What is the impact of new technologies and novel therapeutic …€¦ · Aeterna Zentaris Current challenges for pharma development Kaitin KI, Clin Pharmacol Ther. 2010 March ; 87(3):

Dr. Michael Teifel, VP Preclinical Development

Bio Deutschland Business Development Conference - Sept 23, 2013

What is the impact of new technologies and novel therapeutic approaches to fight cancer?

Aeterna Zentaris

Current challenges for pharma development

Kaitin KI, Clin Pharmacol Ther. 2010 March ; 87(3): 356–361.

Market capitalization of top-tier pharmaceutical companies in January 2001 and September 2009. Cumulative loss in marketcapitalization for these companies over the period is $626 billion. Ticker symbols are as follows: ABT, Abbott; AZN, AstraZeneca; BMY, Bristol-Myers Squibb; GSK, GlaxoSmithKline; LLY, Lilly; MRK, Merck; PFE, Pfizer; SGP, Schering- Plough; WYE, Wyeth. Data from http://www.valueline.com; Tufts Center for the Study of Drug Development analysis.

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� Between 2010-2014 about 200 billion USD in revenue are at risk due toexpiry of patents. Approx. 100 billion USD are expected to go to generics.

� Continuous decline in NME approvals

� Increasing role of payers in pricing and prescribing

� Generics market is rapidly growing, >50% of subscribed medications

� Safety and efficacy continues to present a major concern by regulatoryauthorities leading to increased regulatory and clinical requirements

� Increasing R&D spend, over 50 billion USD in 2010

� Average cost for development of NME over 1 billion USD

� Loss of trust in pharmaceutical industry

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Adapted from: Kaitin KI, Clin Pharmacol Ther. 2010 March ; 87(3): 356–361.

Patent expirations for 10 top-selling drugs each year

2009 2010 2011 2012Product Sales Product Sales Product Sales Product SalesPrevacid 3,962 Protonix 4,221 Lipitor 13,652 Diovan 5,012Topamax 2,453 Cozaar/Hyzaar 3,350 Plavix 8,079 Singulair 4,266Lamictal 2,194 Aricept 3,311 Advair 6,998 Lexapro 3,044Valtrex 1,868 Levaquin 2,862 Zyprexa 4,661 Viagra 1,764Cellcept 1,677 Effexor XR 2,657a Actos 4,333 Avandia 1,754Keppra 1,407 Taxotere 2,569 Seroquel 4,219 Symbicort 1,575Flomax 1,399 Arimidex 1,730 Avapro 2,685 Zometa 1,297Imitrex 1,370 Gemzar 1,592 Xalatan 1,604 Detrol 1,190Adderall XR 1,031 Coreg 1,174 Avelox 1,013 Geodon 854Suboxone 531a NovoSeven 1,078 Xeloda 959 Provigil 852

Total $17,892 Total $24,544 Total $48,203 Total $21,608

a US sales only.

Data from Tufts center for the study of Drug Development, 2010; MedNews 27(7), 2008; http://www.drugs.com/top200.

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Bethan Hughes, Nature Reviews Drug Discovery 9, 89-92 (February 2010)doi:10.1038/nrd3101

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Growing generics market

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EFPIA, The Pharmaceutical Industry in Figures, 2013

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Lack of credibility

Reasons for continued lack of credibility:

“… pharma is spending too much on too little output…”

“… perception that the industry is preoccupied with drugs that offer only short-term health benefits…”

“… lack of fair pricing policies leading to unseemly profits…”

“… lack of transparency in reporting results from negative clinical trials…”

„ … management of adverse event news…”

“… inappropriate marketing of drugs…”

http://www.forbes.com/sites/johnlamattina/2013/01/18/pharmas-reputation-continues-to-suffer-what-can-be-done-to-fix-it/

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What can be done to improve this situation?

� Closer interaction with regulators, patients and payors– Gain trust and confidence

� Pharma needs to move from blockbuster approach to personalized therapies

– Discovery and development of blockbuster drugs for large patientpopulations increasingly difficult

– Scientific advances in understanding of pathophysiology and development of new technologies offer new approaches

– Establish integrated pharmaceutical development networks, collaboration of pharma with academia, biotech and CROs to utilize individual strength and streamline development process

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Pharma development as a team effort


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New technologies

„Omics“Data

Pharmacology

Systems Biology / „Panomics“http://pubs.niaaa.nih.gov/publications/arh311/49-59.htm

„… interaction of all biological functions within a cell and with other bodyfunctions…“

„…This understanding is increasingly guiding drug development and targeted cancer therapeutic and prevention strategies…“

„ACCELERATING PROGRESS AGAINST CANCER“, ASCO, November 2011

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„Omics“…

Innovation: Metabolomics: the apogee of the omics trilogy, Patti GJ, Yanes O, Siuzdak GNature Reviews Molecular Cell Biology 13, 263-269 (April 2012), doi:10.1038/nrm3314

DNA(3.2 billion bp, ~ 21,000 genes)

RNA

Proteins(est. 250,000-1,000,000)

Cell Function

Metabolites(~ 2,500 small molecules)

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How to utilize this data?

� Understanding the disease– Validation of disease model

– Translation from preclinical model to man

� Earlier initiation of clinical investigation (Phase 0 trials ?)

� Bigger and more complex phase I / II trials integratingevaluation of pharmacogenomics / pharmacoproteomics

– e.g. tumor biopsies, blood, CTCs, urine (pre-/post dose…)

� Smaller phase III trials is selected subpopulations with highersuccess rate

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Personalized Medicine

“We can no longer think of cancer as one disease. Even something like lung cancer could be hundreds of distinct cancers, each defined by specific molecular characteristics requiringdifferent treatment approaches. This makes research morechallenging, but the payoff for patients will be enormous.”

Michael P. Link, MD, President of ASCO

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Personalized Medicine – Next steps to take

� Key technological and medical advances as prerequisites forbroad applicability of personalized medicine

– Fast, accurate and low-cost DNA sequencing

– Rapid and low-cost sequence alignment and data interpretation

– Consequent utilization of genetic information for medical care

– Absorption of cost by the payors

http://venturebeat.com/2013/01/27/the-personalized-medicine-revolution-is-almost-here/

e.g. CompanionDiagnostics

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Companion diagnostic devices / tests

• Regulators and payors are putting increasing pressure on companies to develop companion diagnostic tests to identify patients likely to benefit from a treatment, and thereby sparingother patients from unnecessary side effects and expense.

• In 2010, approval of ChemGenex drug omacetaxine was delayed by the FDA, because the company had not specified a companion test that could reliably detect the BCR-ABL T315I mutation in CML patients for which the treatment was intended.

� FDA draft guidance on in vitro companion diagnostic devicesissued July 14, 2011

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FDA Draft Guidance on Companion Diagnostics

An IVD companion diagnostic device could beessential for the safe and effective use of a corresponding therapeutic product to:

• Identify patients who are most likely to benefit from a particular therapeutic product

• Identify patients likely to be at increased riskfor serious adverse reactions as a result oftreatment with a particular therapeutic product

• Monitor response to treatment for the purposeof adjusting treatment (e.g., schedule, dose,discontinuation) to achieve improved safety oreffectiveness

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Publications on „omics“ and biomarker research

Total number of publications in PubMed on companion diagnostics ~131 (112 within last 5 years)

# of publications on biomarker per year / PubMed

0

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10000

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20000

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30000

35000

40000

45000

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1940 1950 1960 1970 1980 1990 2000 2010 2020

# of "omics" publications per year / PubMed

0

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1985 1990 1995 2000 2005 2010 2015

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FDA approved Companion Diagnostic Devices

For In Vitro Diagnostic Use. HER2 CISH Kit to determine HER2 gene amplification in FFPE tissue.Aid in the assessment of patients for whom Herceptin (trastuzumab) treatment is being considered.

Life TechnologiesSPOT-LIGHT HER2 CISH Kit

Herceptin(trastuzumab)

10

Her-2/neu Mouse Monoclonal Antibody (Clone C1B11) In Vitro Diagnostic use in IHC assaysAid in the assessment of breast cancer patients for whom Herceptin therapy is being considered.

BiogenexLaboratories

INSITE HER-2/NEU KIT


9

Mouse monoclonal antibody for laboratory use for the semi-quantitative detection of c-erbB-2 FFPE tissueAid in the assessment of breast cancer patients for whom Herceptin treatment is being considered.

Ventana MedicalSystems

PATHWAY ANTI-HER-2/NEU (4B5) Rabbit MoAb


8

HER-2 DNA Probe Kit to detect amplification of the HER-2/neu gene in addition to existing clinical and pathologic information currently used as prognostic factors in stage II, node-positive breast cancer patients.

Abbott MolecularPATHVYSION HER-2 DNA Probe Kit


7

In situ hybridization (FISH) DNA probe assay for Her-2/Neu gene amplification to stratify breast cancer patients according to risk for recurrence or disease-related death.


INFORM HER-2/NEUHerceptin(trastuzumab)

6

The c-Kit pharmDX assay is a qualitative immunohistochemical (IHC) kit system to aid in the differential diagnosis of gastrointestinal stromal tumors (GIST). After diagnosis of GIST, results from c-Kit pharmDx maybe used as an aid in identifying those patients eligible for treatment with Gleevec/Glivec (imatinib mesylate).

DakoDAKO C-KITPharmDx

Gleevec/Glivec(imatinib mesylate)

5

Real-time PCR to select patients with NSCLC for whom GILOTRIF (afatinib), an EGFR tyrosine kinase inhibitor (TKI), is indicated.

Qiagentherascreen EGFRRGQ PCR Kit

Gilotrif(afatinib)

4

FerriScan R2-MRI Analysis System to measure liver iron concentration to aid in the identification and monitoring of non-transfusion dependent thalassemia patients receiving therapy with deferasirox.

ResonanceHealth Analysis

FerriscanExjade(deferasirox)

3

Qualitative immunohistochemical test (IHC) to identify colorectal cancer patients eligible for treatment withErbitux (cetuximab) or Vectibix (panitumumab).

DakoDAKO EGFRPharmDx Kit

Erbitux (cetuximab);Vectibix(panitumumab)

2

Real-time qualitative PCR to identify CRC patients for treatment with Erbitux (cetuximab) based on a KRAS mutation status

Qiagentherascreen KRASRGQ PCR Kit

Erbitux (cetuximab)1

Intended Use (IU)/ Indications for Use (IFU)Device

ManufacturerDevice Trade Name

Drug Trade Name(Generic Name)

List of FDA cleared or approved Companion Diagnostic Devices: In vitro and Imaging Tools

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FDA approved Companion Diagnostic Devices

BRAF V600 Mutation Test in DNA extracted from FFPE human melanoma tissue.Selection of melanoma patients for treatment with vemurafenib.

Roche MolecularSystems

COBAS 4800 BRAF V600 Mutation Test

Zelboraf(vemurafenib)

19

ALK FISH Probe Kit to detect rearrangements of ALK gene in non-small cell lung cancer (NSCLC) tissuespecimens to identify patients eligible for treatment with Xalkori (crizotinib).

Abbott MolecularVYSIS ALK Break Apart FISH Probe Kit

Xalkori (crizotinib)18

EGFR Mutation Test (real-time PCR) to select patients with metastatic NSCLC for whom Tarceva®(erlotinib), an EGFR tyrosine kinase inhibitor (TKI), is indicated.

Roche MolecularSystems

cobas EGFRMutation Test

Tarceva (erlotinib)17

BRAF kit (real-time PCR) for detection of the BRAF V600E and V600K mutations in DNA samples extractedfrom FFPE human melanoma tissue to select melanoma patients for treatment with trametinib [Mekinist].

bioMérieuxTHxID™ BRAF KitMekinist (tramatenib) Tafinlar (dabrafenib)

16

HER2 FISH assay for detection of HER2 gene amplification in FFPE cancer tissue (breast, metastatic gastricgastroesophageal junction adenocarcinoma) to identify breast and gastric cancer patients for whomHerceptin (trastuzumab) treatment is being considered and for breast cancer patients for whom Perjeta(pertuzumab) or Kadcyla (ado-trastuzumab emtansine) treatment is being considered.

DakoHER2 FISH PharmDxKit

Herceptin(trastuzumab);Perjeta (pertuzumab)

15

Immunocytochemical assay to determine HER2 protein overexpression in FFPE cancer tissues to identifybreast and gastric cancer patients for whom Herceptin (trastuzumab) or PERJETA (pertuzumab) / KADCYLA (ado-trastuzumab emtansine) treatment is being considered.

DakoHERCEPTEST HER2Herceptin(trastuzumab);Perjeta (pertuzumab)

14

HER2 Dual ISH DNA Probe Aid in the assessment of patients for whom Herceptin (trastuzumab) treatment is being considered.


INFORM HER2 DUAL ISH DNA Probe


13

HER2 CISH PharmDx kit for in situ hybridization probes targeting the HER2 gene. Aid in the assessment of patients for whom Herceptin (trastuzumab) is being considered.

DakoHER2 CISH PharmDxKit


12

Semi-quantitative immunohistochemical (IHC) assay to determine Her2 oncoprotein status in FFPEAid in the assessment of patients for whom herceptin (trastuzumab) treatment is being considered.

Leica BiosystemsBond Oracle Her2 IHC System


11

Intended Use (IU)/ Indications for Use (IFU)Device

ManufacturerDevice Trade Name

Drug Trade Name(Generic Name)

List of FDA cleared or approved Companion Diagnostic Devices: In vitro and Imaging Tools (continued)

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Novel therapeutic approaches

� Targeted therapies, Combination Products, …

� Biologicals– Proteins (Factor VIII, Epo, Interferons, GH, …)

– Monoclonal antibodies (>30 MoAbs approved by FDA, e.g. Infliximab, Trastuzumab, Bevacizumab, )

– Antibody-drug conjugates (Mylotarg, AML; Adcetris, relapsed HL and relapsed systemic anaplastic large cell lymphoma; T-DM1 / Kadcyla, HER2-positive metastatic breast cancer)

– Preventive and Therapeutic Vaccines (e.g. Provenge)

� Advanced Therapy Medicinal Products (ATMPs)– Somatic cell therapies

– Gene therapy

– Tissue Engineering Products

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Small Molecules vs. Biologicals

� Biosimilars, biobetters� Generic competition

� Aggregation, denaturation, …� High stability

� Immunogenicity (biologic, host cellproteins)

� Non immunogenic

� Well defined target� Often multiple targets, off-targeteffects

� Heterogenous product� Well defined compound

� High cost, complex process� Low manufacturing cost

� Purified or fermentation� Chemical synthesis

� High molecular weight� Low molecular weight

BiologicalsSmall molecules

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AEZS Case Studies

1. Zoptarelin Doxorubicin (AEZS-108)

2. AEZS-120 / Therapeutic Tumor Vaccine

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Deep Pipeline – Products at All Stages of Development

Product Candidate Discovery Preclinical Phase 1 Phase 2 Phase 3 Commercial

AEZS-125 LHRH – Disorazol Z***

Compound library 120,000

AEZS-137 Disorazol Z (Oncology)***

AEZS-129-136 Erk & PI3K Inhibitors

AEZS-120 Prostate Cancer Vaccine

AEZS-112 Multiple Cancers

Zoptarelin doxorubicin (AEZS-108) Endometrial Cancer

Ozarelix Prostate Cancer*

Macimorelin acetate (AEZS-130) Cancer Cachexia*

Macimorelin acetate (AEZS-130) Growth Hormone Deficiency Diagnostic

Perifosine Multiple Cancers*

Cetrotide® In vitro Fertilization Partnered with Merck Serono

Partnered with Spectrum, Nippon Kayaku

Partnered with Handok, Yakult, Hikma

Cooperation with NCI

29

Zoptarelin doxorubicin (AEZS-108) LHRH-R Positive Ovarian,** Breast, Bladder and Prostate* Cancers

* Fully sponsored through grants and/or partners ** Ovarian cancer Phase 2 completed *** Partially sponsored through grants and/or partners

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ProductLead

IndicationStatus

PotentialMarket

Zoptarelin doxorubicin

Endometrialcancer

Phase 3Estimated annual

new cases ~ 95,000

Case Study 1

30

• Peptide-Drug Conjugate

• Collaboration with Prof. Schally, University of New Orleans / Miami

• Partnership with Ergomed (Clinical CRO)

• Opportunity to develop companion diagnostic test / Personalized Medicine Approach

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Endometrial Cancer – The Unmet Need

The Disease� Develops when cells in the inner lining of the uterus

(the endometrium) become abnormal and grow uncontrollably

The Symptoms� Bleeding or discharge not related to menstruation � Difficult or painful urination � Pain during sexual intercourse

The Prognosis� The five year survival rates for endometrial cancer by stage are:

– Stage I: 70-95%, stage II: up to 55%, stage III: up to 25%, stage IV: up to 5%

� Often spreads to lungs, liver, bones, brain, vagina, and certain lymph nodes

Current Treatments� Stage III or IV: surgery, followed by chemotherapy (combination of

platinums and paclitaxel) and/or radiation therapy

31Source: NCI and SEER

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Zoptarelin doxorubicin (AEZS-108)

Powerful Trojan Horse for Targeting Cancer Cells

DOX LHRHtargeting agent

MDR-1

Apoptosis induction

Binding on the LHRH receptor

Migration to the nucleus

32

LHRH targeted DOX conjugate

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Unique Mode of Action

� Allows specific targeting of tumor cells expressing the LHRH receptor

� LHRH receptor – ideal target for personalized medicine approach

– Expressed in human cancer tissue*

• Breast ~ 60%• Endometrial ~ 80%• Ovarian ~ 80%• Prostate and bladder cancer

– Only detectable in reproductive tissue and pituitary

– LHRH agonist can be used for targeting LHRH receptors

– Companion diagnostic opportunity

*Source: Limonta et al., Endocrine Reviews, 2012

33

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Gründker et al.; Am J Obstet Gynecol. 2002

Tumor volume of SK-OV-3 human ovarian cancers(LHRH receptor-negative) xenografted into nude mice.

i.v. once on day 0 to 5 animalssaline solution (control),doxorubicin (300 nmol/20 g), and AEZS-108(300 nmol/20 g)

Tumor volume of NIH:OVCAR-3 human ovarian cancers (LHRH receptor-positive)xenografted into nude mice.

i.v. once on day 0 to 5 animalssaline solution (control),doxorubicin (300 nmol/20 g), andAEZS-108(300 nmol/20 g)

AEZS-108

AEZS-108


Proof of concept in animal models

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* Partial response not confirmed at a subsequent time point** Progressive disease based on occurrence of new lesions*** Symptomatic deterioration or death due to malignancy prior to cycle 2: maximum change arbitrarily assigned as 120%One patient excluded from plot because no tumor size assessment available

******

** ** **

**

** *

> +20 %: PD

< -30 %: PR

-120%-100%

-80%-60%-40%-20%

0%20%40%60%80%

100%120%140%

Max

imum

cha

nge

from

bas

elin

e (%

)

Reviewer: not evaluable

Reviewer: confirmed


Encouraging Phase 2 Results - Waterfall Plot

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Phase 3 Study Design in Recurrent Endometrial Cancer Under SPA

36

Phase 3 “ZoptEC”(Zoptarelin doxorubicin in Endometrial Cancer) trial in women with endometrial cancer resistant to platinum/taxane-based chemotherapy

Patients� n = 500� Randomized one to one� Zoptarelin doxorubicin (AEZS-108) against doxorubicin

Dosing� 267 mg/m2 (AEZS-108) against 60 mg/m2 (doxorubicin) � IV infusion every 3 weeks

Primary endpoint � Overall survival (minimum 3 month improvement)

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ProductLead

IndicationStatus

PotentialMarket

AEZS-120Prostatecancer

Preparing for Phase 1Estimated annual

new cases ~ 505,000

Case Study 2

37

• Innovative Therapeutic Concept (ATMP)

• Collaboration with Prof. Rapp and Prof. Rudel at University of Würzburg, Germany

• BMBF Research Grant

• Early advice by Regulatory Authorities regarding nonlinical & clinical program, CMC-related topics

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Prostate Cancer

The Disease

� Malignant (cancer) cells form in the tissues of the prostate

The Symptoms

� Weak or interrupted urine flow; the inability tourinate or difficulty starting or stopping the urineflow; the need to urinate frequently

The Prognosis

� 5-Year Relative Survival (%) by stage at diagnostic:– Localized: 100%

– Regional: 100%

– Distant: 27.9%

– Unstaged: 72.9%

38Source: NCI and SEER

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AEZS-120

Unique Mode of Action

RecombinantDNA

PSA-CtxBfusion protein

Secretion

Genetically modified live bacterium(Salmonella typhi Ty21a MoPC)for cancer vaccination

Free antigenicfusion protein

Secretion of the prostate cancer antigen (PSA) fused to the non-toxic immunostimulatorybeta-subunit of cholera toxin B (CtxB) through the recombinant E. coli hemolysin

secretion system by the attenuated Salmonella typhi Ty21a carrier strain .

� Based on Salmonella typhi Ty21a, a vaccine carrier strain which is an approved oral typhoid live vaccine with an excellent safety profile (> 350 M doses)

� Intracellular bacteria can be delivered orally and typically target cells of the immune system

� Proposed pathways by which bacteria can induce antitumor immunity:– Reprogramming of tumor milieu by bacterial

components

– Induction of tumor specific immunity by bacteria carrying tumor antigen

All sequences of events lead to death or retardation of growth in cancer cells

39

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AEZS-120

Preclinical Proof of Concept

40

Challenge Experiment – 14 days observation period

Median Tumor Volume

0.00

100.00

200.00

300.00

400.00

0 5 10 15Study Day

Tum

or V

olum

e (m

m³)

EF1 - naive

EF2 - Sl 1C

EF3 - Sl 2C

EF5 - Sl MoPC 1C

EF-6 Sl MoPC 2C

EF7 - pCDNA PSA

Complete observation period: 21 daysAfter day 14: several mice had to be taken out of experiment due to tumor volume or ulceration(naive group and group 2)

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AEZS-120

Product Profile and Status Today

Product� Innovative live recombinant oral vaccine candidate for prostate cancer

� Induces cellular and innate immune response

– May bypass immunotolerance through T-cell suppression and exerts a long-lasting immune response

– Off-the-shelf product

Status� Clinical Trial Application (CTA) approved in Denmark in preparation

for upcoming Phase 1 trial in prostate cancer

� IND under consideration

41

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http://www.forbes.com/sites/edsilverman/2012/09/25/and-the-crystal-ball-says-the-pharma-future-is-improving/

Problems solved?

“… The stable outlook reflects our view that the worst of the industry’s blockbuster patent expirations has passed,” says Michael Levesque, a Moody’s senior vp, in a statement. “Although industry earnings will still be affected by very recent patent expirations, earnings for large, branded (drugmakers) will reach a trough point in late 2012 and rebound in 2013…”

“… Levesque believes the industry “remains challenged by a difficult regulatory approval environment for new products, and by areas of research that are still seeing limited success…”

„ … Other problems include efforts in numerous countries to contain costs, particularly for prescription medicines, which is accompanied by an increasing use in generics…”

September 23, 2013

Providing Therapies for Unmet Medical Needs in Oncology & Endocrinology

Documents

What is the impact of new technologies and novel therapeutic …€¦ · Aeterna Zentaris Current challenges for pharma development Kaitin KI, Clin Pharmacol Ther. 2010 March ; 87(3):