Moving Experimental Vaccines and Medicines for Ebola Virus into Clinical Practice Leem Press Workshop March 10, 2015 Gary J. Nabel M.D. PhD. Chief Scientific Officer Sanofi
Gene-based vaccination for Ebola Virus Nature Medicine 4, 37 - 42 1998 Development of a Immunization for preventive vaccine Ebola virus infection for Ebola virus infection in primates Ling Xu, Anthony Sanchez, Zhi-Yong Yang, Sherif R. Zaki, Nancy J. Sullivan, Anthony Sanchez, Elizabeth G. Nabel, Pierre E. Rollin, Zhi-yong Yang & Stuart T. Nichol & Gary J. Nabel Gary J. Nabel Nature Medicine 4, 37 - 42 1998 Nature, 408, 605-609, 2000
The Genetic Economy of Ebola Virus- a Tool for Vaccine and Drug Development L(polymerase) VP30 VP24 VP40 GP NP VP35 18,957 bp 5' 3' Overlap Overlap Overlap NP, VP35 and VP24 are Necessary and Sufficient for Nucleocapsid Formation Huang Y, Xu L, Sun Y, Nabel G, Mol. Cell 10:307-316, 2002 3
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CD8 Cells Mediate Ad Vaccine Protection Against Ebola CD8+ Cellular Immunity Mediates rAd5 Vaccine CD8+ Cellular Immunity Mediates rAd5 Vaccine CD8+ Cellular Immunity Mediates rAd5 Vaccine Protection Against Ebola virus Infection of Nonhuman Protection Against Ebola virus Infection of Nonhuman Protection Against Ebola virus Infection of Nonhuman Primates. Primates. Primates. Sullivan NJ, Hensley L, Asiedu C, Geisbert TW, Stanley D, Johnson J, Honko A, Olinger Sullivan NJ, Hensley L, Asiedu C, Geisbert TW, Stanley D, Johnson J, Honko A, Olinger Sullivan NJ, Hensley L, Asiedu C, Geisbert TW, Stanley D, Johnson J, Honko A, Olinger G, Bailey M, Geisbert JB, Reimann KA, Bao S, Rao S, Roederer M, Jahrling PB, Koup G, Bailey M, Geisbert JB, Reimann KA, Bao S, Rao S, Roederer M, Jahrling PB, Koup G, Bailey M, Geisbert JB, Reimann KA, Bao S, Rao S, Roederer M, Jahrling PB, Koup RA, Nabel GJ. RA, Nabel GJ. RA, Nabel GJ. Nat Med. 2011 Aug 21;17(9):1128-31. Nat Med. 2011 Aug 21;17(9):1128-31. Nat Med. 2011 Aug 21;17(9):1128-31.
Pre-existing Ad5 Immunity Abrogates Ebola Vaccine Protection in NHP Non-immune 100 Ad5-naïve 80 Percent Survival 60 40 Ad5-immune Immune 20 No vaccine Ad5-naïve/No vaccine n=1 (50 historical controls) 0 0 5 10 15 20 25 30 Day Post Infection • Ad5-immune and –naïve macaques • Vaccinate with rAd5-GP • Immune response and challenge at 4 wks 7
Definition of an Ebola Vaccine with Rapid Onset and Durable Protection in Monkeys ChAd3 Prime MVA Boost Received 18 August; accepted 2 September; published online 7 September 2014; doi:10.1038/nm.3702 8
Pharmaceutical Drug and Vaccine Development-A Slow Process Lead Lead Target ID and Val Preclinical Development Identification Optimization Historical 115 cycle times Target cycle times 54 small molecule Target cycle times 42 biologics Average cycle times 0 20 40 60 80 100 120 140 (months) Research & Early Development | 9
Sanofi names chief scientific officer Gary Nabel as Sanofi Ebola response coordinator Monday, November 24, 2014 02:30 PM As part of its contribution to the global response to the Ebola epidemic, Sanofi has appointed chief scientific officer Dr. Gary J. Nabel, M.D., Ph.D., as its Ebola response coordinator. In his mission, Dr. Nabel will identify how Sanofi can help advance countermeasures to contain the current outbreak and prioritize and foster opportunities to develop novel treatments for the future. "Given his past experience in public health epidemics as director of the NIH Vaccine Research Center and his leadership in developing an Ebola vaccine at NIH, Nabel is uniquely qualified for this position," said Dr. Elias Zerhouni, M.D., president of Sanofi Global R&D. "Nabel is working with other organizations, including providing guidance to researchers based on the company's extensive experience in vaccine and drug development, to determine how Sanofi can assist in making progress with this global challenge." "Working with our colleagues across the industry, Sanofi is helping to find ways to advance medicines to prevent or treat Ebola virus infection. We also are sharing our scientific, medical, regulatory and manufacturing expertise with the World Health Organization, government and non- governmental organizations—public and private—in an effort to contain this epidemic,". Nabel said.
A Spectrum of Ebola Countermeasures From Vaccines to Anti-virals Prevention Treatment Small Vaccines Biologics Molecules Gene- Live Viral Cell Antibodies siRNA based Vector Genes Targets
Sanofi Priorities for Ebola Virus Countermeasures Tier 1 Tier 1 Vaccines/Antivirals Already in Clinical Trials Tier 2 Tier 2 Proof of Concept in NHP Not in Clinical Development Tier 3 Tier 3 Antiviral activity but no NHP proof of concept
Diverse Target Product Profiles Modality Prophylaxis Vaccines Biologics Small Molecules (Pre or Post Exposure) Treatment, EBOV+ Vaccines Biologics Small Molecules (early symptoms) Ebola VHF Vaccines Biologics Small (late stage) Molecules
PHRMA Response to Ebola Outbreak: Ebola Response Coordination Team (ERCT) ● Organized by BMAC Co-Chairs Elias Zerhouni and Tachi Yamada ● Chaired by Gary J Nabel, Sanofi CSO, ● Other Members: Mark Feinberg, MD, PhD, Chief Public Health and Science Officer, Merck Vaccines, Merck & Co., Inc. John Houston, PhD, Senior Vice President, Disease Sciences and Biologics, Bristol-Myers Squibb Dale Kempf, PhD, Director of Antiviral Research, AbbVie Machelle Sanders, MHA, Vice President, Manufacturing & General Biogen Idec Inc. Jonathan “JZ” Zalevsky, PhD, Head, Immunology Research, Takeda Pharmaceuticals U.S.A., Inc. Ex officio (PHRMA): Bill Chin-Executive VP: Scientific and Regulatory Affairs Sanofi US | 14
Sanofi and PHRMA Ebola Activities ● Participated in Hever Group Ebola Medicines Day ● November 24, 2014 ● Pharma, biotech and government representatives developed a Global Call for clinical compounds to be tested in the NIH and USAMRIID Ebola Screening Cascades ● Reviewed External Requests for Support of Discovery Programs Sanofi Contributions ● 136 compounds identified for screening at USAMRIID ● 5 Biotech/Academic groups referred to USAMRIID for further testing. Sanofi US | 15
Policy and Regulatory Concerns Indemnification Indemnification Clinical Trials Clinical Trials Ethics Ethics Vaccines/Prevention Specific for TPP’s Ethical Review Committees Anti-Viral Therapy POC in humans Informal Consent Efficacy Studies (Placebo Controlled, Adaptive) Licensure Requirements
Licensure is only one step in combating disease Lead Lead Target ID and Val Preclinical Development Identification Optimization Research & Early Development | 17
Manufacturing Production Capacity Production Capacity Reagents for Testing and Lot Reagents for Testing and Lot Release Release Formulation Formulation Delivery Strategies Delivery Strategies
Managing the Flow of Ebola Drugs or Vaccines to Patients Vaccine or Drug Clinical Trials, Data Collection, Manufacturer Pharmacovigilance 1 2 Territory (Guinea, Liberia, Sierra Leone) Ebola Treatment Centers Physicians 5 6 Embassy or Designated Reciever Local 7 Patients Delivery 3 Distribution Guinea Sierra Partner 4 Leone Liberia http://media1.s-nbcnews.com/j/newscms/2014_39/680316/140923-ebola-treatment-unit-1009_ce02989f72ffb0890d8bba12e9257b74.nbcnews-fp-1040-600.jpg http://i100.independent.co.uk/image/27060- res386.jpghttps://www.google.com/search?q=ebola+PATIENT+INJECTION&hl=en&gl=us&authuser=0&biw=1619&bih=944&source=lnms&tbm=isch&sa=X&ei=bcv 1VP_pGIzFggTeyoH4Aw&ved=0CAYQ_AUoAQ#hl=en&gl=us&authuser=0&tbm=isch&q=ebola+PATIENT+SHOT&imgdii=_&imgrc=6os9aWCpbM_ahM%253A%3BsGAdumEHeI21UM%3Bhttp%253A%252F%252Fs1.ibtimes.com%252Fsites%252Fwww.ibtimes.com%252Ffiles%252Fstyles%252Fv2_article_large%252Fpublic%252F2014%252F08 %252F05%252Fliberia-ebola-outbreak.jpg%253Fitok%253DiwvbbzrY%3Bhttp%253A%252F%252Fwww.ibtimes.com%252Fsecond-us-ebola-patient-treated-zmapp-experimental-drug-leaves-atlanta-1648876%3B770%3B513
Galaxies Colliding: Countering Emerging Infectious Diseases Public Health Sustainable Impact Funding/Commitment The challenge facing countermeasures for emerging pathogens 20
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Summary Ebola virus is a prototypic filovirus with high lethality that is readily spread 1 by human contact during active infection. Ebola mortality is multifactorial, driven by viral cytopathicity for hepatocyte, reticuloendothelial, and endothelial cells whose damage 2 ultimately causes septic shock. It is possible to generate protective immunity to Ebola by vaccination. 3 The cellular immune response plays a critical role in mediating protection. The antibody response correlates but is not responsible for immunity. Two vaccine candidates are progressing in clinical trials. Antiviral 4 therapies, including antibody (ZMapp) and anti-sense oligonucleotides, are in evaluation but are yet unproven in humans. In the interim, barrier precautions and containment represent the key 5 public health tools to control Ebola virus spread. 22
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