for treating hemophilia A patients, who currently are treated with infusions. Shire has entered into a collaboration with Rani to evaluate Factor VIII on the Rani ODP.
“If successful, the Rani Pill would allow Factor VIII to be delivered orally—a first-of-its-kind innovation,” Imran said. “The Rani Pill is an oral capsule that delivers a pain-free intestinal injection of the ther-apy. The goal is higher levels of compli-ance and an improved patient experience. Shire has also made an equity investment into Rani Therapeutics as part of the collaboration.”
The novel approach for the oral deliv-ery of large molecules, including pep-tides, proteins and antibodies, delivers the intestinal injection without exposing medication to digestive enzymes. Once the capsule is consumed, it stays protect-ed until it enters the small intestine and delivers medication into the intestinal wall. Because the intestines do not have sharp pain receptors, the intestinal deliv-ery is expected to be pain-free.
According to Fritz Scheiflinger, Shire’s head of global research, “Shire is proud to partner with Rani Therapeutics to pioneer the investigation of oral deliv-ery of factor therapy for the hemophilia community. With Shire’s in-depth scien-tific expertise and leadership position in hemophilia and Rani Therapeutics’ deep experience in engineering and material science, we are excited by the potential of this partnership to reduce the chronic burden of hemophilia on patients’ every-day lives by researching an oral option to deliver FVIII to patients. We strive to provide hemophilia patients with innova-tive therapies that are effective and do not expose patients to additional risks.”
Shire attempts to develop “best-in-class therapies across a core of rare disease areas—including hematology, immunol-ogy, genetic diseases, neuroscience and internal medicine—with growing thera-peutic areas in ophthalmics and oncol-ogy,” Scheiflinger added. “Our diversified
capabilities enable us to reach patients in more than 100 countries.”
According to Imran, “With this tech-nology, though early in development in hemophilia, we hope to improve com-pliance, quality of life and outcomes for patients with hemophilia by offer-ing a painless and more convenient oral delivery.”
“Rani has the potential to disrupt the industry with its innovative approach to delivering biologics orally,” said David Pyott, member of the board of direc-tors for Rani Therapeutics and former chairman and CEO of Allergan Inc. “The hemophilia market is an excellent appli-cation of Rani’s technology, and we are delighted that Rani is partnering with Shire, a market leader in the space.” nEDITCONNECT: E011809
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Culturing the unculturableBiomillenia leverages QIAGEN bioinformatics in microbiome-on-a-chip discovery of unculturable microbesBY DDNEWS STAFF
PARIS & LONDON—Late 2017 saw Biomil-lenia, the developer of Smart Microbes, announce a collaboration with QIAGEN N.V. for use of the latter company’s Microbial Genomics Pro Suite to generate next-gener-ation sequence data on microbes identified using Biomillenia’s proprietary microbiome-on-a-chip technology. Biomillenia’s approach is able to identify strains of microbes previ-ously deemed unculturable, at what it calls “unprecedented speeds.”
“The inability to culture, screen and isolate live bacterial species directly from the rich diversity of microbiota has previously been a significant limitation in research and product development. The combination of our microbiome-on-a-chip technology with QIAGEN’s industry-leading microbial genomics bioinformatics platform provides a complete and effective solution to this challenge,” said Dr. Dirk Loeffert, CEO of Biomillenia.
Biomillenia has developed a proprietary droplet-based microfluidics chip platform that cultures bacterial species directly from natural samples at the single cells level. This micobiome-on-a-chip technology contains greater than 100 million parallel picoliter-size droplets, reportedly allowing for a much higher diversity of live bacterial species that grow to clonal populations than standard microbiology methods.
Additionally, these picoliter-scale cul-tures can be isolated drop by drop based on phenotypic selection by a broad range of assay capabilities, effectively enabling selection of novel bacterial strains with desired traits directly from original sam-ples. Biomillenia is able to screen up to 100 million microbes in parallel in a 2 milliliter reaction in three days, whereas traditional culture methods would take three years in 10,000 liter reaction volume.
QIAGEN’s bioinformatics platform pro-vides an easy-to-run infrastructure for ana-lyzing microbial genomes, from sequence assembly to microbe identification.
“QIAGEN has developed Microbial Genomics Pro Suite to make state-of-the-art bioinformatics reliable and accessible for researchers that need to analyze and visualize microbial genomes and micro-biomes. Biomillenia has demonstrated an exciting new application for our power-ful microbial bioinformatics. We are very pleased to have been able to reduce the time and costs in developing the required informatics pipelines and thereby enable significant acceleration in the develop-ment of their exciting Microbiome-on-a-chip technology,” commented Dr. Frank Schacherer, vice president and head of products and solutions at QIAGEN Bioin-formatics. n
EDITCONNECT: E011811
“The inability to culture, screen and isolate live bacterial species directly from the rich diversity of microbiota has previously been a significant limitation in research and product development,” says Dr. Dirk Loeffert, CEO of Biomillenia. “The combination of our microbiome-on-a-chip technology with QIAGEN’s industry-leading microbial genomics bioinformatics platform provides a complete and effective solution to this challenge.”
“Shire is proud to partner with Rani Therapeutics to pioneer the investigation of oral delivery of factor therapy for the hemophilia community. With Shire’s in-depth scientific expertise and leadership position in hemophilia and Rani Therapeutics’ deep experience in engineering and material science, we are excited by the potential of this partnership to reduce the chronic burden of hemophilia on patients’ everyday lives,” says Fritz Scheiflinger, Shire’s head of global research.
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benefits to patients by helping our partners reduce therapeutic development time and achieving earlier market approval.”
According to Brooks, MeiraGTx and Oxford Genetics met at an Innovate UK (governmental) meeting, and from there began their collaboration. “Oxford Genet-ics was already committed to the process of developing improved AAV vectors, pack-aging and producer cell lines for the gene therapy industry, of which MeiraGTx is part. This collaboration and licensing agreement allows both companies to pool experience and expertise in this field and accelerate the development of these systems.”
When asked how long it may take to create a fully scalable AAV production system that can satisfy requirements for increased viral vector yields, process robustness and product efficacy, Brooks says the research and development of the AAV vectors, packaging and producer cell lines is expected to take between 12 and 18 months.
He also notes that, “AAV vectors are developed from single-stranded DNA viruses that belong to the Parvoviridae family. This virus is capable of infecting a broad range of host cells, including both dividing and non-dividing cells. In addition, it is a non-
pathogenic virus that does not generate an immune response in most patients.
“Over the last few years, AAV vectors have emerged as an extremely useful and promising mode of gene delivery. This is owing to the properties of these vectors. AAVs are small, non-enveloped and have only two native genes. Thus [they] can be easily manipulated to develop vectors for different gene therapies. AAV particles are not easily degraded by shear forces, enzymes or solvents. This facilitates easy purification and final formulation of these viral vectors.”
“AAVs are non-pathogenic and have a low immunogenicity. The use of these vectors further reduces the risk of adverse inflammatory reactions. Unlike other viral vectors, such as lentivirus, herpes virus and adenovirus, AAVs are harmless and are not responsible for causing any human disease,” Brooks tells DDNews. “Genetic sequences up to 4000 bp (~4 kb) can be delivered into a patient using AAV vectors.”
As part of the agreement, MeiraGTx gains exclusive, worldwide research and manufac-turing rights to novel serotype specific AAV vectors, along with associated packaging and producer cell lines. “We are very excited to begin this collaboration with Oxford Genet-ics. It’s one of many vital steps that we are taking to meet the demand for a broadening
range of gene therapies. We hope that our approach will lead to quicker development of effective new therapies for patients,” com-mented Dr. Alexandria Forbes, president and CEO of MeiraGTx.
“Both companies see this initial collabora-tion as the first step in a wider and ongoing collaboration in the development and appli-
cation of viral vectors and viral production cell lines for gene therapy,” Brooks finishes. “The excitement for us lies in bringing together tremendous talent from both orga-nizations to tackle the challenges facing the efficient production of AAV for use in gene therapy.” nEDITCONNECT: E011810
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Oxford Genetics and MeiraGTx will collaborate on the development of novel adeno-associated virus vectors—a key aspect of many gene therapies—as well as packaging and producer cell lines.
platform and scientific approach focused on the development of investigational RNA interference (RNAi) therapeutics. RNAi therapies carry the potential to treat many diseases—including rare diseases, chronic liver diseases, cardiovascular disease and viral infectious diseases—by silencing some of the most well-validated drug tar-gets that have nevertheless remained inac-cessible with conventional therapies.
“Boehringer is a natural partner to speed the development of the first GalXC RNAi program targeting chronic liver disease,” says Jim Weissman, chief business officer of Dicerna Pharmaceuticals. “The collaboration combines the strong capabilities of both companies to pursue the full potential of our GalXC technology to bring valuable and differentiated RNAi therapies to patients with liver diseases.”
GalXC is a proprietary technology platform of Dicerna’s invention. The platform facilitates the development of subcutaneously administered RNAi-based therapies designed to silence disease-driving genes in the liver across multiple therapeutic areas, including rare diseases, chronic liver diseases, cardiovascular disease and viral infectious diseases.
“Each GalXC molecule is a chemically optimized, double -stranded RNA designed to potently induce RNAi,” explains Weissman. “We attach N-acetyl galactosamine sugars to one or more points on GalXC compounds, yielding multiple effective and proprietary conjugate delivery configurations. These molecules specifically bind to highly expressed asialoglycoprotein (ASGPR) receptors on the target cells, leading to internalization via endosomes and access to the RNAi machinery within the cells. Within the endosome, the ASGPR releases the GalXC and recycles to the cell surface, enabling delivery of the GalXC into the cytoplasm of the cell (hepatocytes in the liver).”
According to Weissman, in preclinical s tudies GalXC compounds have demonstrated potency on par with or better than comparable platforms, high specificity to their gene targets and long duration of action. They also offer a convenient subcutaneous route of administration.
Under the terms of the agreement, BI agreed to make an upfront payment of $10 million to Dicerna. Dicerna is eligible to receive up to $191 million in potential development and commercial milestone payments, and research and development reimbursement for a GalXC candidate product addressing an undisclosed NASH target. Dicerna also stands to receive royalty payments on potential global net sales, subject to certain adjustments, tiered from high-single-digits up to low-double-digits. BI retains an option to add a second target in exchange for additional payments to Dicerna, including an option fee payment, success-based development and commercialization milestones and royalties.
The collaboration will initially focus on investigating RNAi therapeutic options
for NASH, a chronic liver disease caused by buildup of fat in the liver, for which there is no approved treatment. Weissman estimates that about 20 percent of all people with nonalcoholic fatty liver disease (NAFLD)—one of the most common causes of liver disease in the United States—have NASH. It has an especially high prevalence among obese and diabetic patients, and is an area of high unmet medical need. NASH is among the most common causes of advanced liver disorders including liver fibrosis and cirrhosis, and the disease often necessitates liver transplantation.
“Boehringer Ingelheim has a long history of excellence in the discovery a n d d e v e l o p m e n t o f m e d i c i n e s for cardiometabolic diseases,” says Michael Mark, head of research for cardiometabolism at Boehringer Ingelheim. “The cardiometabolic diseases pipeline and discovery focus extends beyond type 2 diabetes and anticoagulation. We focus on innovative drugs for the treatment of the devastating consequences of diabetes or on concomitant diseases like NASH/
liver diseases. Furthermore, obesity is an important underlying reason for the development of diabetes and is also part of our research and development efforts.”
“As the opportunity to work together advanced through the deal-making process, [Boehringer Ingelheim] demonstrated keen collaborative spirit and teamwork and impressed upon Dicerna their ability to be a great partner,” Weissman tells DDNews. “This partnership complements both companies’ existing research efforts and expertise.”
Dicerna is building a portfolio of research and development programs to advance the treatment of diseases involving the liver, leveraging its proprietary GalXC technology to develop innovative RNAi therapeutics. Dicerna filed a clinical trial application (CTA) for its lead GalXC product candidate, DCR-PHXC, in October 2017, which is currently in Phase 1 trials. According to Weissman, the company expects to file additional CTAs and/or IND applications in 2018 and 2019. Dicerna currently has three priority therapeutic programs and a series of programs in the clinical candidate selection stage.
“Our three priority programs are: DCR-PHXC for the treatment of primary hyperoxaluria (PH); a program against an undisclosed rare disease; and DCR-HBVS for the treatment of chronic hepatitis B virus (HBV) infection,” Weissman reports. “Our programs in clinical candidate selection include DCR-PCSK9 for the treatment of hypercholesterolemia, for which a provisional clinical candidate has been selected, and multiple programs targeting undisclosed targets in chronic liver diseases, cardiovascular diseases and additional rare diseases.
“At Dicerna, we believe that strategic partnerships, research collaborations and licensing arrangements should add value to both parties, assisting each in attaining goals beyond those that could be achieved individually.” nEDITCONNECT: E011802
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Boehringer Ingelheim is making an upfront payment of $10 million to Dicerna, plus potentially $191 million in development and commercial milestone payments, for a GalXC candidate product addressing an undisclosed NASH target.
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Support for Aduro’s ADU-1604BERKELEY, Calif.—Aduro Biotech Inc. shared preclinical data at the 32nd Annual Meeting of the Society for Immunotherapy of Cancer supporting ADU-1604, its humanized anti-CTLA-4 monoclonal antibody. In in-vitro and in-vivo studies, the candidate showed potency and the ability to inhibit tumor growth and enhance T cell-dependent antibody responses. Proof-of-concept studies in syngeneic mouse models showed that anti-CTLA-4 boosts antitumor activity when combined with ADU-S100, Aduro’s lead investigational STING agonist.
“These data from preclinical studies of ADU-1604, a novel anti-CTLA-4 product candidate derived from our proprietary B-select antibody platform, are encouraging and provide support to file an Investigational New Drug Application to advance ADU-1604 into clinical studies,” stated Dr. Andrea van Elsas, chief scientific officer of Aduro. “As a company with multiple programs and proprietary technology platforms, we are well positioned to leverage our product candidates, as monotherapies and in rational combinations, to develop new treatment options for patients in need.”
Grant program to support preclinical, PDX advancements
SANTA CLARA, Calif.—A new grant program is underway thanks to Crown Bioscience, which launched the initiative to support oncology research scientists by providing funding to projects with potential to advance patient-derived xenograft (PDX) technology. The program will award research grants of up to $50,000 to projects that will accelerate preclinical innovation and novel PDX methodologies that improve clinical predictions.
“Crown Biosciences recognizes the importance of supporting investigators in early discovery,” said Laurie Heilmann, chief business officer at Crown Bioscience. “By investing in the brightest scientific minds, we can evolve the current research paradigms and establish novel tools that will help researchers and drug developers address global health challenges.”
IN THIS SECTIONCardiovascular/ metabolic diseaseMore answers on mavacamten .............. 16Telemetry device advances metabolic disease research ................... 18
Muscular dystrophy/DMDDialing in on a new DMD target ............ 16
OncologyGrant program to support preclinical, PDX advancements .............. 16Support for Aduro’s ADU-1604 ............... 16
OphthalmologyHope for rare eye disease patients ........ 16
Hope for rare eye disease patientsNanoViricides presents ‘highly effective’ treatment for acute retinal necrosisBY LORI LESKO
SHELTON, Conn.—In what could become the first significant treatment for acute retinal necrosis (ARN), a recent study presented by NanoViricides Inc. ophthalmologist consultant Dr. Vivien Boniuk has reportedly shown that treating ARN with an experimental nanoviricide in a small animal model was “highly effective.”
This study will be repeated for verification, but if confirmed
Dialing in on a new DMD targetSummit shares preclinical data supporting utrophin as a target for slowing muscular dystrophy progressionBY KELSEY KAUSTINEN
OXFORD, U.K.—The 15th Action Duchenne International Conference 2017, an event that unites individuals with Duchenne and Becker muscular dystrophy (and their families) with experts and industry members focused on tackling the diseases, met in Birmingham, U.K., this past November. Among the industry members in attendance were Summit Therapeutics plc and collaborators from the University of Oxford, who presented data supporting utrophin modulation as a universal treatment for Duchenne muscular dystrophy (DMD).
The preclinical data in question were presented by Prof. Kay Davies of the University of Oxford, scientific advisor and co-founder of Summit. The data revealed that continuous
expression of utrophin in a dystrophin-deficient environment can reduce mitochondrial aberration and oxidative stress—the former drives the latter, which contributes to DMD muscle damage. Davies also covered previously published preclinical results related to utrophin modulators, including ezutromid,
that captured the candidates’ potential to prevent molecular disease. Ezutromid is the company’s lead utrophin modulator.
Davies commented in a press release that, “My team at the University of Oxford continues to gather scientific evidence
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More answers on mavacamtenNew research on drug elucidates successful HCM treatment mechanismBY RACHEL FLEHINGER
SOUTH SAN FRANCISCO, Calif.—MyoKardia Inc., which specializes in precision cardiovascular therapeutics, recently shared data that further clarify the mechanism of action of its lead drug candidate, mavacamten. A presentation detailing these results, “In Vivo Cardiac Effects of Mavacamten (MYK-461): Evidence for Negative Inotropy and Improved Compliance (#405),” was part of the Drug Discovery for Heart Failure session of the American Heart Association Scientific Sessions.
M a v a c a m t e n i s a n investigational compound that
has demonstrated the ability to modulate cardiac myosin to reduce the excess contractility characteristic of hypertrophic cardiomyopathy (HCM). This severe, progressive genetic condition causes the walls of the heart to thicken, which can lead to obstructed blood flow from the left ventricle. In addition, this thickened heart muscle is less compliant and fills with less blood, thereby reducing cardiac output. The most recently released data from the in-vivo study demonstrated that mavacamten successfully improved myocardial compliance while preserving systemic pressures.
“ The obser va t ion that mavacamten may improve distensibility while reducing contractility increases our understanding of mavacamten’s mechanism of action and hemodynamic effects,” said Dr.
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Duchenne muscular dystrophy is a rare disease that primarily affects males, with an estimated incidence of one in 3,300 births. Pictured here is histopathology of gastrocnemius muscle from patient who died of pseudohypertrophic muscular dystrophy, Duchenne type—the cross section of muscle shows extensive replacement of muscle fibers by adipose cells.
Acute retinal necrosis is a painful HSV-retinol infection that can cause blindness. NanoViricides researchers may be on the path to making a breakthrough in treating the disease.
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For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 17PRECLINICAL
showing how utrophin can substitute for dystrophin in animal muscle and prevent many of the molecular hallmarks of DMD from occurring in these animal models. Importantly, these underlying changes in muscle health have the potential to lead to functional benefits, providing hope for a universal, disease-modifying treatment for families living with Duchenne.”
As explained by Glyn Edwards, CEO of Summit, “Utrophin and dystrophin both act as molecular shock absorbers in normal muscle function. This helps the muscle fibers to deal with the shock of muscle contractions. The difference is when they perform this function—utrophin is present along the muscle fiber when a muscle is first forming or repairing. As the muscle matures, utrophin production is switched off and dystrophin production is switched on to take its place. Utrophin has additional roles in mature muscles where the nerve meets the muscle (neuromuscular junction) and where the tendon meets the muscle (myotendinous junction). It is also expressed in other cells throughout the body.”
An advantage of targeting utrophin rather dystrophin, says Edwards, is that it could help all DMD patients, regardless of their specific dystrophin mutation.
“Many of the dystrophin-restoration approaches are specific to certain dystrophin mutations and therefore can only treat a subset of patients,” Edwards tells DDNews. “Based on our animal work, we believe that utrophin can substitute for dystrophin and could work as a stand-alone therapy for DMD. We also believe that utrophin modulation could work in combination with dystrophin restoration therapies and other therapies in development for DMD.”
“There are a finite number of sites along the muscle fibers where either utrophin or dystrophin could be present,” he adds. “The current generation of dystrophin-restoration therapies does not appear to restore dystrophin to 100 percent, meaning there are some
DMDCONTINUED FROM PAGE 16
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sites along the muscle that are vacant. The potential is for utrophin to fill some of those vacant sites. We don’t believe there would be any complications with expressing both utrophin and dystrophin at once, and have observed this in animal studies, but this would need to be tested in a clinical setting. We are first focused on showing benefit with utrophin modulation alone.”
The recent presentation also covered Summit’s ongoing Phase 2 proof-of-concept trial, PhaseOut
DMD, which is evaluating ezutro-mid in 40 patients with DMD. The company announced on Nov. 20 that it had completed the initial 24 weeks of dosing of ezutromid for the clinical trial.
“These new preclinical data from Prof. Davies’ team at the University of Oxford provide another piece of evidence highlighting the potential of utrophin modulation in being able to treat this devastating muscle wasting disease,” said Dr. David Roblin, chief operating officer and medical
officer at Summit. “We remain on track to report the first results of ezutromid treatment in boys with DMD in PhaseOut DMD in the first quarter of 2018, and if results provide evidence of the mechanism of utrophin modulation in patients, we believe it would represent a major advancement for ezutromid. It would bring closer to all patients a therapy that has the potential to be disease modifying in DMD.”
Edwards says that pending positive results from PhaseOut
DMD, Summit plans to conduct a placebo-controlled trial to secure “accelerated and conditional approvals in the U.S. and EU, respectively.”
“We also have a pipeline of future generation utrophin modulators under development with the University of Oxford,” he adds. “These are much earlier in development, but we’ve identified a series of molecules that may have a different mechanism to ezutromid.” nEDITCONNECT: E011812
“One of the advantages to utrophin modulation is that it could be applicable to all patients with DMD. Many of the dystrophin-restoration approaches are specific to certain dystrophin mutations and therefore can only treat a subset of patients.”
Glyn Edwards, CEO of Summit Therapeutics
PRECLINICAL18 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
Telemetry device advances metabolic disease researchCrown Bioscience and Data Sciences International partner to use device for long-term blood glucose monitoringBY DDNEWS STAFF
SANTA CLARA, Calif.—Crown Bioscience, a wholly owned subsidiary of Crown Bio-science International and a global drug discovery and development services com-pany providing translational platforms to advance oncol-ogy, inflammation cardiovas-cular and metabolic disease research, announced late last year the successful develop-ment of an enhanced method for preclinical obesity and type 2 diabetes studies in partnership with Data Sciences International (DSI).
According to Crown, its “clinically rele-vant models and DSI’s HD-XG implantable glucose device combine to create a superior approach to preclinical metabolic disease research.”
Recently published work in the Journal of
Endocrinological Investigation and Scientific Reports demonstrates the advantages of a new method using DSI’s HD-XG implant-able glucose device and Crown Bioscience’s models of spontaneous and diet-induced
diabetes. The HD-XG device allows for continuous, long-term measurement of blood glu-cose, temperature and locomo-tor activity and eliminates stress inducing blood sampling that can inadvertently skew glucose
levels and cause blood volume to decline. The published data reportedly support use of this method to thoroughly monitor glucose levels in Crown Bioscience’s clini-cally relevant models of human metabolic disease.
“We are excited to provide researchers with this powerful new method to advance preclinical obesity and diabetes programs,”
said Dr. Jim Wang, Crown Bioscience’s senior vice president for cardiovascular and metabolic diseases research. “By leveraging Crown Bioscience’s models to recapitulate human metabolic disease and DSI’s HD-XG device to reliably investi-gate changes in blood glucose, research-ers can gain unprecedented insight into the pathophysiology of metabolic diseases and the pharmacology of related investi-gational compounds.”
“We are pleased to collaborate with CrownBio to further promote the adop-tion of continuous glucose telemetry in
research studies,” said Eric Rieux, vice president of global sales and marketing at DSI. “We share a common goal of helping scientists better understand blood glucose levels, and ultimately develop better drugs, devices and therapies for humans.” nEDITCONNECT: E011815
TOOLS & TECHNOLOGY
Crown Bioscience believes that by leveraging its models for human metabolic disease and DSI’s HD-XG telemetry device to reliably investigate changes in blood glucose, researchers can gain better insight into the pathophysiology of metabolic diseases and the pharmacology of investigational compounds to treat such diseases.
Robert McDowell, chief scientific officer of MyoKardia, in a press release. “We look forward to potentially verifying the clinical implications of this early evidence of improved myocardial relaxation and of a rightward shift in the diastolic pressure-volume relationship, as it could greatly inform MyoKardia’s ongoing research to address diseases of impaired diastolic function.”
MyoKardia had previously reported positive top-line results from its first patient cohort in late summer, which indicated that Mavacamten treatment led to a meaningful reduction, in the first few weeks of treatment, in resting left ventricle outflow tract (LVOT) gradient, with a less pronounced reduction in resting left ventricle ejection fraction (LVEF). The reduction in LVOT gradient seen in nine out of 10 patients by week 2 led to the addition of a second, low-dose cohort in the PIONEER-HCM trial. The trial demonstrated a clinically and statistically significant reduction in left ventricular outflow tract gradient. Additional data indicated meaningful improvements in patients’ exercise capacity as measured by peak VO2, as well as a reversal of positive outcomes after the therapy was discontinued.
“These data strengthen the case, initially seen with the release of the topline results, that Mavacamten, by targeting the underlying biomechanical defect of the disease, can affect multiple clinically meaningful metrics that characterize the oHCM disease burden,” commented Dr. Stephen Heitner, director of the HCM Clinic at Oregon Health and Science University’s Knight Cardiovascular Institute, and lead investigator for the PIONEER-HCM study. “On behalf of the investigators, I am pleased to present these additional data showing the concordant and positive effects of mavacamten, with patients feeling better and displaying improvements in exercise capacity.”
A second, low dose cohort from the PIO-NEER-HCM trial is now being completed, and data from this group of patients are expected in the first quarter of 2018. The
low-dose cohort will provide researchers a detailed understanding of the relationship between mavacamten’s dose and responses as measured by reductions in gradient, ejec-tion fraction and peak VO2. In the second quarter of 2018, a pivotal Phase 3 trial of mavacamten will begin.
In healthy animals, the pharmacological effect of mavacamten was compared to that of metoprolol, a beta blocker commonly prescribed in the management of HCM, in an acute setting. Mavacamten reduced systolic performance and increased end diastolic volume (EDV) while preserving
end diastolic pressures (EDP) and systemic blood pressure. By contrast, metoprolol, at matched levels of negative systolic perfor-mance, caused increased EDP with signifi-cantly less increase in EDV. Chronic treat-ment with mavacamten over a nine-month period showed a comparable profile, char-acterized by preserved echocardiographic indices of diastole and filling pressure. Taken together, these data indicate a dis-tinct and unique mode of action for mava-camten, providing evidence of improved left ventricular compliance that accompa-nies reduced myocardial contractility.
“We are excited by the preclinical find-ings that mavacamten can improve dia-stolic compliance in healthy animals, and we will shortly be sharing data from our PIONEER-HCM study looking at diastolic impact of the drug in obstructive HCM patients,” adds McDowell. “In addition, our upcoming Phase 2 trial in non-obstructive patients is designed to test whether, in the absence of an outflow tract obstruction, treatment with mavacamten can still yield the same improvement in feel and function reported in the obstructive population, and whether those improvements can be attrib-uted to improving diastolic compliance. Non-obstructive HCM is largely a disease of impaired relaxation. If mavacamten or another of our research candidates can be shown to increase relaxation of the heart, this could allow us to look at new indica-tions in which diastolic dysfunction is the primary cause. We are actively exploring the potential lusitropic effects of our preclinical, discovery-stage leads.”
According to McDowell, approximately 40 percent of heart failure patients suffer from impaired relaxation during diastole. Those patients whose relaxation defects can be attributed to the heart muscle itself might benefit from a therapeutic agent that improves relaxation, particularly if it does not impair systolic contraction. Positive find-ings with mavacamten in non-obstructive HCM could offer promise that this or similar mechanisms could provide benefit for these other patient populations.
“We are actively looking for second-generation mechanisms that increase diastolic compliance with reduced impact on systolic performance. We know HCM is characterized by increased contractility and a thickening of the heart walls. With mavacamten, we tried to target the biomechanical defects underlying the condition by modulating cardiac myosin activation to bring down that excessive contractility. If mavacamten is also acting by addressing the impaired distensibility of the heart that is part of HCM, it opens the door to a new understanding of mavacamten’s hemodynamic effects on disease,” says McDowell. nEDITCONNECT: E011813
MYOKARDIACONTINUED FROM PAGE 16
MyoKardia is a biopharma specializing in developing precision cardiovascular medicine, and it recently shared data clarifying the mechanism of action of its lead drug candidate, mavacamten, which is designed to modulate cardiac myosin to reduce the excess contractility characteristic of hypertrophic cardiomyopathy.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 19PRECLINICAL
in both animals and humans, it could well represent a major breakthrough in the treatment of this highly devastating blinding disease, the company reports. ARN is a painful HSV-retinol infection that can cause blindness.
Borniuk presented the “Effect of NanoViricides Anti-Viral Agents in a Mouse Model of Acute Retinal Necrosis (ARN)” in a slide show at the Ocular Microbiology and Immunology Group (OMIG) of the American Academy of Ophthalmology.
“The main point of the presen-tation was to show the impressive effectiveness of our drug candidates in a well-established animal model of acute retinal necrosis, which is a severe and blinding disease dif-ficult to treat in humans and with invariably poor outcomes,” Borniuk told DDNews.
“Our broad-spectrum herpes candidate is consistently effective in preclinical trials against VZV (shingles) HSV-2 (genital herpes) and HSV-1 (cold sores and ocular herpetic keratitis),” she says. “The important slides are those which show the mechanism of action of this platform, which is unique in that it actually kills the virus—not just inactivates it—but that it is safe and non-toxic, and that the platform can be used to develop viricides against any virus whose structure is known. The key slides are the data slides at the end, which showed by several parameters measured (including viral load and retention of normal structure of the retina), that our drug can-didates were superior to the stan-dard treatment currently used for therapy, which is the drug acyclovir in various forms.”
The company has developed a patented unique platform for actu-ally killing viruses, Borniuk notes. There is no existing antiviral which does this. All of the current anti-virals merely inhibit a metabolic pathway of the particular virus, slowing its growth.
“The nanoviricide has a core structure consisting of a micelle, to which is attached a ligand, the structure of which is computer generated to mimic the attach-ment point of the virus onto the cell,” Boniuk explains. “One of the first diagrams describing this, the nanomolecule of the NanoViricides drug, is very tiny, and several of the nanomolecules engulf the virus, breaking up its surface structure and rendering it inactive.”
“The particles break down into non-toxic organic substances which are easily removed by normal bodily digestive processes,” she adds. “The material is extremely safe and non-toxic and has been studied for the past 12 years in many animals and against many viruses (including influenza, HIV, dengue and others) with no toxic effects.”
EYECONTINUED FROM PAGE 16
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Currently, the company “has developed a broad-spectrum anti-herpetic drug, which has been shown in tissue culture and in ani-mal testing to be highly effective against several species of herpes, including VZV (varicella zoster virus, which causes shingles), HSV-2, which is the main causative agent of genital herpes, and HSV-1, which causes cold sores of the lip and most cases of viral herpetic keratitis of the cornea of the eye.
According to Borniuk, there are
likely no more than 1,500 cases of ARN in the United States every year, and as such, “it is not prac-tical at this point to shepherd this through the various clinical studies required by the FDA.” Instead, she tells DDNews, “We are focusing our efforts at this point on the HSV-2 which is much more frequent—present in about 50 million people in the U.S.—and the herpes kerati-tis and cold sores.”
It is significant to note that drugs used as the standard of care (acyclo-
vir and foscarnet) showed no effect, whereas the intravitreal injection of the NanoViricides compound was highly effective in the treat-ment of viral-induced retinal dis-ease and viral replication, Borniak concludes.
In other news, on Dec. 6, NanoViricides Inc. announced the start of an initial safety and pre-toxicology evaluation of its nanoviricides drug candidates targeted toward combating VZV. For reasons still unknown, one-
third of Americans who have had chickenpox will develop shingles. There is no cure because the virus resides within the body for life.
Although a shingles vaccination is available if prescribed by a physician, it is not indicated for those who have already had shingles and therefore compromised their immune systems. The market size for anti-shingles drugs is currently estimated to be in the range of billions of dollars, according to the company. nEDITCONNECT: E011814
20 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
Society for Laboratory Automation and ScreeningSLAS2018 International Conference and Exhibition
February 3–7, 2018 n San Diego Convention Center
BY JEFFREY BOULEY
ANNUAL MEETINGS of professional societies are always very interactive affairs, with networking, reuniting and socializing high among the goals in addition to educational sessions. The annual meeting of the Society for Laboratory Auto-
mation and Screening (SLAS)—this year’s SLAS2018 International Conference and Exhibition—hits that theme of connection and togetherness doubly, though, with not only a show tagline of “Where discovery meets technology” but also a message at the top of the SLAS2018 website home page that reads: “Be where the life sciences community converges—Be in San Diego for SLAS2018.”
It’s also a theme that carries into a brand new program launching at SLAS2018, called SLAS Ignite, which aims to connect industry and academic researchers on collaborative projects. As the society notes on its annual meeting website of SLAS Ignite, “Life scienc-es research today is an increasingly collabora-tive endeavor, with individuals and organiza-tions realizing tremendous benefit by tapping into the experience, insights and capabilities of peers and complementary organizations to develop the medicines and innovations that improve the human condition.
“SLAS is proud to have served as a venue for collaboration since the society’s found-ing. Bringing together a diverse community of engineers, researchers, scientists, business leaders and pioneering academic experts has enabled SLAS members to advance scientific research by using the latest technologies and insights provided by fellow members of the SLAS community.”
Where the life sciences community converges
SLAS IGNITE PRESENTATIONSAt SLAS2018, the following presentations have been selected to partake in the inaugural SLAS Ignite Academic Theater (all presentations will take place in the Exhibition Theater on the SLAS2018 Exhibition show floor):
■n Microreactor Based Online Reaction Monitoring Using Mass Spectrometry for Structural and Elemental Measurements, Heidi Fleischer, University of Rostock (Monday)
■n Label-free Raman Spectroscopy for Rapid Identification of Biologics, Santosh Paidi, Johns Hopkins University (Monday)
■n Introduction to Disulfide Trapping, a site-directed fragment screening technology, Michelle Arkin, University of California, San Francisco (Monday)
■n Identifying New Drug Targets by Illuminating the Druggable Genome, Aaron Pawlyk, National Institutes of Health (Tuesday)
■n Combinatorial Drug Discovery in Nanoliter Droplets, Paul Blainey, The Broad Institute (Tuesday)
■n A large-scale microfluidic technology for high-content screening of C. elegans using commercial imaging platforms, Sudip Mondal, University of Texas, Austin (Tuesday)
NEW: SOLUTIONS SPOTLIGHT & MORE TRACKSAlso new for SLAS2018 is a program for exhibitors called Solutions Spotlight presentations. These 20-minute presentations are for highlighting a new product or customer case study enabled by way of a company’s technology, and they will take place in the SLAS2018 Exhibition Theater, which is also making its debut at SLAS2018 in San Diego.
On the educational side of the meeting, there are also several new tracks added: Biologics Discovery, Chemical Biology and High-Definition Biotechnology.
San Diego plays host to this year’s International Conference and Exhibition of the Society for Laboratory Automation and Screening
ALL PHOTOS IN THIS FEATURE ARE PROVIDED COURTESY OF SLAS, AND REPRESENT SCENES AND ACTIVITIES FROM THE SLAS2017 MEETING IN WASHINGTON, D.C.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 21SLAS2018 MEETING
February 3–7, 2018 n San Diego Convention Center
BIOLOGICS DISCOVERYSLAS describes the Biologics Discovery track thus: The success of biologic therapeutics in the clinic has put greater emphasis on earlier stage efforts to increase efficiency, productivity and innovation. This track will emphasize innovative solutions to increase the breadth, depth and impact of early stage efforts to fuel the biologics pipeline. How automation and screening can play a key role in the progression of new therapeutics as well as the impact of novel assays, microfluidics and biorepositories. Planned sessions include:
■n Assays and Screening for Biologics■n Next-Generation Biologics Discovery
■n Biobanking: At the Intersection of Biospecimens and Discovery
The following SLAS2018 Short Courses are recommended for those interested in biologics discovery:
■n 3D Cell-Based Assays for Drug De-Risking
■n Sample Management: Best Practice, Trends and Challenges
CHEMICAL BIOLOGYThe Chemical Biology track will focus on the challenges of addressing targets with small molecules, including validation of targets using tool molecules and proof of target engagement through appropriate biomarker identification. Additionally, this track will cover advances in library design and keeping libraries current, and a session will be dedicated to DNA-encoded libraries. Planned sessions include:
■n A Chemistry Focus on Small Molecule Libraries
■n Affinity-Based Lead Discovery using DNA Encoded Chemistry
■n Target Selection and ValidationThe following SLAS2018 Short Courses are recommended by the society for those interested in chemical biology:
■n Next Generation Sequencing Technology Fundamentals and Applications
■n Phenotypic Screening: Why, When and How
■n Sample Management: Best Practice, Trends and Challenges
HIGH-DEFINITION BIOTECHNOLOGYAs for the High-Definition Biotechnology track, SLAS says: This track focuses on the application of microfluidic, optical and molecular tools in disease biology, diagnostics, screening and translational medicine. The session will emphasize state-of-the-art quantitative high-throughput and high-resolution approaches in both simple cellular systems and complex tissues. These approaches enable multiparametric studies that reveal the interplay of genetics, disease and therapeutic opportunities and move personalized medicine ahead. Topics include the latest specialized engineering and assay technologies, including single-cell and sequencing-based approaches, and cutting-edge application and disease areas including immuno-oncology. Planned sessions include:
■n High-Definition Technology Platforms for Single Cell Analysis
■n Novel Approaches to Identify
www.horizondiscovery.com
Combining whole-genome (interference)
and (activation) screening to understand
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with Horizon’s next generation functional genomicsPower up your discovery pipeline
Targets for Specialized Medicine■n Genomic and Proteomic Assays and Devices for Diagnostics and Translatable Biomarker Approaches
The following SLAS2018 Short Courses are recommended for those interested in high-definition biotechnology:
■n Next-Generation Sequencing Technology Fundamentals and Applications
■n Introduction to Flow Cytometry■n Advanced Flow Cytometry
SLAS2018 CONTINUED ON PAGE 23
22 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.comSLAS2018 MEETING
On Your Mark, Get Set, Go!Pack your running shoes. Start your Tuesday morning with a brisk run or walk along the San Diego waterfront with your fellow SLAS2018 attendees. This non-competitive event benefits the SLAS Educational Fund.Date: Tuesday, Feb. 6Start Time: 6:30 a.m.Location: Roy’s Restaurant at Marriott Marquis (Outdoors; Seaside Boardwalk)
SLAS2018 KEYNOTE SPEAKERSMONDAY, FEBRUARY 5Dr. Benjamin F. Cravatt will deliver the SLAS2018 opening keynote address. Cravatt is a professor and co-chair of the Department of Molecular Medicine at The Scripps Research Institute. His research group is interested in understanding the roles that enzymes play in physiological and pathological processes, especially as pertains to the nervous system and cancer.
WEDNESDAY, FEBRUARY 7Marc Abrahams will deliver the SLAS2018 closing keynote. Abrahams writes about research that makes people laugh, then think. He founded Ig Nobel Prize Ceremony in 1991, and serves as its master of ceremonies. He co-founded and edits the magazine Annals of Improbable Research (AIR), hosts the Improbable Research weekly podcast (distributed by CBS), and wrote This is Improbable, The Ig Nobel Prizes and other books. He edits and writes much of the website and blog www.improbable.com and the monthly newsletter mini-AIR.
Assay Guidance Workshop for High-Throughput Screening and Lead DiscoverySATURDAY, FEBRUARY 38 A.M. TO 5 P.M. Registration: This workshop is available to SLAS2018 registrants only and requires an additional registration fee of $399.
Summary: This full-day workshop will cover a broad range of critical concepts underlying assay development for high-throughput screening (HTS) and lead discovery projects. Many of the methodologies successfully implemented in such projects have been “tribal knowledge” within the pharmaceutical industry and not readily found in a classroom or the literature. This tribal knowledge has been developed for decades into detailed chapters within the AGM [Assay Guidance Manual] to facilitate reproducible assays that can identify the most promising compounds for development of molecular probes or clinical candidates for drug discovery and development. An increasing number of researchers are actively developing well validated assays for drug discovery that include phenotypic and biochemical assays for lead optimization. This workshop is designed to disseminate critical information about the implementation of robust assay methods and intended to benefit the entire drug discovery community. Many of the workshop instructors have 20 to 30 years of experience in the field of drug discovery.
Who Should Attend? The target audience is individuals involved in bioassay development for drug discovery and development. The AGM and this workshop will be a valuable resource for academic, industrial and government laboratory scientists who are planning or beginning to develop test methods for high or low throughput screening that are amenable to automation using appropriate statistical and operational concepts. The workshop will also be useful for early career researchers and experienced investigators who wish to learn about the latest assay concepts for HTS and lead optimization.
Benefits: The workshop will provide participants with a broad, practical perspective on assay development so that they can: (1) improve research projects involving drug discovery, and know where to find further information; (2) identify reagents, methods and instrumentation that are well suited to robust assays; and (3) be able to develop robust assays and counter assays for new targets. Additionally, participants will have the opportunity to seek practical advice about individual research challenges.
WORKSHOP OBJECTIVES:■n Overview of the Assay Guidance Manual eBook as an important resource for detailed information about robust assay methods and best practices in quantitative biology.
■n Practical approaches for developing robust assays for biochemical, cell-based, and high-content screening as well as the selection and development of optimal assay reagents.
■n Overview on sources of assay artifacts and strategies to identify artifacts through the development and implementation of counter assays.
■n Discussion of important statistical and data analysis concepts with an emphasis on using these concepts to collect the best possible data and make go/no go decisions based on experimental results.
■n Open discussions to share experiences and seek practical advice about individual research concerns.
Ten podium presenters will vie for the $10,000 SLAS Innovation Award cash prize at SLAS2018. Hailing from academia, industry and government and selected by a panel of judges based on the potential impact of the innovation, originality/creativity and quality of science represented in their work are:
■n Santiago Costantino, Ph.D. (University of Montreal, Quebec)■n Dennis Eastburn, Ph.D. (Mission Bio Inc., South San Francisco)■n Olivier Frey, Ph.D. (InSphero AG, Basel, Switzerland)■n Rajarshi Guha, Ph.D. (National Institutes of Health, Rockville, Md.)■n Shane Horman, Ph.D. (Genomics Institute of the Novartis Research Foundation, San Diego)■n Paul Ju Sung Hung, Ph.D. (COMBiNATi Inc., Palo Alto, Calif.)■n Transon V. Nguyen (Notable Labs, San Francisco)■n Amy Rowat, Ph.D. (University of California, Los Angeles)■n Kevin Tsia, Ph.D. (The University of Hong Kong)■n Julea Vlassakis (University of California, Berkeley)
Details on each finalist, including their presentation abstracts and titles, can be viewed on the SLAS2018 Event Scheduler. The final judging takes place at SLAS2018.
SLAS2018 FUND RUN
MEET THE SLAS2018 INNOVATION AWARD FINALISTS
LOOKING FORWARD TO SLAS2019
OBVIOUSLY, MUCH REMAINS to be done after SLAS2018 to put together the next meeting, but the Society for Laboratory Automation and Screening did share with DDNews some high-level generalities for next year’s meeting.
■n SLAS2019 will be held February 2-6 at the Wal-ter E. Washington Convention Center in Washing-ton, D.C.
■n The opening keynote will be Dr. Teresa K. Woodruff, the dean and associate provost for graduate edu-cation in The Graduate School at Northwestern University.
She is also the Thomas J. Watkins Professor of Obstetrics & Gynecology, the vice chair for research and the chief of the Division of Reproductive Science in Medicine in the Depart-ment of Obstetrics and Gynecology at the Feinberg School of Medicine.
■n The closing keynote and other program details will be determined by end of summer 2018.
■n The call for abstracts will open in April.The conference site for next year’s event (www.SLAS2019.
org) was currently under development as of the writing of this article, but was expected to be live by end of January. n
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 23SLAS2018 MEETING
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IN TERMS OF SOME of the big issues on tap this year that really stand out among the podium pre-sentations and other edu-cational programming, SLAS Director of Edu-cation Steve Hamilton
says, “Continued growth of cel-lular assays, including single-cell technology. Also, machine learn-ing continues to evolve, riding on the coattails of the broad tech-nology market push in artificial intelligence.”
Looking at some specific podi-um presentations that Hamilton thought might be particularly interesting to DDNews readers, he started with the presentation titled “Automating gene editing for deciphering cancer pathways using microfluidics” and noting that the use of microfluidics to automate CRISPR workflow repre-sents an interesting combination of technologies.
Hamilton also told DDNews, “The development of antibody drugs is a very hot field. But the automated discovery platforms for this work have lagged behind that of small molecules because biologics are more challenging to work with.” However, one example of automation development over-coming some of those challenges can be found in the presentation “Accelerating Discovery: Develop-ment of a High-throughput Mam-malian Expression Platform as Part of a Fully Integrated Biologics Workflow.”
Also, he notes, machine learning (artificial intelligence) is beginning to make its way into our daily lives in many ways, and that is true in the field of drug discovery, too. The presentation titled “Prepar-ing Early Drug Discovery for the Machine Learning Revolution,” he says, “describes custom software written at Merck that uses machine learning to assist scientists in their decision-making. It’s early in this evolution, but this presentation shows how things are getting started.”
Advances in fast and inexpensive DNA sequencing have allowed this tool to be used in ways never imag-ined before, Hamilton also noted, pointing to the podium presen-tation titled “High-throughput Binder Confirmation: A New Non-combinatorial Synthesis Platform Created to Enhance and Accelerate Hit ID,” saying: “In this case, DNA is used to label and identify synthe-sized compounds that are screened in large pooled libraries to evaluate their drug-like efficacy.”
Then there is the presentation “Evaluation of DESI-MS as a Novel Platform for Label-Free Ultrahigh-Throughput Screening” of which
Hamilton comments, “Mass spec-trometry (MS) is one of the fast-est growing techniques for high-throughput screening detection. This paper describes a version of MS, desorption electrospray ioniza-tion MS, used for high-throughput screening platform.”
Also of interest: “New approach-es for single cell genome sequenc-ing and mutation analysis,” of which Hamilton notes, “The study of mutations in cells is key to understanding mutation-driven
diseases, like cancer. Looking at the DNA sequences in individual cells is the ultimate way to follow mutation pathways. This paper explains a new approach for doing that type of analysis that requires far less specialized equipment than in the past.”
Finally, Hamilton highlighted “Inflammation-on-a-Chip—High-Throughput Microscale Arrays for Human Neutrophil Swarming,” a presentation that stands out for him because: “Developing disease
models that reside on a microflu-idic chip is a recently emerging technology. This paper describes developing such a model to study the very complex disease mecha-nisms of inflammation.”
But as to why you should be attending SLAS annual meet-ings, or at least strongly consid-ering doing so, SLAS Director of Marketing Communications Tom Manning says, “Ultimately, it’s the unique combination of access to new technology, relevant, peer-
selected education and abundant networking opportunities. What’s especially unique about SLAS and this annual conference in particu-lar is the unprecedented mix of attendees diverse in professional discipline (researchers, scientists, engineers, tech developers) and organization type (industry, aca-demia, government, tech develop-ers/providers) brought together under the unique SLAS culture of friendly collaboration.” n
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24 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
CLINICAL TRIALSGood news out of Fortress
NEW YORK—Fortress Biotech Inc. recently shared clinical data on therapies being developed at its subsidiaries Caelum Biosciences Inc. and Mus-tang Bio Inc. at the 59th American Society of Hematology Annual Meeting.
Dr. Lindsay A. Rosenwald, Fortress Biotech’s chairman, president and CEO, said, “Trial inves-tigators at Columbia concluded that Caelum’s CAEL-101 dosed once weekly demonstrated early and clinically efficacious organ responses throughout a Phase 1a/1b trial, underscoring its potential to be a best-in-class treatment in AL amyloidosis and providing signals to support advancement into a Phase 2b/3 trial in the second half of 2018. In addition, trial investigators at City of Hope found that Mustang Bio’s MB-102 CAR T therapy was safe, well tolerated and achieved a complete response in acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm in an ongoing Phase 1 trial. According to City of Hope, this is the first BPDCN patient to achieve a complete response to a CAR T cell therapy.”
Interim results for MRG-106BOULDER, Colo.—miRagen Therapeutics Inc. has released interim results from its Phase 1 clinical trial of MRG-106 with the mycosis fungoides form of cutaneous T-cell lymphoma. Nine of 14 patients treated for more than a month saw a 50-percent or greater improvement in total skin disease, and patients who saw an initial response gener-ally maintained those responses with continued therapy. Additionally, it has been generally well tolerated at doses from 75 mg to 900 mg.
“We are pleased with these interim results from our MRG-106 Phase 1 trial, which includes seven patients who maintained a durable response for at least four months,” said Dr. Paul Rubin, miRagen’s executive vice president of Research and Development. “We plan to initiate a controlled Phase 2 trial in the second half of 2018 to further evaluate the potential of MRG-106.”
IN THIS SECTIONData handling/managementMore trials, more data sources, more problems ......................... 26
HematologyGood news out of Fortress ..................... 24
Neurology/Alzheimer’s diseaseClinical support for pGlu-Abeta targeting .............................. 24
OncologyCell replacement therapy ....................... 24Interim results for MRG-106 .................. 24New angle on immunotherapy ............... 24
OphthalmologyNovartis eyes nAMD (NOVARTIS from cover) ......................... 27
New angle on immunotherapySalk researchers get $2.5 million for pancreatic cancer trial involving vitamin D and KeytrudaBY DDNEWS STAFF
LA JOLLA, Calif.—Salk Institute professor and Howard Hughes Medical Institute investigator Dr. Ronald Evans has been awarded $2.5 million by Stand Up To Cancer (SU2C) as part of a multi-institution team to conduct clinical studies to open up a new avenue for immunotherapy in the treatment of pan-creatic cancer. While the cancer normally excludes immune T cells, the Evans lab discovered that modified vitamin D repro-grams the cancer environment in a way that may allow the Merck & Co. drug Keytruda to invade and destroy the tumor.
The award, spread out over three years, is part of SU2C Cata-lyst, which uses “funding and materials from the pharmaceuti-cal, biotechnology, diagnostic and medical devices industries to accelerate research on cancer prevention, detection and treatment,” according to SU2C. This award is supported by the U.S.-based pharmaceutical company Merck (known as MSD outside the United States and Canada), which is providing funding and the immunotherapy drug Keytruda (pembroli-zumab) for the clinical trial.
“The Evans lab’s discovery that vitamin D can make pancre-atic tumors more susceptible to drug therapy suggested the
Cell replacement therapyCompanies collaborate in clinical trials of ex-vivo expanded cord blood stem cellsBY ILENE SCHNEIDER
LONDON & STEVENAGE, U.K.—Plasticell, a developer of innovative stem cell technolo-gies and cell therapies, will collaborate with Anthony Nolan, a leading research organiza-tion dedicated to saving the lives of people with blood cancers, to advance clinical development of Plasticell’s ex-vivo expanded cord blood-derived hematopoietic stem cell product.
Allogeneic hematopoietic stem cell transplantation (HSCT), a curative therapy for patients with life-threatening hematological disorders, is said to be the most successful cell replacement therapy developed to date, with more than 40,000 transplantations performed per year worldwide. Cord blood, an ideal starting point for allogeneic HSCT, can be collected and banked without compromising
the donor and is more easily matched to recipients relative to bone marrow–derived material. However, the limited number of stem cells available in a single cord unit limits their use to pediatric patients and can cause delayed engraftment.
Initially, Plasticell approached Anthony Nolan to source cord blood cells for the research and development of the stem cell product from its cord blood bank. Further discussions led to the realization that
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Clinical support for pGlu-Abeta targetingProbiodrug to start Phase 2b clinical trial of PQ912 in Alzheimer’sBY LORI LESKO
HALLE, Germany—Aimed at ultimately finding a cure for Alzheimer’s disease (AD), bio-pharmaceutical company Pro-biodrug AG has begun Phase 2b trials, a double-pronged parallel
strategy of clinical studies with lead drug candidate PQ912, while reviewing potential pharma part-ners. The decision to go forward followed a successful Phase 2a clinical trial in June 2017, in
PQ912 CONTINUED ON PAGE 27 KEYTRUDA CONTINUED ON PAGE 26
Biopharma Probiodrug has begun Phase 2b studies with lead drug candidate PQ912, while reviewing potential pharma partners.
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Stem cell tech and therapy company Plasticell and research organization Anthony Nolan will collaborate to advance clinical development of Plasticell’s ex-vivo expanded cord blood-derived hematopoietic stem cells.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 25CLINICAL TRIALS
multiple synergies could be found between the two organizations. The common goal is to develop products that will ultimately improve the outcomes of stem cell transplant patients.
According to Dr. Diana Her-nandez, head of immunotherapy at Anthony Nolan, “Despite our success in connecting donors and recipients of HSCT through the Anthony Nolan stem cell register, we currently fail to find a suitable match for some of the patients wait-ing for a stem cell transplant. We see Plasticell’s expanded cord blood product as an exciting opportunity to save the lives of these patients and to improve the treatment out-come for many more blood cancer patients.”
Dr. Yen Choo, founder and executive chairman of Plasticell, added, “The partnership with Anthony Nolan and its network of transplant centers and surgeons will accelerate clinical translation of this therapy by providing world-class clinical expertise, access to cord blood banking and experience in cord blood manipulation, and importantly will greatly facilitate patient recruitment which can be a bottleneck in clinical development of expanded cord blood products.”
Plasticell has developed a small-molecule driven, GMP-compliant method of expanding hematopoietic stem cells from cord blood, bone marrow and peripheral blood. The project is part of Plasticell’s hematopoietic cell therapy portfolio, which includes the expansion of hematopoietic stem cells and the manufacture of various blood cell types from pluripotent cell sources. In the past year Plasticell has announced two separate academic collaborations in the hematology space, one with the University of Edinburgh and one with Kings College London, as well as a larger commercial collaboration with GlaxoSmithKline.
In this agreement, Plasticell will be responsible for GMP manufac-turing and clinical development of the expanded cord blood product, as well as all commercialization of the product. The company’s pat-ented formulation for the ex-vivo expansion of human hematopoi-etic stem cells from cord blood is currently in late preclinical test-ing. The next step in the develop-ment of this product is to apply for clinical trials authorization, tap-ping into the expertise at Anthony Nolan for strategic advice and help with the supply of cord blood cells.
With more than 40 years of experience in hematopoietic stem cell transplants, Anthony Nolan set up the first unrelated bone marrow donor register in the United Kingdom and led the way globally in increasing the number of unrelated donors to the combined
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worldwide register. The company’s groundbreaking research in HLA typing and matching “has already vastly improved the outcomes for many transplant patients, and it is now the gold standard across the world,” according to Hernandez.
Anthony Nolan has a substantial network of clinical professionals who understand the clinical landscape dedicated to the care of transplant patients and expertise in the logistics of cell procurement (cord blood bank) and delivery to patients. The organization uses its
stem cell register to match potential stem cell donors to patients with blood cancer and blood disorders in need of a stem cell transplant. It also carries out research to increase stem cell transplant success, and supports patients through their transplant journeys.
“We believe the partnership will allow both parties to reach the common goal of improving the outcomes of patients undergoing stem cell transplants to be reached much faster and more efficiently than it otherwise would have,”
Choo remarked. “We hope it will also lead to further research and development in other cell therapy products of mutual interest.”
“HSCT can be used to treat over 70 indications, ranging from cancer to
metabolic diseases. The commercial potential is to significantly increase the market for HSCT by allowing cord blood to be used as a source of HSCs,” he concluded. nEDITCONNECT: E011816
“We believe the partnership will allow both parties to reach the common goal of improving the outcomes of patients undergoing stem cell transplants to be reached much faster and more efficiently than it otherwise would have.”Dr. Yen Choo, executive chairman of Plasticell
CLINICAL TRIALS26 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
More trials, more data sources, more problemsTufts survey reveals that plans to use greater range of patient data in clinical trials also means a need to prepare for management challengesBY DDNEWS STAFF
BOSTON & PLEASANTON, Calif.—The volume and diversity of data sources used in clinical trials are expected to increase significantly over the next three years, according to new research from the Tufts Center for the Study of Drug Development, bringing complications as well as potential advantages.
In the “2017 eClinical Landscape Study: Assessing Data Management Practices, Performance, and Challenges” survey report, one of the larg-est, most in-depth surveys of clinical data management professionals, 97 percent of companies say they will increase use of at least one clinical data source to make fast-er, more accurate decisions during trials. However, 98 percent of respondents cur-rently report challenges with their clinical data management systems, indicating that companies will need to be better prepared to collect and analyze the growing volume of real-world patient data available from a variety of sources.
“Clinical trial complexity is challeng-ing scientific, operating and technology solution domains,” said Ken Getz, research associate professor and director at the Tufts Center for the Study of Drug Devel-opment. “At the same time that clinical teams are managing traditional data from case report forms and local and central labs, they are being forced to step out of their comfort zone to manage, integrate and analyze data from more diverse and less compatible sources, including smart-phone and wearable devices, real-world evidence and social media.”
According to Tufts, life-sciences com-panies use an average of four data sources in clinical trials today. In three years, the number of data sources utilized is projected
to increase to six, with 70 percent of com-panies planning to use a new data source that they are not leveraging today.
The survey also showed very significant changes in the range of clinical information organizations plan to use in the next three years. Nearly all (93 percent) respondents
expect to use electronic informed consent data (up 62 percentage points from today). A majority of companies also plan to use mobile health and smart phone data (each increasing 47 percent-age points) and e-source data
(increasing 46 percentage points).Significant differences were also
observed when comparing company type and size. CROs report they plan to use more data sources than sponsors. Simi-larly, those with the highest trial volumes (greater than 15 trials per year) say they will use more sources of clinical data with-in the next three years compared to those
with lower trial volumes.While the industry expects to leverage
a greater range of patient data in clinical trials, today companies are primarily man-aging electronic case report form (eCRF) data in their primary electronic data cap-ture (EDC) system. In three years, 93 per-cent of respondents aim to use electronic patient-reported outcomes (ePRO) and electronic clinical outcomes assessment (eCOA) as sources, but today that data makes up only 4 percent of the total data managed in EDC. Similarly, 76 percent
plan to use mobile health data as a source, but only 10 percent are currently manag-ing it in their primary EDC application, and it represents just 0.3 percent of the total data managed in EDC.
The majority of data in EDC (78 percent) is eCRF, which only provides one dimen-
sion of data into a patient’s overall health. Moving forward, to collect and analyze a higher volume and variety of electronic data beyond just eCRF, there will be a greater need for EDC applications to better access and centralize clinical information.
When asked about the single biggest challenge with their clinical data man-agement systems today, most respondents cite cycle time (30 percent). Cost was the second most prevalent challenge among respondents (29 percent), followed by the number of clinical systems (18 percent).
The amount of companies that cite “num-ber of systems” as their single biggest chal-lenge rises to 28 percent as trial volume increases. Respondents with high trial volumes have seven applications versus four for those with low trial volume. As companies manage more trials, the abil-
ity to unify applications and processes will become increasingly important in improv-ing trial efficiency.
Specific to EDC, loading data into the primary EDC application is an issue for the majority (77 percent) of sponsors and CROs, and 66 percent of those point to EDC system or integration issues as the main cause. Data loading challenges risk becoming a larger problem as companies utilize more data from more sources over the next three years. nEDITCONNECT: E011819
“At the same time that clinical teams are managing traditional data from case report forms and local and central labs, they are being forced to step out of their comfort zone to manage, integrate and analyze data from more diverse and less compatible sources, including smartphone and wearable devices, real-world evidence and social media.”Ken Getz, director of the Tufts Center for the Study of Drug Development
According to Tufts research, almost all companies surveyed plan to boost use of one or more clinical data sources, but almost all of them are also reporting challenges with their current clinical data management systems.
TOOLS & TECHNOLOGY
added potential to also wake up the patient’s own immune system,” says Salk President Elizabeth Blackburn. “Combining vitamin D and immuno-oncology gives new hope to tens of thousands of pancreatic cancer patients whose treatment options have been devastatingly limited thus far. This could be a game changer.”
Pancreatic cancer is one of the deadliest types of cancers, both because it is often diagnosed late and because its unique tumor environment makes it impervious to both chemotherapy and immunotherapy, Salk points out. Pancreatic tumors co-opt the body’s natural wound-healing response, hiding behind a wall of immune cells and inflammatory molecules almost like an armor that drugs can’t penetrate. In the meantime, the tumor uses the nutrients that should be supporting the immune cells to nourish itself.
“We have to bring pancreatic cancer treatment into the modern age,” stressed Evans, who is the director of Salk’s Gene Expression Laboratory and holder of Salk’s
March of Dimes Chair in Molecular and Developmental Biology. “This cancer is a particularly strong foe. It has resisted basically everything thrown at it. But we believe that it can be tamed, conquered and hopefully cured. This grant is a big step toward making that happen.”
As Salk notes, the “armor” surrounding and protecting pancreatic tumors is controlled by a molecular switch that the Evans lab showed can be controlled by a special synthetic form of vitamin D. When Evans and colleagues administered the drug to mice and a small number of humans, it “cooled down” the inflamed environment, allowing chemotherapy to be more effective.
“The Salk team will work with Transla-tional Genomics Research Institute (TGen) in analyzing patient samples to figure out whether our theories about combining vita-min D and immunotherapy are correct or not—and we’ll know that pretty rapidly,” said Dr. Michael Downes, a Salk senior sci-entist and co-principal investigator of the new grant.
Heading the clinical group in Arizona is Dr. Daniel Von Hoff of TGen, who also is the chief scientific officer at HonorHealth,
a primary clinical trial site. Salk will also work closely with Dr. Andrew Lowy and the clinical oncology group at the University of California, San Diego Cancer Center.
“We are extremely excited about this trial, because for the first time we’re able to get patients into remission—even stage IV patients—where we see the tumor
shrink,” noted Von Hoff. “The high dose of this vitamin D derivative allows the body’s immune system to go from viewing the cancerous cells from something that is normal, to recognizing them for the invaders they are and hopefully attacking them as they would a common infection.” nEDITCONNECT: E011818
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Upcoming clinical trials will explore a discovery that vitamin D can make pancreatic tumors more susceptible to drug therapy.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 27CLINICAL TRIALS
which early-onset Alzheimer’s patients showed improvement in memory and cognition.
Konrad Glund, co-founder and CEO at Probiodrug, states that in the Phase 2a, SAPHIR program, PQ912 showed “a very strong target engagement of 92-percent QC inhibition, significant cognitive improvements in working memory in the ‘one card back’ test, a clear trend on psychomotor speed in the detection test at the functional level, a very significant positive effect on the EEG theta power and encouraging positive results on synaptic and inflammatory cerebrospinal markers.”
“Altogether, these results are very encouraging, as they provide evidence for pGlu-Abeta being synaptotoxic and strongly support the therapeutic strategy pursued by Probiodrug,” Glund says, who adds that the upcoming Phase 2b core program will consist of two clinical trials: one to be executed in the European Union and the other in the United States.
“This program will build on the excellent and efficient infrastructure which was established for the Phase 2a SAPHIR study,” he says. “More-over, it is based on the valuable results of the SAPHIR study, and
has been designed with the guidance of international KOLs [key opinion leaders] in the Alzheimer’s field.”
The study “will include AD patients similar to those included in the SAPHIR Phase 2a trial, i.e. early-stage AD patients charac-terized by their cognitive status,” Glund adds. “We need the data from core Phase 2b to design any Phase 3 trial.”
The “increasing evidence for targeting toxic Abeta oligomers as a key culprit of the AD pathology, in which pGlu-Abeta seems to play a
significant role, is providing sound support for our efforts,” Glund explains. “We are confident that this double-pronged strategy will efficiently expedite and safeguard the advanced development of PQ912.”
The Probiodrug design is revolutionary, he says. Probiodrug’s innovative approach involves the development of specific inhibitors for the enzyme glutaminyl cyclase, the enzyme which is inhibited by PQ912 and instrumental in the creation of pGlu-Abeta.
Contemporary approaches to treat Alzheimer’s are aiming for disease modification, Glund says. Probiodrug has identified a new concept based on the current understanding of early Alzheimer’s pathology.
This approach “is unprec-edented,” he adds. “Prof. (Philip) Scheltens, a well-experienced and known neurologist who has been involved in many AD studies, was instrumental to set up the clinical development plan. We are follow-ing the path forward to translate the early findings into robust effi-cacy data. It is too early, however, to define the specific scope and characteristic effects.”
There “is a big medical need to find a cure for Alzheimer’s, and it is a big problem for society,” Glund says. “Germany’s previous prime
minister made it a goal for 2025 of achieving a cure or an effective treatment for Alzheimer’s.”
Today, 47 million people live with dementia worldwide, and this number is projected to triple to more than 131 million by 2050, as the population ages, according to the World Alzheimer Report, 2016. Alzheimer’s has an estimated global societal cost of $818 billion, and will become a trillion-dollar disease by 2018.
Scheltens, director of the Alzheimer Center VU University Medical Center Amsterdam, presented a poster of the Phase 2a results at the 10th Clinical Trials on Alzheimer’s Disease Conference in Boston entitled “Phase 2a Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel-group Safety and Tolerability Study of PQ912 in Subjects with Early Alzheimer’s Disease (SAPHIR).”
Scheltens reported positive top-line pharmacodynamic and efficacy results in early-stage AD patients, showing significant improvements in a working memory test and a clear trend in a detection test.
Scheltens explained that pGlu-Abeta is crucial in the formation of synapto-/neurotoxic oligomers. These oligomers impair synaptic function and integrity. As pGlu-Abeta is formed by the enzyme Glutaminylcyclase and PQ912 is an
inhibitor of the enzyme, treatment with PQ912 prevents pGlu-Abeta and oligomer formation, causing improved memory and cognition in early Alzheimer’s patients.
The primary endpoint was safety and tolerability, with no overall major safety concerns, he said. “Secondary endpoints: Very strong QC-inhibition in the brain, significant improvement in a cognitive test of the work-ing memory domain and a shift towards normal in the theta wave of quantitative EEG, as well as encouraging results in the right direction on synaptic and inflam-matory biomarkers determined in the spinal fluid.”
“The encouraging positive effects on secondary readouts are support-ing the hypothesis of p-Glu-Abeta being a synaptotoxic Abeta variant and are making the program attrac-tive to go forward,” he noted. “The study reveals a positive benefit-risk ratio and provides important guid-ance how to go forward.”
Scheltens said the Phase 2a study resulted in some anecdotal progress, as well. When the clinical trial concluded, some families of the patients/subjects remarked seeing improvement in their loved ones, who seemed more connected, less confused and to feel better. They wanted the trial to continue. nEDITCONNECT: E011817
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“Altogether, these results are very encouraging, as they provide evidence for pGlu-Abeta being synaptotoxic and strongly support the therapeutic strategy pursued by Probiodrug,” says CEO Konrad Glund of Phase 2a results for PQ912 as his company gears up for Phase 2b.
(q12w) treatment interval, follow-ing the loading phase in clinical trials.
According to a Novartis spokes-person, “Both brolucizumab and aflibercept are vascular endothe-lial growth factor (VEGF) inhibi-tors. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases. Brolucizumab is the most clini-cally advanced humanized single-chain antibody fragment to reach this stage of development.”
In both trials, patients were randomized to either broluci-zumab or aflibercept. Following the three-month loading phase, patients in the brolucizumab arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits. Aflibercept was dosed bi-monthly according to its label.
Brolucizumab met the primary efficacy endpoint of non-inferior-ity to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48 in both trials. These results were achieved while a major-ity of brolucizumab patients—57 percent in HAWK and 52 percent in HARRIER—were maintained
on a q12w dosing interval immedi-ately following the loading phase through week 48.
“While the primary endpoint of the trial was non-inferiority vs. aflibercept in mean change in best-corrected visual acuity (BCVA), superiority was shown in three secondary endpoints that are considered key markers of nAMD disease—CST, retinal fluid and disease activity,” notes the Novartis spokesperson. “In these three secondary endpoints, significantly fewer brolucizumab patients showed signs of disease activity as well as retinal fluid (intraretinal fluid and/or sub-retinal fluid). The most frequent ocular adverse events for brolu-cizumab (greater than 5 percent of patients in either study) were reduced visual acuity, conjuncti-val hemorrhage, vitreous floaters and eye pain.”
Brolucizumab 6 mg patients demonstrated superior reduc-tions in central subfield thick-ness (CST). In nAMD, an elevat-ed CST—as measured by optical coherence tomography (OCT)—is a key indicator of abnormal fluid accumulation in the retina. Sig-nificantly improved CST reduc-tions were evident at week 16 and at week 48.
“HAWK and HARRIER dem-onstrated that brolucizumab has the potential to positively impact disease management and provide long-lasting treatment effect,” said Dr. Pravin U. Dugel, manag-
ing partner of Retinal Consultants of Arizona, clinical professor of theRoski Eye Institute at the Keck School of Medicine of the Univer-sity of Southern California and principal investigator of both trials. “HAWK and HARRIER showed that brolucizumab out-performed aflibercept on disease activity assessments, including key measures of disease progres-sion seen on OCT, which forms the basis of a clinician’s treatment decisions. Improvements in these key OCT measures were seen as early as week 16 and maintained at week 48, with a majority of bro-lucizumab patients on a 12-week treatment interval.”
Week 16 was an important data point when the treatment assessment for brolucizumab and
aflibercept were identical, pro-viding an opportunity to observe how both drugs performed in a matched comparison. At week 16, relative to aflibercept, 35 percent fewer brolucizumab 6 mg patients showed presence of intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) in HAWK, and 33 percent fewer in HARRIER. At week 48, relative to aflibercept, 31 percent fewer patients on broluci-zumab 6 mg had IRF and/or SRF in HAWK, and 41 percent fewer in HARRIER. The absence of fluid for patients in the brolucizumab arm suggests the potential for a long-lasting effect and decreased treatment need.
With brolucizumab, fewer patients had active disease at week 16. Active disease was observed
in 23.5 percent of brolucizumab 6 mg patients versus 33.5 percent of aflibercept patients in HAWK, and in 21.9 percent of brolucizum-ab patients versus 31.4 percent of aflibercept patients in HARRIER.
“Having delivered on our non-inferiority endpoint with a majority of patients on a q12 week interval, we’re truly excited to share these data showing that brolucizumab clearly improves key anatomical outcomes that are biomarkers of disease,” said Vas Narasimhan, global head of drug development and chief medical officer at Novartis. “Brolucizumab represents a major scientific and clinical advancement for patients, caregivers and retina specialists around the world.”
In other recent Novartis news, Biospace reports that Novartis has received a priority review voucher in a $130-million agreement with Ultragenyx Pharmaceutical Inc., the second it has gained in the past few months.
“Novartis has provided guid-ance that it anticipates filing for U.S. regulatory approval in Q4 2018 for an nAMD indication,” concludes the company spokes-person. “With regard to the ongo-ing Phase 3 studies, it is anticipat-ed that the readout of the two-year data will occur in mid-2018. We [also] look forward to exploring the potential of brolucizumab in a number of indications, includ-ing DME and RVO.” nEDITCONNECT: E011803
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Novartis recently announced positive results from two Phase 3 studies of brolucizumab vs. aflibercept, showing non-inferiority in the primary endpoint, superiority in key retinal health outcomes and long-lasting effect in patients with neovascular AMD.
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DIAGNOSTICS28 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
TruGraf can identify stable kidney transplant patients
MANSFIELD, Mass.—Molecular diagnostics com-pany Transplant Genomics Inc. recently had a report published in the Journal of Transplanta-tion Technologies & Research detailing the use of its TruGraf blood test on 125 kidney transplant recipients with known stable renal function. Each had surveillance biopsies performed at the same time, ones that confirmed normal histology. The test was able to identify almost 90 percent of patients who were adequately immunosup-pressed and could have avoided the biopsy. The retrospective data modeling study showed that TruGraf testing of blinded samples saw an overall sensitivity of 88 percent with a positive predictive value of 86 percent.
“The results of this study indicate clinical util-ity of TruGraf testing as a non-invasive alterna-tive to surveillance “protocol” biopsies to confirm immune quiescence in kidney transplant recipi-ents with stable renal function,” said Dr. M. Roy First, chief medical officer at TGI and lead author of the study.
A new collaboration for early disease detection
HEIDELBERG & SAARBRÜCKEN, Germany—An exist-ing partnership is getting a boost with the news that Hummingbird Diagnostics GmbH and Saar-land University have reached a comprehensive framework agreement regarding an expanded collaboration in molecular diagnostics. Their work will focus on validating miRNA biomarkers in blood samples to enable early detection of diseases such as lung cancer, COPD, Alzheimer’s disease and Parkinson’s disease. The plan is to assess approximately 5,000 samples from patients with the aforementioned diseases. The agreement covers intellectual property rights and the software, results and publica-tions related to the work, and under its aus-pices, Hummingbird Diagnostics acquired rights in eight patents.
IN THIS SECTIONAutoimmune/InflammatoryPredicting lupus flares? .......................... 28
Kidney/Non-invasive testingTruGraf can identify stable kidney transplant patients ...................... 28
Molecular diagnostics/ miRNA biomarkersA new collaboration for early disease detection ................................................. 28
Neurology/DementiaExtending the team-up against AD ........ 28
OncologyA companion diagnostic with greater breadth .............................. 28
Predicting lupus flares?Progentec completes first round of financing for $1.25 million BY MEL J. YEATES
OKLAHOMA CITY—Lead investor i2E, along with Chicago-based OCA Ventures and Rochester-based Mayo Clinic Ventures, funded in late November the first round of investment to assist Progentec Diagnostics in moving its predictive technology for the onset of lupus flares closer to commercialization. Technology created by the Oklahoma Medical Research Foundation (OMRF) is at the core of the platform being developed by Progentec.
According to Dr. Mohan Purushothaman, president and CEO of the company, “Progentec, after its establishment in 2015, was looking for technologies in the diagnostic space. Progentec’s [prediction] technology was licensed from OMRF based on work done by Dr. Judith James. We continue our collaborative relationship with OMRF, and additional studies have been conducted by scientists at OMRF to further refine the algorithm and develop new areas where the technology platform could be applied.”
Progentec is working closely with OMRF’s Dr. Judith James, a world leader in lupus research and an inventor of Progentec’s technology, to further advance and refine the
Extending the team-up against ADContinuation of Probiodrug and Crossbeta partnership to identify Alzheimer’s biomarkers BY RACHEL FLEHINGER
HALLE, Germany & UTRECHT, Netherlands—Probiodrug, a biopharmaceutical company heavily focused on finding therapeutic solutions to treat Alzheimer’s disease (AD), and the Dutch biotech company Crossbeta Biosciences recently announced an extension of their 18-month-long strategic partnership governing the use of Crossbeta’s proprietary technology for biomarker development in support of Probiodrug’s clinical program in AD.
Alzheimer’s is thought to be caused by “tangles,” or twisted fibers of certain proteins. The oligomeric forms of these misfolded beta-amyloid and tau proteins play a pivotal role in the pathophysiology of the disease.
“The quantification of amyloid beta oligomers is challenging because of the very tiny amounts in which they are present in the CSF [cerebrospinal fluid], but we believe [ourselves] to be uniquely and very
well positioned to be successful because our partnership brings together the key elements to find optimized alternatives to currently available Abeta oligomer assays,” says Inge Lues, chief development officer of Probiodrug.
The companies first established the partnership in 2016 to harness Crossbeta’s
capacity to stabilize oligomers and further Probiodrug’s search for a breakthrough in AD treatment. Research specific to oligomers is very challenging due to the inherent instability of their protein aggregates. Crossbeta’s proprietary stabilization technology generates pure and functional
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A companion diagnostic with greater breadthFDA approves FoundationOne CDx companion diagnostic test for multiple solid tumorsBY LORI LESKO
CAMBRIDGE, Mass.—In a land-mark decision, the U.S. Food and Drug Administration (FDA) in December 2017 approved Foun-dation Medicine’s Foundation-One CDx, the company’s com-panion diagnostic test for solid
tumors. The approval—for what is the first-ever comprehensive companion diagnostic for mul-tiple types of cancer—advances personalized cancer care, as an estimated one in three patients across five common advanced FOUNDATION CONTINUED ON PAGE 30 LUPUS CONTINUED ON PAGE 30
FoundationOne CDx assesses all classes of genomic alterations in 324 genes known to drive cancer growth, providing crucial information to help guide treatment decisions, identifying those patients who may benefit from treatment with one of 17 on-label targeted therapies—including 12 therapies currently approved as first-line treatments.
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Probiodrug (pictured here) has extended a collaboration with Crossbeta to use that company’s proprietary technology for biomarker development in support of Probiodrug’s clinical program in Alzheimer’s disease.
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preparations of oligomeric protein species and thereby overcomes this problem, enabling highly reproducible and well-controlled assays for preclinical and clinical research and development related to therapeutics, biomarkers and diagnostics.
“We are very pleased [at] the collaboration with Crossbeta. The potential of Crossbeta’s unique technology has significant impact to overcome the challenge of establishing and validating sensitive and specific assays for Abeta- and pGlu-Abeta-oligomers to be used in the clinical studies of Probiodrug’s lead candidate, glutaminyl cyclase (QC) inhibitor PQ912,” commented Lues in 2016.
Pr o b i o d r u g h a s f o c u s e d on target ing a key neuro/synaptotoxic component of the pathology, pyroglutamate-Abeta (pGlu-Abeta), as a therapeutic strategy to fight AD. Probiodrug’s lead candidate for the treatment of the disease is PQ912, a first-in-class small-molecule inhibitor of the enzyme glutaminylcyclase. Mechanistically, the inhibitor prevents the formation of pGlu-Abeta, a modified Abeta version leading to the formation of synaptotoxic Abeta oligomers. Having successfully completed the Phase 2a SAPHIR trial, Probiodrug announced recently the preparation of a Phase 2b core program which will include this new biomarker assay.
Since the partnership began, the program has made excellent progress and has successfully met all critical milestones, the companies say. By leveraging the pivotal role of protein oligomers in AD pathology, the partners are aiming to develop a biomarker assay that allows users to detect and quantify the Abeta and pGlu-Abeta oligomer content in CSF, which would serve as a truly disease-specific AD biomarker and diagnostic with prognostic clinical value.
“Our partnership with Crossbeta has granted us access to a truly
unique technology which has proven to be crucially important for the development of high-quality biomarker assays, with adequate sensitivity and specificity to support and further the clinical program of Probiodrug’s QC inhibitor PQ912,” asserts Lues.
According to Lues, Probiodrug is now able to measure the amyloid beta plaque burden by PET imag-ing, which gives information on the insoluble amyloid plaque load. They are also able to assess the amy-
loid beta content in CSF, but this does not relate to the oligomers of amyloid beta, which are the main neurotoxic species and represent only a very small fraction of the total amount of amyloid beta that is present in the brain. Having a tool that specifically quantifies the sol-uble oligomer content would open the possibility to test and selective-ly include patients in clinical stud-ies, thereby helping to improve the likelihood that these people would benefit from the treatment.
“Another important aspect is that it would help to see the effect of disease-modifying treatments on the Abeta oligomer content. This would add important information regarding the efficacy of the treatment because oligomers are playing a critical role in the pathology. In addition, it could also help to better diagnose other diseases by ruling out the involvement of these ‘Alzheimer’s oligomers,’” notes Lues.
Guus Scheefhals, CEO of Crossbeta, added: “We are very
pleased about the extension of our partnership with Probiodrug. It is an honor being able to contribute to Probiodrug’s exciting and encouraging therapeutic program in AD with our proprietary technology. In case of successful achievement of our goals, not only will many other scientists and companies benefit from the availability of this novel, prognostic biomarker and diagnostic, but it will bring urgently needed benefit to AD patients.” nEDITCONNECT: E011820
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“Not only will many other scientists and companies benefit from the availability of this novel, prognostic biomarker and diagnostic, but it will bring urgently needed benefit to AD patients,” says Guus Scheefhals, CEO of Crossbeta regarding work in partnership with Probiodrug.
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cancers are expected to match with an FDA-approved therapy.
Foundat ionOne CDx ac t s a s a comprehensive companion diagnostic to identify patients who may benefit from treatment with specific FDA-approved targeted therapies, Foundation Medicine reports. It is also a genomic profiling test that includes genomic biomarkers to target oncology therapies, including immunotherapies. The test is also a tool for physicians to better identify patient opportunities for clinical trial participation, and it is a platform for companion diagnostic development for biopharma companies developing precision therapeutics.
FoundationOne CDx assesses all classes of genomic alterations in 324 genes known to drive cancer growth, providing crucial infor-mation to help guide treatment decisions, according to the company. It covers patients with certain types of non-small cell lung can-cer (NSCLC), melanoma, colorectal cancer, ovarian cancer and breast cancer, identify-ing those patients who may benefit from treatment with one of 17 on-label targeted therapies—including 12 therapies currently approved as first-line treatments.
The diagnostic test also reports genomic biomarkers, such as microsatellite instabil-ity (MSI) and tumor mutational burden (TMB), which can help inform the use of immunotherapies.
The number of matched on-label thera-pies indicated on FoundationOne CDx is expected to increase over time as Foundation Medicine and its biopharma partners pur-
sue FDA approval for additional companion diagnostics on the platform. Today, approxi-mately 50 percent of new cancer drugs in development are projected to have a com-panion biomarker.
“Today we know that many people with cancer do not receive biomarker testing, let alone the comprehensive genomic testing they need to be efficiently matched to the best therapeutic option,” states Andrea Ferris, president and CEO of the LUNGevity Foundation. “This FDA approval means that, in one test, patients can access therapies where companion diagnostics have been established for their cancer while getting a broad tumor profile that can identify the therapies and clinical trials they could most benefit from.”
“Along with the preliminary national coverage determination, this has the potential to democratize next-generation sequencing, lowering the barriers for patients treated in the community to access these biomarker-driven treatments,” adds Ferris.
“Comprehensive genomic profiling is the gateway to precision medicine … and offering potentially improved healthcare coverage,” states Dr. Ankur R. Parikh, who serves as medical director of precision medicine for Cancer Treatment Centers of America. “Access to important genomic information is a critical step in being able to offer innovative and targeted treatment options.”
FoundationOne CDx results are delivered
in an integrated report that identifies altera-tions matched to FDA approved therapies; identifies additional alterations in genes known to drive cancer growth; furnishes information about genomic biomarkers, including MSI and TMB; provides relevant clinical trial information; and includes inter-pretive content.
“Physicians will have an FDA-approved test for all solid tumors in their toolkit that can inform targeted and immunotherapy selection, as well as identify patient opportunities for clinical trial participation,” states Troy Cox, CEO of Foundation Medicine. “Beyond its implications for patient care, we expect that FoundationOne CDx … can help accelerate drug development and enable personalized oncology care.”
FoundationOne CDx is expected to be commercially available following finalization of the NCD from CMS. Currently, companion diagnostics only probe for alterations in a single or small number of genes, which can cost valuable time, require multiple tissue samples and miss potentially actionable information, Foundation Medicine says. FoundationOne CDx has the potential to help streamline the treatment decision process for both oncologist and patient.
Study results presented in October 2017 at the IASLC World Conference on Lung Cancer showed that FoundationOne CDx detected alterations in the EGFR, ALK, BRAF, ERBB2, KRAS and BRCA1/2 genes and demonstrated concordance with FDA-approved companion diagnostics currently used to match targeted therapies to patients with certain types of NSCLC, melanoma, colorectal cancer, ovar-ian cancer and breast cancer. nEDITCONNECT: E011821
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platform and its associated algorithms. The company’s technologies include highly accurate tests for early diagnosis, a score to track underlying disease activity and a predictive score for lupus flares. With the current funding round, which brought in $1.25 million, Progentec plans to conduct a retrospective study at OMRF and prospective studies at OMRF and Mayo Clinic to further refine these algorithms.
“The ability to predict an impending flare represents significant value to lupus patients and their physicians. This test is currently not available and is a focus area for us,” said Sanjiv Sharma, chairman of Progentec.
OMRF has established a significant focus on lupus. “OMRF has been at the forefront of leading scientific research, especially in the field of lupus,” noted Manu Nair, Vice president of technology ventures at OMRF. “Progentec is going on a trajectory that we have traversed in the past, and we believe that our science, combined with the entrepreneurial and management skills brought in by Progentec, will successfully bring these tests to the market.”
“There was clear recognition of the
value that a test of this nature can bring to the world of lupus care and management. Lupus is a terrible condition, and the flare-ups experienced by patients not only affect their quality of life, but also their health in very adverse ways,” Purushothaman con-tinues. “Thus, there is a significant unmet need for solutions that can help manage lupus in a better way. This aspect was clearly recognized by the investors in this current round.”
“We are pleased to work with OCA Ventures and Mayo Clinic on this prom-ising, Oklahoma-born project,” said Scott Meacham, president and CEO of i2E Inc. “It is important to work together to identify and develop technologies like these in their early stages when they most need help.”
Mayo Clinic Ventures also found Progen-tec’s technology aligned with their clinical interest in lupus, particularly in manag-ing patients with a diagnostic to improve patient care, while potentially reducing clinical costs. “We are excited to work with Progentec and OMRF to advance this tech-nology and hopefully bring about a change in how lupus patients are diagnosed, man-aged and treated,” said Andrew Danielsen, vice chair of Mayo Clinic Ventures. Mayo Clinic plans to use any revenue it receives to support its not-for-profit mission in
patient care, education and research.Lupus causes the immune system
to attack the body’s own tissues, and sufferers of the condition have periods of flares and remission, with organs such as the skin, kidneys, lungs and reproductive organs typically affected, as well as the cardiovascular system.
“For flare prediction, we have used a large number of biomarkers—both regula-tory and inflammatory. A soluble media-tor score is then developed using certain proprietary weights assigned to these readings. This diagnostic test is not based on any existing test. In fact, as far as we know, this would be the first test in the market to predict lupus flares,” points out
Purushothaman.“We do have plans to build at least two
other tests that will use a similar approach; however, the biomarkers involved and the algorithms used are expected to be different,” adds Purushothaman. “These tests are currently under development. The areas in focus are a test to classify lupus patients accurately and well before symptoms appear, and a test to track the underlying disease activity. [Tracking] underlying disease activity will fundamentally change how lupus patients are identified for specific interventions and allow for better management decisions at all levels of the healthcare system.” nEDITCONNECT: E011822
Progentec’s lupus flare prediction technology was licensed from OMRF based on work done by Dr. Judith James (pictured here).
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Foundation Medicine’s FoundationOne CDx, a companion diagnostic test for multiple solid tumor types, recently received FDA approval.
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“The ability to predict an impending flare represents significant value to lupus patients and their physicians. This test is currently not available and is a focus area for us.”Sanjiv Sharma, chairman of Progentec
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CONTRACT SERVICESA ‘MileStone’
acquisitionBILTHOVEN, The Netherlands—Global contract research organization Factory CRO announced in the fourth quarter of 2017 that it had acquired MileStone Research Organization, a San Diego-based company that specializes in clinical research and reimbursement solutions for the medical device and biologics industries. Financial details were not released.
“The combination of Factory and MileStone is good for everyone,” said Dr. Kevin Liang, founder of MileStone Research Organization. “Our specialization in clinical and regulatory affairs, as well as reimbursement for innova-tive technologies, aligns us perfectly with Fac-tory. Factory’s full-service clinical offerings and extensive knowledge of the European regulatory environment will greatly expand our reach. The mutual commitment of both organizations to pro-vide world-class solutions and superior client support will continue to motivate the company’s growth moving forward.”
Frost & Sullivan recognizes Sartorius Stedim Biotech
GOETTINGEN, Germany & GLASGOW, U.K.—The Frost & Sullivan’s 2017 European Customer Service Leadership Award for Bioanalytical Contract Test-ing Services was awarded to Sartorius Stedim Biotech this past October. The award recognized the product and service combination of Sartorius Stedim BioOutsource, the company’s Glasgow-based subsidiary. Frost & Sullivan’s Excellence in Best Practices Awards acknowledge companies and individuals that demonstrate world-class performance in their industries.
“Sartorius Stedim BioOutsource cultivates transparent relationships with business partners to enhance the overall service experience and customer satisfaction,” said Norma Vela-Roch, Best Practices Analyst at Frost & Sullivan. “The company has an impeccable reputation in its approach to customer service and understands the regulatory pathways and specific milestones in their customers’ development programs.”
IN THIS SECTIONAwards and honorsFrost & Sullivan recognizes Sartorius Stedim Biotech ....................... 31
Business and strategyA busy end to 2017 ................................. 31A fivefold increase in sales ....................31
M&A activityA ‘MileStone’ acquisition ....................... 31Quotient Sciences acquires Pharmaterials...........................................32
A BUSY END TO 2017PPD’s Q4 includes awards, a new NIH contract and expanded service offeringsBY KELSEY KAUSTINEN
WILMINGTON, N.C.—The fourth quarter of 2017 saw Pharmaceutical Product Develop-ment LLC (PPD) sharing news that the Clin-ical Research Support Services (CRSS) pro-gram of the Division of AIDS in the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, had awarded the company a seven-year contract. The contract covers support for the assess-ment and auditing of investigative sites and laboratories, as well as capacity building, biostatistics, site training and data manage-
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A fivefold increase in salesApconiX benefits from boost via pharma sector demand for drug safety expertiseBY DDNEWS STAFF
ALDERLEY PARK, U.K.—ApconiX, a nonclini-cal safety company working with the phar-maceutical sector, has achieved a fivefold sales increase in its second year of trading, far exceeding its predicted annual forecast. On top of that, the business recently received the accolade of Start-Up of the Year at the 17th awards hosted by BioNow, the northern England biomedical and life-sciences mem-bership organization.
The company’s early success is based on delivering expertise in safety toxicology and ion channel electrophysiology to a chang-ing pharmaceutical sector, in which more companies are outsourcing their essential drug safety testing and analysis, according to ApconiX.
Founded in 2015 by Prof. Ruth Roberts, Dr. Richard Knight and Dr. Michael Morton following many years working at AstraZen-eca, ApconiX has already recruited a group of leading scientists with wide-ranging skills in preclinical drug safety. The com-pany now has more than 60 clients across the United Kingdom, United States and Europe, including Pfizer, UCB and Gilead, as well as biotechs, startups and university spinouts. Current clients also include the U.S. Food and Drug Administration and the
Institute for Cancer Research. “We formed the company with a drive and
ambition to create a world-renowned busi-ness known for nonclinical expertise sup-porting drug discovery and development. Since then, the take-up of our services has gone way beyond our expectations and includes companies, venture-capital fund-ed organizations, charities and academia,”
said Roberts, ApconiX director as well as co-founder. “Our cost-effective, flexible approach complements the way the phar-maceutical industry has evolved in recent years, with large pharma reducing its inter-nal capability and outsourcing key skills to trusted partners. Meanwhile, there are many more pharma sector SMEs [small- to
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Among other fourth-quarter activities last year, Pharmaceutical Product Development (PPD) was awarded a seven-year contract by the National Institute of Allergy and Infectious Diseases, and PPD also expanded patient-centered research services at Evidera, its peri- and post-approval business unit.
ApconiX co-founders and directors—Dr. Michael Morton, Prof. Ruth Roberts and Dr. Richard Knight (left to right)—celebrate their Start-up of the Year Award at the BioNow Awards.
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ment. Under the agreement, PPD will offer a variety of clinical and related research support services for the NIAID/DAIDS-supported clinical research portfolio, as well as other infectious diseases relevant to those with or at risk for HIV.
“We are pleased to help NIAID develop and maintain a strong clinical infrastructure to meet the needs of DAIDS’ scientific agenda,” said William Sharbaugh, chief operating officer of PPD, in a press release. “Our dedicated professionals are committed to supporting the agencies’ initiatives to improve health.”
This is hardly the first time PPD has worked together with a division of the NIH. PPD announced in March 2017 that they had extended their existing work with NIAID/DAIDS through 2024. This is the fifth renew-al of that contract, which was originally established in 1990. The contract consists
of support for a range of research related to HIV or co-infections, including monitoring therapeutic trials, prevention trials and vac-cines work. In addition, PPD predicts safety risks to participants in clinical trials as well as risks to data integrity.
In other ‘extension’ news, Evidera, PPD’s peri- and post-approval business unit, recently announced that it had expanded its patient-centered research services to help clients better gather and incorporate patient perspectives into their drug development programs. Evidera’s offerings now include clinical outcome assessment; burden of illness studies; perceptions of treatment and quality of care; patient engagement; patient-centered benefit-risk assessment, preference, utility and adherence studies;
technology (m/eHealth) validation studies; and related strategic and regulatory con-sulting. The new complement of services is expected to allow companies to gain a more complete grasp of the patient experience, from burden of illness to unmet needs and treatment preferences, in order to produce more patient-centered trial designs.
“The patient’s voice always has been core to Evidera’s work,” Dr. Nancy Kline Leidy, Evidera’s senior vice president of scientific affairs, remarked in a press release. “Our team of health outcomes research scientists is the largest in the field, with more than 20 years of experience in COA science and strat-egy. This new suite of patient-centered ser-vices builds on this expertise and will enable our clients to effectively navigate this new world of patient-focused drug development and value-based market access.”
“Evidera’s emphasis on patient engage-ment addresses the need for patient-centered evidence, which is increasingly required by key stakeholders and decision-makers,”
added Dr. Margaret Vernon, vice president and general manager of the patient-centered research team. “Our aim is to leverage our regulatory insights and scientific expertise to help our clients successfully engage patients throughout the drug development process.”
The end of 2017 brought some awards with it as well for PPD. At the 2017 TOPRA (The Organization for Professionals in Reg-ulatory Affairs) Awards in London, also held in the fourth quarter of the year, PPD took home two honors for excellence in regula-tory affairs.
Evolus Inc. nominated the Evolus-PPD team for the TOPRA Award for Support, which acknowledges the pivotal role of sup-porting organizations in drug developing. PPD has provided Evolus with an end-to-
end service solution that includes scientific advice through to clinical trials and the filing of global marketing applications.
The second award, the TOPRA Award in the Contribution category, was received by Dr. Clare Ryder, PPD’s associate director of regulatory affairs. This award highlights significant, consistent contributions to a team, project, regulatory science or the profession. Ryder, a member of the Evolus-PPD team, was acknowledged for meeting clients’ deadlines with regards to submitting
marketing applications.“PPD’s regulatory affairs teams are com-
mitted to the pursuit of excellence in pro-viding regulatory intelligence for product development and registration strategies and ensuring high-quality submissions to regula-tory authorities,” Sharbaugh remarked. “Con-gratulations to our employees for being rec-ognized as industry leaders for their exper-tise and efforts to help our clients improve patient health.”
PPD was recognized at another award event in the same quarter. The fourth annual World ADC Awards, which celebrate distinction within the field of antibody-drug conjugate research, were held in conjunc-tion with the 2017 World ADC San Diego Conference. At the event, PPD was named Best CRO Provider, an award that “acknowl-edges the excellence and dedication of PPD Laboratories professionals in supporting cli-ents’ antibody-drug conjugate research to develop new anticancer therapies,” as noted in a press release.
“This award is evidence that PPD Labo-ratories’ employees are at the leading edge of ADC research and are driven to help clients succeed in combating cancer,” Dr. Chris Fikry, executive vice president of PPD Laboratories for PPD, commented in a state-ment. “In the past five years, the bioanalyti-cal lab has completed more than 5,000 stud-ies, providing vital pharmacokinetic, phar-macodynamic and immunogenicity data to support our clients’ efforts to develop new medicines to improve health.” nEDITCONNECT: E011824
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medium-sized enterprises] needing access to specialized services. That’s why we have established our own laboratory to help meet the market need for high-quality data.”
ApconiX is building a number of strategic alliances with organizations—for example, a close relationship with one local pharma company has led ApconiX to act as an outsourced safety department across its operations. Apco-niX has also established several strate-gic international alliances, including French company PhysioStim, creating a European center of excellence for preclinical cardiovascular safety evalua-tion. Its recent alliance with Sygnature Discovery ensures the Nottingham-based CRO can provide its customers
with a broader range of drug discovery services.
“Ultimately, our knowledge and expertise helps companies developing new drugs to make better decisions on drug safety,” said Roberts. “As identified in the government’s life-sciences review [for 2016], drug discovery and development needs greater collaboration to de-risk the process and reduce the number of project failures caused by safety toxicity. The changing face of drug discovery and development means a safe pair of hands is needed to help companies navigate the difficult pathway towards safe, effective and profitable drugs.” nEDITCONNECT: E011825
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“The patient’s voice always has been core to Evidera’s work. Our team of health outcomes research scientists is the largest in the field, with more than 20 years of experience in COA science and strategy.”Dr. Nancy Kline Leidy, senior vice president of scientific affairs for Evidera
“We formed the company with a drive and ambition to create a world-renowned business known for nonclinical expertise supporting drug discovery and development. Since then, the take-up of our services has gone way beyond our expectations.”Prof. Ruth Roberts, co-founder of ApconiX
Quotient Sciences acquires PharmaterialsMove strengthens and expands formulation and manufacturing services footprint in the U.K.BY DDNEWS STAFF
NOTTINGHAM, U.K.—In late 2017, Quo-tient Sciences, a drug development services organization, announced it had acquired Pharmaterials, a contract development and manufacturing organization (CDMO) based in Reading, U.K. The acquisition strengthens and expands Quotient’s for-mulation and manufacturing services foot-print in the United Kingdom and further supports the growth of Quotient’s Transla-tional Pharmaceutics platform, following the acquisitions of SeaView Research and QS Pharma in February 2017.
Pharmaterials has a significant track record in supporting the development of small-molecule drug products for oral and inhaled delivery, according to Quotient. The company’s portfolio of services spans the characterization and optimization of drug substance physical forms, the devel-opment of preclinical and clinical formula-tions, through to clinical trial manufactur-ing and subsequent global drug product supply. The business was founded in 2000 and is located in a 48,000-square-foot facility that houses 13 GMP manufactur-ing suites, with space for future expansion.
Mark Egerton, CEO of Quotient Scienc-es, said: “The acquisition of Pharmaterials strengthens Quotient’s service portfolio from preclinical formulation develop-ment through to commercial manufac-
turing. The addition expands Quotient’s global CDMO services with added capac-ity and capabilities to better serve our cli-ents’ needs.” n
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In addition to its business activities in the fourth quarter of 2017, Pharmaceutical Product Development received multiple awards.
“The acquisition of Pharmaterials strengthens Quotient’s service portfolio from preclinical formulation development through to commercial manufacturing.”Mark Egerton, CEO of Quotient Sciences
BUSINESS & GOVERNMENT POLICY
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 33
BRIEFSON THE CUTTING EDGEA roundup of instrumentation, software and other tools and technology newsBY JEFFREY BOULEY
LONDON & SHEFFIELD, U.K.—Late last year, IN-PART, a technology company that brings together universities and businesses across the globe,
a n n o u n c e d that following s u c c e s s f u l beta testing, it is launching a new, bespoke s c o u t i n g
service for R&D professionals, called IN-PART: Discover. The new service, the company says, will “revolutionize open innovation by providing companies with novel opportunities for collaboration, specific to their requirements and often unseen elsewhere.”
Discover was successfully beta-tested with four multinational companies from the healthcare, consumer goods, electronics and chemical sector. IN-PART is now in discussion with companies spanning from large pharmaceutical companies to aeronautical engineering firms wishing to use the service.
In recent years, the company notes, interest has increased regarding open innovation, particularly as universi-ties are becoming more aware of—and open to—the benefits of collaborating with industry. However, many busi-nesses have a limited number of uni-versity contacts to target when looking for new research and struggle to make new connections beyond this network.
IN-PART maintains that while there are existing technologies that find new leads for corporate R&D teams, many of them are neither time- nor cost-effec-tive, as the company says “they rely on ‘scraping’ often outdated websites and databases, resulting in irrelevant and unavailable opportunities. By contrast,
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Soleno to relinquish Capnia subsidiary
REDWOOD CITY, Calif.—Soleno Therapeutics Inc. and Capnia Inc., its wholly owned subsidiary, have established a joint venture agreement with OptAsia Healthcare Ltd. (OAHL) to develop and commercialize Capnia’s Sensalyze technology, including a monitor that helps detect excessive hemolysis in neonates, as well as related products. This agreement precedes changes for all three organizations—OAHL will invest up to $2.2 million in tranches to buy shares of Capnia, after which Capnia will cease to be a subsidiary of Soleno and instead OAHL will be responsible for funding its operations.
“The completion of this transaction focuses our business solely on the development of rare disease therapeutics with diazoxide choline controlled-release being the lead asset,” said Dr. Anish Bhatnagar, CEO of Soleno. “This JV allows the financing of further development of CoSense and related assets by OAHL, while providing the possibility of delivering future value to Soleno.”
NIH awards $2.3M to Thetis for colitis work
BRANFORD, Conn.—Biopharma company Thetis Pharmaceuticals has received a Fast-Track SBIR grant from the National Institutes of Health that will provide up to $2.3 million for the development of TP-317 as an oral therapy for ulcerative colitis. TP-317 delivers Resolvin E1 (RvE1), a naturally occurring lipid that manages the resolution of inflammation and the body’s return to normal after an immune response. Preclinical efficacy studies are underway and, thus far, preclinical work in colitis has shown that TP-317 and RvE1 can control disease activity at small doses.
Gary Mathias, co-founder and CEO of Thetis, said: “TP-317 offers a fundamentally new approach to IBD treatment based on active resolution of inflammation and the promotion of tissue regeneration without suppressing the immune system. The grant will support the advancement of this promising, potential new therapy into the clinic.”
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GastroinestinalNIH awards $2.3M to Thetis for colitis work ............................. 33
Government/RegulatoryA ‘softer’ Brexit? ..................................... 33
M&A activityMallinckrodt to acquire Sucampo for $1.2 billion ........................ 33
Tools and technologyOn the cutting edge ................................ 33
A ‘softer’ Brexit?U.K. government’s narrow defeat on amendment in withdrawal bill could have wide impactBY DDNEWS STAFF
LONDON—The U.K. government’s nar-row defeat in November on amendment seven of the European Union withdrawal bill, demanding that Parliament have a binding vote on the final Brexit deal, has fueled debate on whether the United Kingdom could now be heading for a soft-er Brexit and what impact this will have on leading industries like U.K. pharmas, according to GlobalData, a data and ana-lytics company.
A recent webinar by GlobalData brought together industry leaders to review the rep-utational, economic and R&D implications of Brexit for the U.K. pharma sector.
From a reputational point of view, the U.K.’s status as a first-tier drugs market could come to an end and its regulator, the Medicines and Healthcare products Regula-tory Agency (MHRA), may no longer serve as a model to other agencies.
Jennifer C. Smith-Parker, healthcare editor BREXIT CONTINUED ON PAGE 34
Mallinckrodt to acquire Sucampo for $1.2 billionTransaction expected to be immediately accretive thanks to Amitiza and other Sucampo assetsBY JEFFREY BOULEY
STAINES-UPON-THAMES, U.K. & ROCK-VILLE, Md.—Mallinckrodt plc, a global specialty pharmaceutical company, and Sucampo Pharmaceuticals Inc., a global biopharmaceutical company, announced in December that they have entered into an agreement under which Mallinckrodt will acquire Sucampo, including its commercial and development assets. The transaction was approved by the boards of directors of both companies and would total approxi-mately $1.2 billion.
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TOOLS & TECHNOLOGY
Mallinckrodt expects that its acquisition of Sucampo would be immediately accretive to earnings thanks to development and commercial assets that include Amitiza, a leading product in the branded constipation market.
BUSINESS & GOVERNMENT POLICY34 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
the IN-PART matchmaking plat-form features a unique, intuitive algorithm to smart-match com-panies with the best and most rel-evant commercially ready research from 96 university clients—includ-ing some of the most prestigious research institutions worldwide.”
IN-PART: Discover builds on this offering by providing a personalized scouting service, involving not only direct engage-ment with teams from IN-PART’s established university client net-work, but also universities around the world.
Currently, IN-PART: Discover reaches teams from 272 institutions globally with corporate require-ments, and this is expected to increase to over 400 universities by early this year.
“Discover was born out of feed-back from our industry audience,” said Robin Knight, co-founder and director of IN-PART. “Com-panies are looking for a proac-tive and resource-efficient way to seek out university collaboration opportunities fitting their own bespoke requirements, before anyone else.”
Analyzing retinal angiogenic diseasesCOLOGNE, Germany—AYOXXA Biosystems GmbH, a biotech focused on the development and commercialization of innovative multiplex protein analysis tech-nologies enabling translational
research in basic and clinical research, in December announced the launch of LUNARIS Human 11-Plex Ophthalmology Kit for the quantitative analysis of biomarker signatures from human vitreous and aqueous samples. The assay is optimized for usage on LUNARIS, AYOXXA’s innovative multiplex protein analysis system.
“LUNARIS Human 11-Plex Ophthalmology Kit is a reliable and precise assay for the analysis of proteins from minute amounts of ocular fluids. This will support the development of diagnostic kits that may provide biomarker detection in a variety of the most common RADs in order to pave the way for the development of innovative and novel therapies and to support clinicians in tailored treatment decisions,” said Rodney Turner, CEO of AYOXXA. “With the launch of the new LUNARIS Human Cytokine 11-Plex Ophthalmology Kit, we thus follow our primary mission to provide tools that enable translational research.”
Personalized immuno-vaccines for cancerRUTHERFORD, N.J.—Cancer Genetics Inc. (CGI), a biotech company working to enable preci-sion medicine for oncology through molecular markers and diagnostics, announced late last year the launch of its neoantigen discovery service offering, AntigenID, based on neo-antigen identification technology using unique and comprehensive sequencing combinations and sophisticated bioinformatics algo-rithms and computational work-flows. The accurate identification of neoantigens, cancer markers that are unique to an individual’s tumor, has become an emerging area of immuno-oncology (IO) believed to be critical in the devel-opment of personalized cancer immunotherapy and predicting potential response to existing immune-oncology therapies, the company notes.
“We are pleased to be able to broaden our precision medicine
offerings to support personalized and targeted immune therapies,” said Panna Sharma, president and CEO of CGI. “The identification of a patient’s unique repertoire of cancer antigens holds great potential for the success of IO therapies, and we have focused our efforts on building a compre-hensive immuno-oncology testing portfolio and service offerings for use in clinical trials, translational research and therapy selection. We believe adding a neoantigen discovery service was the logical next step in helping personalized therapies become a reality for can-cer patients, and we look forward to future collaborations that will apply the discoveries made possi-ble with neoantigen identification platform, AntigenID.”
Recent studies show that the manipulation of neoantigens used alone or in combination with other immunotherapies could prove to be an important thera-peutic tool to reduce and con-trol cancer. There are currently over 50 clinical trials and studies involving neoantigen identifica-tion as a core component, with many distinctly geared towards developing personalized neo-antigen-based cancer vaccines.
According to industry analysts, these therapies and combinations will help drive a future predicted global cancer immunotherapy market of close to $200 billion by 2021, from $61.97 billion in 2016.
Improved data sharingBAR HARBOR, Maine—The Jack-son Laboratory (JAX)-designed software for biomedical research is part of National Institutes of Health (NIH) Data Commons Pilot Phase, a multi-institutional and international effort to make research data findable, acces-sible, interoperable and reusable (sometimes referred to by the acronym FAIR).
JAX is piloting software specifi-cally focusing on cardiomyopathy, a common disease of the heart muscle. This new online Disease Navigator will enable scientists who study cardiovascular disease to fast-track their research by accessing rel-evant genomic and other data from
animal models (mouse and rat) cross-referenced to human data.
Because of the genetic and bio-logical similarities among humans, mice and rats, researchers use data from these model organisms to elu-cidate the mechanisms of human disease, with the ultimate goal of finding new treatments and preven-tive strategies.
“The Disease Navigator is an important step in understand-ing the functional significance of human genome variation data,” said Dr. Carol Bult, a JAX profes-sor, “because it will make it easier for researchers to find the rele-vant connections between human
genetics and genomics data and the expertly curated knowledge available for animal models in the Mouse Genome Informatics and Rat Genome Databases.”
The Disease Navigator will be developed in conjunction with a consortium of model organism databases called the Alliance of Genome Resources.
Better selection of bioinformatics and AI softwareSANTA MONICA, Calif.—Late last year, the G6G Consulting Group LLC announced the new ver-sion of the G6GFINDR system. The system reportedly allows a focused search for finding bio-informatics and artificial intel-ligence (AI) software. The sys-tem, according to G6G, strives to answer the question “What software do I use?” for the high-growth fields of bioinformatics and artificial intelligence. The platform is also being general-
ized to other industries and will employ artificial intelligence and natural language processing.
Powered by semantic annota-tion, the G6GFINDR system is a two-step process. In the first step, a query is entered, generating sev-eral semantic annotations. After the user chooses relevant anno-tations to their query, the search is re-submitted, generating a list of prioritized URLs for finding software of interest. Both specific annotations for each URL (Detail Page) and also the number of anno-tations for each URL (Summary Page) are listed in the results. nEDITCONNECT: E011828
EDGECONTINUED FROM PAGE 33
Jackson Laboratory’s software for biomedical research is part of the National Institutes of Health Data Commons Pilot Phase.
“The identification of a patient’s unique repertoire of cancer antigens holds great potential for the success of IO therapies, and we have focused our efforts on building a comprehensive immuno-oncology testing portfolio and service offerings for use in clinical trials, translational research, and therapy selection,” says Panna Sharma, president and CEO of CGI.
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EMEA at GlobalData, commented, “The U.K. has already lost The European Medicines Agency (EMA), which will relocate from London to Amsterdam in the wake of Brexit. However, the National Institute of Health and Care Excellence (NICE), the U.K.’s drug pricing watchdog, will likely continue to serve as an international model due to the organization’s expertise in drug pricing and reimbursement.”
Economically, the United Kingdom will remain an important market, but depending on the outcome of negotiations, specifically in regards to regulation of drugs, the nation may experience delays in its ability to launch new products. MHRA, or a new agency that may form post-Brexit, may have to take on marketing authorization, orphan drug
approvals and small and medium enterprise designations. Sharing pharmacovigilance data is a key concern for U.K. pharma R&D in the post-Brexit environment.
As far as R&D issues, despite Merck opening a $1.3-billion research hub in London recently, much of the country’s life-sciences R&D work could be driven to the continent, as exiting the single market and potential immigration restrictions will make the United Kingdom a less attractive place for drug firms. Any perception that the country has become less hospitable to migrant workers and overseas researchers due to Brexit will make it more difficult to recruit and retain R&D talent, impacting pharma operations.
Smith-Parker agreed with another webinar contributor, Steve Bradshaw, managing director at Valid Insight, who added: “Ultimately, what changes will take
place as a result of Brexit remains the great unknown, but change brings opportunities to spearhead positive reform and new ways to attract investment. The opportunity to strengthen relationships between the National Health Service, industry and
government should also be explored to further the U.K.’s role as a center for medical research and build the infrastructure to accelerate bringing better medicines to patients who need them.” nEDITCONNECT: E011827
BREXITCONTINUED FROM PAGE 33
“The U.K. has already lost The European Medicines Agency (EMA), which will relocate from London to Amsterdam in the wake of Brexit. However, the National Institute of Health and Care Excellence (NICE), the U.K.’s drug pricing watchdog, will likely continue to serve as an international model due to the organization’s expertise in drug pricing and reimbursement.”Jennifer C. Smith-Parker, healthcare editor EMEA at GlobalData
IN-PART: Discovery is a bespoke scouting service to help connect universities and businesses for open innovations efforts. The service was beta-tested with one healthcare company and plan include spreading the service to pharmaceutical companies, among others.
For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 35BUSINESS & GOVERNMENT POLICY
“Mallinckrodt’s acquisition of Sucampo is the latest milestone towards our vision of becoming an innovation-driven specialty pharmaceutical growth company focused on improving outcomes for patients with severe and critical conditions,” said Mark Trudeau, CEO and president of Mallinckrodt. “The acquisition brings near-term net sales and earnings accretion through Amitiza and bol-sters our pipeline in rare diseases with VTS-270 and CPP-1X/sulindac. We look forward to adding the Sucampo portfolio and welcoming members of its team to Mallinckrodt.”
“With the addition of its significant resources and expertise, we believe Mallinck-rodt is a natural partner to accelerate the development of our rare disease assets in NPC and FAP, and to continue to provide Amitiza for patients suffering from consti-pation-related disorders,” added Peter Green-leaf, chairman and CEO of Sucampo.
Amitiza (lubiprostone), a leading global product in the branded constipation mar-ket, is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic idiopathic constipation in adults, irritable bowel syndrome with constipa-tion in women 18 years of age and older and opioid-induced constipation in adult patients with chronic, non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent opioid dosage escalation. The FDA is currently reviewing a supplemental New Drug Application for Amitiza in children 6 to 17 years of age with pediatric functional constipation.
Also in the mix would be Rescula (unopro-stone isopropyl ophthalmic solution) 0.15 percent, which is indicated for ocular hyper-tension and open-angle glaucoma and mar-keted in Japan. Mallinckrodt will acquire global rights to the product, with annual net sales of approximately $9 million.
As far as development assets, VTS-270 is in Phase 3 development for Niemann-Pick Type C (NPC). NPC is a rare, neurodegenerative and ultimately fatal disease that can present at any age. NPC is caused by mutations in either the NPC1 or NPC2 genes, resulting in the disruption of the trafficking of intracellu-lar cholesterol, leading to intracellular lipid accumulation in various tissues, including the brain, liver and spleen. The FDA granted VTS-270 its Orphan Drug Designation, and the resulting seven years’ exclusivity would be applied upon approval of the drug. The European Medicines Agency (EMA) also granted VTS-270 Orphan Drug status.
SUCAMPOCONTINUED FROM PAGE 33
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“With the addition of its significant resources and expertise, we believe Mallinckrodt is a natural partner to accelerate the development of our rare disease assets in NPC and FAP, and to continue to provide Amitiza for patients suffering from constipation-related disorders.”Peter Greenleaf, chairman and CEO of Sucampo
In addition, CPP-1X/sulindac is in Phase 3 development for familial adenomatous pol-yposis (FAP) under a collaborative agreement between Cancer Prevention Pharmaceuticals and Sucampo. FAP results from a genetic mutation leading to uncontrolled growth of hundreds to thousands of polyps in the lower digestive tract. Left untreated, there is almost a 100-percent lifetime risk of develop-ing colorectal cancer. The FDA granted CPP-1X/sulindac its Orphan Drug Designation, as well as its Fast Track designation, a pro-cess designed to facilitate development and expedite the review of drugs to treat serious
conditions and fill an unmet medical need. Orphan Drug status was also granted to the therapy by the EMA.
“Both NPC and FAP are devastating conditions associated with substantial morbidity and mortality, and effective therapies are needed,” said Dr. Steven Romano, chief scientific officer and executive vice president of Mallinckrodt. “In addition to the current patient benefits provided by Amitiza, we look forward to bringing VTS-270 and CPP-1X/sulindac to patients with critical unmet medical needs.”
As Zacks Investment Research noted
of the deal, “Mallinckrodt, like Valeant Pharmaceuticals International Inc., has always been on the lookout for acquisitions to expand/diversify its portfolio. However, the company has been under tremendous pressure in 2017 ... The company’s largest product, Acthar’s, sales declined in the third quarter as the payer environment has become increasingly complex for specialty drugs ... Though the addition of Amitiza will add to Mallinckrodt’s sales, it might not be enough to counter the decline in Acthar sales.” n
EDITCONNECT: E011829
AWARDS & HONORS36 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.com
LIU Pharmacy dean recognized by Roskilde University for resveratrol researchROSKILDE, Denmark—In late 2017, Dr. John Pezzuto, dean of LIU Pharmacy and vice president of LIU Health and Research, received an honorary doctorate from Roskilde University in Denmark for his groundbreaking research on resveratrol.
“Prof. Pezzuto is one of the pivotal scientists in the field of the health effects of resveratrol and derivatives,” stated Ole Vang, associate professor in the Department of Science and Environment at Roskilde University, who has conducted follow-up research into resveratrol. “The breakthrough paper from January 1997 in the international journal Science showed the potential cancer preventive effect of resveratrol on skin cancer in mice.”
The 1997 paper was the jumping-off point for a second round of resveratrol research that led to the understanding of the health effects of resveratrol—a substance found in various edible plants like grapes, peanuts and
berries—including cancer prevention, longevity and obesity-related diseases such as diabetes and cardiovascular disease. According to the Web of Science Core Collection, Pezzuto’s work on resveratrol has been cited more than 3,000 times.
“I am honored to receive this recognition from Roskilde University,” Dr. Pezzuto said. “But more importantly, I am honored to work with my colleagues in the international research community to advance our understanding of how resveratrol can help improve our health.”
Pezzuto is the 2014 recipient of the Volwiler Research Award by the American Association of Colleges of Pharmacy. His current research interests are predominantly in the areas of biology-driven natural product drug discovery and characterization, with primary emphasis in the fields of cancer chemotherapy and cancer chemoprevention. n
Heptares co-founder shares Nobel Prize honor
LONDON & TOKYO—Heptares Therapeutics, a wholly owned subsidiary of Sosei Group Corp., announced last year that one of its founders, Richard Henderson (MRC Laboratory of Molecular Biology in Cambridge, U.K.), was awarded the Nobel Prize in Chemistry 2017 together with Jacques Dubochet (University of Lausanne, Switzerland) and Joachim Frank (Columbia University, New York) “for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution.”
Cryo-electron microscopy (cryo-EM) is a technique for determining three-dimensional information about protein structures at the molecular level. Along with traditional methods for structure determination, such as X-ray crys-tallography and nuclear magnetic resonance spectroscopy, cryo-EM can reveal the structure of complex molecular assemblies to near atomic level. Detailed information from such technol-ogy is expected to improve understanding of the structure and function of proteins under investigation, and thereby advance the design of new drugs targeting specific proteins.
Heptares itself is applying the techniques of cryo-EM to study G protein-coupled receptor (GPCR) protein complexes, the insights from which are helping to advance the discovery of potential new medicines.
“We are delighted that Richard has received this most prestigious of awards. It is very well deserved and justified recognition of his outstand-ing contribution to science as a true pioneer of structural biology,” said Malcolm Weir, CEO and co-founder of Heptares. “His work on membrane protein structure in particular provided the inspira-tion and scientific foundation for Heptares’ work on GPCR structure-based drug design, and we continue to benefit enormously from his contribu-tions. We would like to offer Richard and his fellow prize winners our warmest congratulations for this fantastic achievement.”
Henderson co-founded Heptares Therapeutics with Weir, Fiona Marshall and Chris Tate in 2007.
Italian scientist wins 2017 Eppendorf & Science Prize
HAMBURG, Germany—Italian scientist Dr. Flavio Donato in late 2017 was named the winner of the 2017 Eppendorf & Science Prize for Neurobiology for his work on the driving forces that orchestrate the maturation of circuits representing space in the brain.
Donato carried out his research in the laboratory of Prof. May-Britt Moser and Prof. Edvard Moser at the Kavli Institute of the Norwegian University of Science and Technology in Trondheim. Donato’s work has revealed that, dur-ing development, stellate cells in the medial entorhi-nal cortex are the source of an activity-dependent instructive signal neces-sary for the maturation of those neurons that give us a sense of where we are. This finding proves the exis-tence of autonomous, intrin-sic drivers that guide the maturation of widespread regions of cortex from deep within the brain. Unravelling the unique contribution of these specific neuronal populations to the func-tion of neural circuits is expected to advance the understanding of how the brain processes abstract cognitive functions.
The annual $25,000 Eppendorf & Science Prize for Neurobiology honors scientists like Donato for their groundbreaking research—he is the 16th recipient of this international prize, which is awarded jointly by Eppendorf and the journal Science. Researchers who are 35 years of age or younger and have made outstanding contributions to neurobiological research based on methods of molecular and cell biology are invited to apply. The next deadline for applications is June 15, 2018. For more information about Donato and the Eppendorf and Science Prize for Neurobiology, visit www.eppendorf.com/prize.
Eppendorf is a life-sciences company that develops and sells instruments, consumables and services for liquid handling, sample handling and cell handling in laboratories worldwide. Its product range includes pipettes and automated pipetting systems, dispensers, centrifuges, mixers, spectrometers and DNA amplification equipment, as well as ultra-low temperature freezers, fermentors, bioreactors, CO2 incubators, shakers and cell manipulation systems.
Thought Leader Award goes to drug discovery researcher Jiandong Jiang
SANTA CLARA, Calif.—In mid-November, Agilent Technologies Inc. announced that Prof. Jiandong Jiang had received an Agilent Thought Leader Award in support of his studies on cancer stem cells differentiation induced by natural products.
“Cancer is a chronic disease generated by multiple factors. Our research is focused on the treatment of cancers with new concepts or principles, using cutting-edge techniques,” said Jiang.
Jiang is director of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China. He is also the vice chairman of the China Pharmaceutical Innovation and Research Development Association. Jiang’s research focuses on antimicrobial drugs, including viruses and bacteria, anticancer drugs and the development of treatments for metabolic syndrome.
The Agilent Thought Leader Award will enable Jiang’s team to implement metabolite flux analy-ses, metabolism analyses and integrated biology approaches to characterize the antitumor activity of natural products. In addition to Agilent mass spectrometry solutions, Jiang’s lab will also make extensive use of Agilent Seahorse XF technology, and Agilent MassHunter and VistaFlux software. The project will also include a collaboration with Prof. Wenbin Li from the Beijing Shijitan Hospital of Capital Medical University to perform clinical-related research.
“Agilent is proud to continue its support of cancer research with the use of our mass spectrometry systems, bioinformatics software and metabolic
analysis tools to facilitate the identification and characterization of cancer drugs,” said Victor Chan, Agilent vice president and general manager of Laboratory Solutions for Agilent Greater China.
DuPont scientist receives Franklin Institute science prize
WILMINGTON, Del.—The Specialty Products Division of DowDuPont announced in November that one of its senior scientists, Philippe Horvath, was awarded the Franklin Institute’s prestigious 2018 Bower Award and Prize for Achievement in Science. Horvath will be honored for his groundbreaking research on CRISPR during a ceremony in April 2018 in Philadelphia.
Horvath’s initial article, published in Science in 2007, provided the first biological evidence that CRISPR/Cas constitutes an immunity system against viruses in bacteria. Beginning in the early 2000s, Horvath and colleagues initially utilized CRISPR for bacterial identification, then for its ability to improve the resistance of starter culture strains against bacteriophage attack. The discoveries opened new research avenues and laid the groundwork that inspired numerous scientists to pursue the CRISPR field.
Based at the DuPont Nutrition & Health site in Dangé-Saint-Romain, France, Horvath already had been honored with three leading science awards: the 2015 Massry Prize, the 2016 Warren Alpert Foundation Prize and the 2016 Canada Gairdner International Award.
“We are proud of the achievements made by Philippe and the entire CRISPR team at DuPont. It is a great testament to our company’s heritage in scientific innovation and the incredible work that has been done to advance new ideas and solve some of the world’s biggest challenges,” said Alexa Dembek, chief technology and sustainability officer for the Specialty Products Division of DowDuPont. “The early discoveries made by Philippe and team opened new areas of research and opportunities to use CRISPR/Cas in a range of scientific fields.”
DowDuPont is a leader in the CRISPR area, with about 60 patents and applications and more than 30 published scientific articles and book chapters. n
Ole Vang (left), a Roskilde University associate professor, introduces Dr. John Pezzuto, dean of LIU Pharmacy, at a ceremony on Sept. 15.
Awards & Honors
Dr. Flavio Donato was named the winner of the 2017 Eppendorf & Science Prize for Neurobiology for his work on the driving forces that orchestrate the maturation of circuits representing space in the brain.
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For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 37ONLINE / PEOPLE & PROMOTIONS
What you may have missed online from DDNews
PEOPLE & PROMOTIONSPeregrine Pharmaceuticals
Roger J. Lias, Ph.D.President and CEOTUSTIN, Calif.—In early December, biologics com-pany Peregrine Pharmaceuticals Inc. announced the appointment of Dr. Roger J. Lias as the com-pany’s new president and CEO. Lias, who has more than 20 years of contract development and manufacturing organization (CDMO) management experience, was serving on the Peregrine board of directors and as president of Avid Bioservices, Peregrine’s wholly-owned CDMO subsidiary, at the time of the appointment.
Lias’ appointment is said to be an important step in Peregrine’s ongoing transition to a dedi-cated CDMO and builds upon the company’s recent appointment of several proven CDMO industry veterans to the company’s board and management team.
“We believe that Roger is best equipped to lead Peregrine ... With the demand for biologics manufacturing exceeding the industry’s current capacity and expected to continue to grow in coming years, Roger and his team have worked aggressively to establish a strategic plan that we anticipate will allow the company to take advantage of this significant market opportunity,” said Dr. Joseph Carleone, chairman of Peregrine.
Intellia Therapeutics
John Leonard, M.D.President and CEOCAMBRIDGE, Mass.—Intellia Therapeutics Inc., a genome-editing company focused on develop-ing curative therapeutics using CRISPR/Cas9 technology, in mid-December named Dr. John Leonard as president and CEO. He succeeds Dr. Nessan Bermingham, Intellia’s founding presi-dent and CEO, who is returning to the venture capital industry.
Leonard joined Intellia in 2014 as the company was being formed. He initially served as Intellia’s
chief medical officer and as a member of its board of directors. Prior to Intellia, he was chief scientific officer and senior vice president of research and development at AbbVie Inc.
Eloxx Pharmaceuticals
Robert WardChairman and CEOWALTHAM, Mass.—Right before the end of 2017, Eloxx Pharmaceuticals Inc., a clinical-stage biopharmaceutical company developing novel small-molecule medicines to treat rare and ultra-rare genetic diseases caused by nonsense mutations, named Robert Ward as chairman of the board of directors and CEO. Ward succeeds both Robert Heft, outgoing chairman, and founder and CEO Dr. Silvia Noiman at what the company calls “a critical inflection point for Eloxx as [it] advances its lead candidate ELX-02, a novel translational read-through inducing drug, through the completion of Phase 1 clinical trials and navigates its transition from a private to a public company.”
Eyevensys
Patricia Zilliox. Ph.D.CEOPARIS—Eyevensys, a clinical stage biotech company developing nonviral gene therapies for ophthalmic diseases, announced in late 2017 the appointment of Dr. Patricia Zilliox as CEO. Zilliox, who joined the Eyevensys board in May 2016, has more than 25 years of global clinical development expertise. She previously served as chief drug development officer of the Clinical Research Institute, a division of the Foundation Fighting Blindness, in Columbia, Md. From late 2008 until May 2011, Zilliox was head of clinical development at Alcon Laboratories, managing clinical development programs in areas of eye diseases such as glaucoma, allergy, dry eye, infectious diseases of the eye and retinal diseases such as dry- and wet-AMD. She previously worked for Alcon in Paris, where she was responsible for
the execution of Alcon’s European ophthalmology clinical trials.
MorphoSys AG
Markus Enzelberger. Ph.D.Chief Scientific OfficerPLANEGG, Germany—MorphoSys announced that Dr. Markus Enzelberger had been appointed as chief scientific officer as of Nov. 1, 2017—he had been the company’s interim CSO since April 15, 2017. He succeeded Dr. Marlies Sproll, who is taking on a new part-time role at MorphoSys as special adviser to the CEO, Dr. Simon Moroney.
“Dr. Enzelberger is the perfect person to take over the CSO role at MorphoSys on a permanent basis. Drawing on his vast scientific expertise and experience in the management of antibody technology, research and discovery,
he will continue to drive MorphoSys’s early-stage research activities with the goal of fueling the Company’s R&D pipeline with novel drug candidates in oncology and immunology. We look forward to continuing to work with him,” commented Dr. Gerald Möller, supervisory board chairman of MorphoSys.
Fibrocor Therapeutics
Mark SteedmanPresident and CEOTORONTO, Ontario—Late November saw Fibrocor Therapeutics announce that Mark Steedman had been appointed as its first president and CEO—he will also serve as a member of Fibrocor’s board of directors. Steedman is the co-founder of Interface Biologics, where he most recently served as vice president of business development. n
Teckro names Dana Poff as chief operating officerLIMERICK, Ireland—In late 2017, Teckro, a global life-sciences tech-nology company that uses infor-mation retrieval and machine learning technologies to improve the speed and accuracy of clinical trial conduct, named Dana Poff as chief operating officer. With more than 28 years of combined healthcare and clinical research experience, Poff joins Teckro from ICON, a global clinical research organization where she held senior global leadership roles in clinical operations, project management and alliance manage-ment. In her most recent role, she served as chief of staff reporting to the CEO.
“Dana’s knowledge and expe-rience of managing global clini-cal trials is matched only by her energy and passion for making things better,” said Gary Hughes, Teckro co-founder and CEO. “She is a key addition to our leadership team and will have a big part to play in delivering solutions for our clients, global research sites and patients.”
Poff’s appointment came on the heels of the company raising $10 million in Series B financing, led by Sands Capital Ventures with participation from Bill Maris’ Section 32 venture fund, Founders Fund and private investors.
Dana Poff
A new approach for bacteria analysisA multicenter team consisting of researchers from the Icahn School of Medicine at Mount Sinai, Sema4 (a Mount Sinai Health System venture) and collaborators New York University and the University of Florida have engineered a new approach to identifying microbes that offers greater accuracy.EDITCONNECT: E12131704
BYU researchers narrow in on genetics of Alzheimer’sLate November brought word from Brigham Young University that researchers there had published findings in Genome Medicine—in an paper titled “Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience”—that detail what could be “a novel and promising approach in the effort to treat Alzheimer’s disease.”EDITCONNECT: E12131703
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Mallinckrodt acquires Ocera TherapeuticsGlobal specialty pharmaceutical company Mallinckrodt plc on Dec. 11 announced it had closed the acquisition of Ocera Therapeutics, a clinical-stage biopharmaceutical company focused on the development and commercialization of novel therapeutics for orphan and other serious liver diseases with high unmet medical need.EDITCONNECT: E12131702
Reducing side effects of chemotherapy with ‘nanoshells’Researchers investigating ways to deliver high doses of cancer-killing drugs inside tumors say that they have demonstrated that using a laser and light-activated gold nanoparticles can effectively and remotely trigger the release of FDA-approved cancer drugs inside cancer cells.EDITCONNECT: E11211702
Moving forward with Cell Design LabsThe acquisition of Cell Design Labs gains Gilead two new proprietary technology platforms: synNotch and Throttle. synNotch is a synthetic gene expression system that responds to external cues and can be used to produce chimeric antigen receptor T cells (CAR T) that need dual antigen recognition to be activated, and Throttle provides an “on switch,” so to speak, that can modulate CAR T activity via small molecules.EDITCONNECT: E12131701
Backup from bacteria?A team led by The University of Texas MD Anderson Cancer Center researchers recently shared results in Science detailing how the gut microbiome can impact response to immunotherapy.EDITCONNECT: E11211704
Nerves and prostate cancerResearch out of the Albert Einstein College of Medicine, part of Montefiore Medicine, has shown that some nerves trigger prostate cancer progression by flipping a switch that leads to an increase in tumor blood vessels.EDITCONNECT: E11081704
38 DDNEWS | | JANUARY 2018 For more information, visit www.DDN-News.comLATE-BREAKING NEWS
Roswell researchers identify cells that may be responsible for prostate cancer recurrenceBUFFALO, N.Y.—Although men with prostate cancer usually respond to standard treatment with hormone therapy or che-motherapy, many will eventually experience progression or recur-rence despite treatment—par-ticularly those with high-risk or aggressive forms of the disease. In preclinical laboratory research, a team led by Dr. Dean Tang, chair of pharmacology and therapeutics at Roswell Park Cancer Institute, has discovered a unique popula-tion of normal stem cells that are intrinsically resistant to conven-
tional treatments and may enable prostate cancer relapse.
In a new study published recent-ly by the journal Stem Cell Reports under the title “Histone 2B-GFP Label-Retaining Prostate Lumi-nal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration,” the team reports its development of a novel preclinical model that allows not only the labeling but also the puri-fication of this rare but persistent population of prostate stem cells, which are dormant and, strikingly, resemble high-risk prostate cancer
at the molecular level.The normal prostate and most
prostate tumors contain a small number of cells called luminal progenitors that, unlike the bulk of cancer cells, are generally dor-mant. They behave like stem cells, lacking expression of the mol-ecules targeted by current cancer treatments. As a result, these cells evade prostate cancer treatments such as chemotherapy and radia-tion, which generally target and eliminate cells that are rapidly multiplying and dividing. Unlike
Late-Breaking NewsHERE ARE SOME NEWS ITEMS THAT ARRIVED TOWARD THE TAIL END OF THIS ISSUE’S PLANNING AND PRODUCTION PROCESS
New structure of key protein holds clues for better drug designLA JOLLA, Calif.—A few days before 2017 drew to a close, scientists at The Scripps Research Institute (TSRI) announced that they “have peered deep into the heart of a key protein used in drug design and discovered dynamic structural fea-tures that may lead to new ways to target diseases” and that the find-ings had been published in the jour-nal Cell under the title “Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2a Adenosine Receptor.”
The protein, called the A2A adenosine receptor (A2aAR), is a member of the G-protein-coupled receptor (GPCR) family, which contains the targets of roughly 40 percent of all approved pharmaceuticals. The new, more detailed image of A2aAR’s signaling mechanism reportedly reveals key parts of its inner workings, including an amino acid that acts like a “toggle switch” to control signaling across the cell membrane.
“This basic knowledge is potentially helpful for improving drug design,” says Nobel laureate Dr. Kurt Wüthrich, the Cecil H. and Ida M. Green Professor of Structural Biology at TSRI and senior author of the study.
All human cells contain A2aAR and other GPCRs embedded in their plasma membrane. More than 800 GPCRs have been discovered in the human body, and each has a role in regulating a bodily function. For
example, A2aAR regulates blood flow and inflammation and medi-ates the effects of caffeine. A2aAR is also a validated target for treating Parkinson’s disease and a relatively new target for targeting cancers.
“GPCRs do just about everything you can imagine,” says Wüthrich. “But for a long time, drug design was being done without knowing how GPCRs looked.”
For the new study, the researchers aimed to better understand the rela-tionship between A2aAR function and dynamic changes in its structure to help inform drug design.
The research built on previ-ous studies where scientists used X-ray crystallography to deter-mine A2aAR’s three-dimensional structure. The images showed that A2aAR looks like a chain that crisscrosses the cell membrane and has an opening on the side facing out of the cell. The region of the GPCR structure that sticks out of the membrane interacts with drugs and other molecules to signal to partner proteins inside the cell.
Although crystal structures pro-vided a key outline of the recep-tor’s shape in inactive and active-like states, they could not show motion and changes in structure when A2aAR meets new binding partners, such as pharmaceutical candidates. In short, the research-ers in the new study needed to investigate why A2aAR works the way it does.
To solve this problem, the researchers used nuclear magnetic resonance (NMR) spectroscopy, which creates strong magnetic fields to locate the positions of probes in a sample. Wüthrich is a world-renowned leader in the NMR field and won the Nobel Prize in Chem-istry in 2002 for pioneering work in NMR to study the structures of biological molecules. With NMR, scientists can determine the struc-tures of proteins and study their dynamic properties in solution at physiological temperatures—the way they exist in the human body.
In work spearheaded by TSRI’s Dr. Matthew Eddy, first author of the new study, the researchers used NMR to observe A2aAR in many
different conformations, shed-ding light on how it changes shape on the surface of human cells in response to drug treatments.
Importantly, NMR let the team visualize changes in the internal architecture of A2aAR. This took them beyond previous solution NMR studies, which focused on the technically less demanding observation of NMR-observable probes attached to flexible parts of GPCRs, mostly located at or near the surface of the receptor. The approach in the new study enabled researchers to follow the effects of drug binding at the extracellular surface on changes in protein struc-ture and dynamics at the intracel-lular surface—the structural basis
of signal transfer—across the heart of the GPCR.
As TSRI described it, “It was like the researchers had seen a car, and with NMR, they could finally inspect its engine.”
Two details in A2aAR’s structure gave researchers insight into how future drugs could manipulate the receptor. One key finding was that replacing one particular amino acid in the receptor’s center destroyed the receptor’s ability to send signals into the cell.
“With this finding, we can say ‘A-ha! It is this change in structure that kills the signaling activity.’ Maybe we can make a change in a drug to overcome this limit,” says Wüthrich.
The researchers also revealed the activity the aformentioned “toggle switch” in A2aAR. Previous studies suggested that one of the trypto-phan amino acids in A2aAR flips up and down in concert with A2aAR’s activity. With NMR, the scientists directly observed this unique tryp-tophan as it changed orientations in response to different drugs. Chem-ists could potentially modify drugs to manipulate this switch and con-trol A2aAR signaling.
The researchers emphasize that this new study is potentially rel-evant for much of the large family of GPCRs. In fact, structural details from this study could apply to more than 600 “class A” GPCRs in our bodies. n
Dr. Matthew Eddy and Nobel laureate Dr. Kurt Wüthrich were the study leaders for “Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2a Adenosine Receptor.”
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A Roswell Park Cancer Institute team has discovered a unique population of normal stem cells that are intrinsically resistant to conventional treatments and may enable prostate cancer relapse.
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For more information, visit www.DDN-News.com JANUARY 2018 | | DDNEWS 39LATE-BREAKING NEWS
Boehringer Ingelheim commits to venture funding
INGELHEIM, Germany & BOSTON—In early January, Boehringer Ingelheim announced an increase in funding for its corporate venture fund, known as the Boehringer Ingelheim Venture Fund (BIVF), from €100 million to €250 million.
The additional funds will be used to invest in promising early stage start-up companies, focusing on regenera-tive medicine, infectious diseases and immune-oncology among others, as well as growing the portfolio in the United States and opening doors for the BIVF in digital health. The significant additional funding goes along with a doubling of the number of investment managers.
“We at the BIVF are inspired by the opportunity to increase investments and work across some of the most promising areas of biomedical research to date,” said Dr. Frank Kalkbrenner, corporate vice president and head of the BIVF. “We are thrilled to be opening a second U.S.-based office in 2018, which will allow us to collaborate more closely with biotech and start-up companies on the West Coast. This also brings us one step closer in our quest to be at the center of the global digital health transformation.”
The expansion builds on the BIVF’s existing portfolio of 21 biotech and early stage start-up companies focused on various therapeutic areas of interest, including immune-oncology. Recent successes of the portfolio include:
• Rigontec is a forerunner in accessing the retinoic acid-inducible gene I pathway, part of the innate immune system, as a novel and distinct approach in cancer immunotherapy to induce both immediate and long-term antitumor immunity. Rigontec was acquired by Merck & Co. (known as MSD outside of the U.S. and Canada) in September 2017, with an upfront payment of €115 million and additional contingent payments of up to €349 million.
• ViraTherapeutics specializes in the development of oncolytic virus therapies. In 2016, BIVF entered into an option agreement with a transaction value of up to €210 million, including co-funding of development activities of ViraTherapeutics’s VSV-GP.
• Okairos is pioneering the develop-ment of T-cell based vaccines for major infectious diseases, as well as cancer. In 2011, one year after the BIVF was founded, the first investment was made in Okairos. The company was acquired by GlaxoSmithKline in 2013, creating the first successful exit for BIVF.
“The key differentiator for Boehringer Ingelheim’s Venture Fund lies in the close and trusted relationships with the portfolios and entrepreneurs with
whom we are privileged to work with,” added Kalkbrenner. “Through these connections, we’ve successfully developed a number of biotech start-ups—from creation to exit—and we look forward to the ground-breaking work that lies ahead. We are a team that welcomes new adventure and risk-taking, if it means delivering novel solutions that will one day help patients everywhere lead healthier lives.”
GlobalData: Clinical trial design in pancreatic cancer needs work
LONDON—Progress in pancreatic ade-nocarcinoma trials is sluggish, which is often attributed to low clinical trial recruitment and substandard design. This results in an inadequate understand-ing of this notoriously difficult-to-treat disease and poor outcomes for patients, according to GlobalData, a data and analytics company.
Clinical trial accrual is poor in pancreatic cancer and there is a need to enroll patients faster to establish the benefit of experimental drugs within a shorter timeframe. In 2011, 4.6 percent of the total patient population with pancreatic cancer was enrolled in U.S.-based clinical trials. Set against the clinical trial accrual rate in oncology, which constitutes less than 3 percent of adult U.S. patients, this rate indicates that comparatively more pancreatic cancer patients enroll in a trial than other cancers.
However, the number of patients required to complete accrual in ongoing pancreatic cancer far superseded the number of patients actually enrolling; for instance, a mere 15 percent of the target enrolment rate was achieved in trials opened in 2011, according to a recent meta-analysis.
“The slow accrual rate is a major cause of trials missing their planned completion dates, and even more unfavorably, trial termination due to insufficient number of patients enrolled,” said Louis Perdios, a healthcare analyst at GlobalData. “Programs providing the appropriate resources and guidelines are required to support accrual to clinical trials.”
In addition to poor recruitment, pan-creatic cancer trials have notoriously poor success rates. Between 1997 and 2015, from a total of 35 unique thera-peutic regimens evaluated in 39 Phase 3 pancreatic adenocarcinoma trials, only 11 percent had favorable outcomes. Notably, 85 percent of these trials were conducted despite preceding Phase 2 studies not meeting their primary end-points. As survival is measured in months rather than years, early determination of whether a treatment is succeeding or failing is required. These shortcomings
translate into difficulties in conducting large-scale pivotal trials.
Perdios concluded: “Early deter-minants of response and prognostic measures are still lacking in pancreatic cancer. The downturn in clinical trials can be addressed by embracing techno-logical advances, by tackling inadequate operational procedures, and improving communication between physicians and patients, as well as between cancer research agencies, the pharmaceutical industry and patient advocacy groups.”
VirionHealth receives up to $4.2m from DARPA
LONDON—VirionHealth Ltd, a biotechnology company developing novel therapeutics for respiratory viral infections, announced that it has won non-dilutive funding worth up to $4.2 million from the U.S. Defense Advanced Research Projects Agency (DARPA). The award will support development of VirionHealth’s new class of biological antivirals, in particular both preclinical and Phase 1 clinical studies for its lead program.
This effort is funded under DARPA’s INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program. Whereas other anti-infective strategies typically take aim at a static target, and become obsolete if the target mutates, INTERCEPT seeks to develop a novel approach that uses evolution to defeat rapidly mutating pathogens and thus keep pace with fast-evolving targets.
VirionHealth’s new class of biological antivirals acts by outcompeting replica-tion of infectious viruses to both prevent and treat viral infections. The company is exploiting this technology to develop the first broad-spectrum therapy, potentially simplifying and accelerating treatment by removing the need for differential diagnosis. In addition, the technology is far less susceptible to resistance than other approaches due to its unique viral out-competition abilities and innate immune system stimulation. Resistance has become one of the most significant concerns for public health globally.
Dr. Jeffrey Almond, chairman of VirionHealth, said: “We are delighted to receive this funding and to be working with DARPA to harness the therapeutic potential of defective interfering viruses and accelerate the progress of our novel antiviral program into the clinic.”
“This new funding recognises the significant potential of VirionHealth’s approach in treating respiratory tract infections,” added Prof. Nigel Dimmock, scientific co-founder at VirionHealth. “Building on innovative work at the University of Warwick, we are the only company to have successfully developed a therapeutically active defective interfering virus.” n
Advanced Analytical..................................... 17 www.aati-us.com
American Association
Cancer Research (AACR) ........................ 19 www.aacr.org
BioTek Instruments, Inc. .............................. 29 www.biotek.com
BMG LABTECH GmbH ................................... 23 www.bmglabtech.com
Cambridge Healthtech Institute ................. 25 www.healthtech.com
Horizon Discovery Ltd. .................................. 21 www.horizondiscovery.com
INTEGRA Biosciences AG ............................. 9 www.integra-biosciences.com
Lonza Rockland, Inc. ....................................... 7 www.lonza.com
Offenberger & White, Inc. ............................ 35 www.offwhite.com
Panasonic Healthcare Corporation
of North America ........................................ 5 www.panasonic-healthcare.com
PerkinElmer Corporation ............................... 2 www.perkinelmer.com
Quanterix Corporation .............................. 1, 40 www.quanterix.com
R&D Systems, Inc. ......................................... 13 www.RnDSystems.com
A D V E R T I S E R ’ S I N D E X
SELLAS merges with Galena BiopharmaHAMILTON, Bermuda & NEW YORK—Late December saw SELLAS Life Sciences Group Inc. announce that the proposed merger of the businesses of SELLAS and Galena Biopharma, Inc. had closed. Upon completion of the merger, Galena was renamed SELLAS Life Sciences Group Inc. and now features a late-stage pipeline led by novel immunotherapies targeting a broad range of indications in hematologic and solid malignancies. SELLAS was expected to commence trading on the Nasdaq Capital Market in early January under the ticker symbol SLS.
“This public listing provides us with the opportunity to further develop our novel immunotherapies for a wide range of cancers with unmet medical needs as a public company,” said Dr. Angelos Stergiou, president and CEO of SELLAS. “Over the past year, we have advanced the development of galinpepimut-S (GPS), our Wilms tumor 1-targeting immunotherapy, through collaborations
with Merck & Co., among others, as well as our ongoing Phase 2 trials of GPS in patients with multiple myeloma, as a monotherapy, and with ovarian cancer, in combination with Bristol-Myers Squibb’s nivolumab. We also had successful End-of-Phase 2 meetings with the FDA pertaining to our planned Phase 3 studies in acute myeloid leukemia and malignant pleural mesothelioma. We are excited by the potential of GPS, both as a monotherapy and in combination with other agents to serve as a promising therapy for patients with a broad array of cancers.”
Following completion of the merger, the combined company relocated its headquarters to New York City.
“I am delighted to be working with Angelos and the rest of the SELLAS Inc. team, who have been responsible for building the company and progressing its novel, high-potential pipeline to address the unmet needs of patients battling various types of cancer. The transition to being a publicly traded company marks a significant milestone, providing the opportunity for greater financial resources and enhanced corporate structure to better advance the company’s clinical programs,” noted Jane Wasman, newly-appointed chair of SELLAS Inc.’s board of directors. n
“This public listing provides us with the opportunity to further develop our novel immunotherapies for a wide range of cancers with unmet medical needs as a public company.”Dr. Angelos Stergiou, president and CEO of SELLAS
most prostate cancer cells, these dormant, stem-like cells are also less dependent on androgens, mak-ing them relatively unresponsive to chemical castration or hormone therapy, approaches designed to “starve” tumors by depriving them of their androgen fuel.
“The existence of a population of quiescent or slow-cycling cells in the prostate has been suggested, but their identity and characteristics were unknown because they are rare and very difficult to study,” explains Dr. Dingxiao Zhang, an assistant professor with the Department of Pharmacology and Therapeutics at Roswell Park and first author on the new study. “We were able
to identify a unique population of cells that might serve as the origin of treatment-resistant prostate cancer. Our genetic model paves the way toward the next step, which is the development of therapies that can target these dormant cancer cells, which are expected to significantly improve the treatment of prostate cancer and delay or even prevent its recurrence.” n
ROSWELLCONTINUED FROM PAGE 38
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