Third Env Manufacturing Workshop July 20 21, July 20, 2017 Mary Marovich, M.D. Director, Vaccine Research Program

Transcription

1 Third Env Manufacturing Workshop July 20 21, 2017 July 20, 2017 Mary Marovich, M.D. Director, Vaccine Research Program

2 Presentation Outline Importance and Impact of an HIV Vaccine DAIDS/VRP Programmatic Focus and Priorities Three Novel Strategies: HIV Vaccine Efficacy Studies 1. AMP Study: Overview and Current Status 2. The Pox Protein Public Private Partnership (P5) 3. Janssen POC Trial Collaboration Where are we now? Next Steps for an AIDS-free Generation CONFIDENTIAL 2

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4 How long does it take to develop a vaccine? 5

5 Global Progress in HIV Increased # HIV+ people on ARVs: 1.3M (2005) --> 18M (2016). Adding other prevention tools: HIV infections hold steady at 2+M per year. Adult infection rates unchanged x 5 years, increases in some regions. Continued challenges: adherence, access and increased at-risk youth. Lancet HIV 2016 Lancet HIV

6 Impact of a (modestly efficacious) AIDS vaccine The potential impact of an AIDS vaccine as part of the UNAIDS Enhanced Investment Framework Modeling project UNAIDS, Futures Institute, IAVI, AVAC. CONFIDENTIAL Source: IAVI 6

7 Future of HIV-1 Vaccines is Bright Major breakthroughs in last 5-7 years converge: 1 st Efficacy signal RV144 New technology viral targets, Env crystal structure Human broadly neutralizing Abs protect NHP Non-neutralizing Abs protect NHP Vaccine elicited CD8 T cells protect NHP, clear SIV infection Development of an HIV Vaccine remains a top priority for NIAID. 7

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9 NIH/NIAID/VRP Priorities Focus: important public health issues AIDS vaccine high priority 2.1M new HIV infections each year Vaccine necessary to bend the epidemic curve Fund and enable high quality scientific research Foundational R&D for vaccines Spectrum from basic/discovery to translational/applied Enable and support clinical efficacy testing Generalizable scientific knowledge 9

10 VRP Mission: safe and effective HIV vaccine Support preclinical, translational, and clinical research portfolios Promote research programs to discover novel vaccine candidates and strategies Identify and characterize selected viral envelopes, targets and immunization strategies that stimulate neutralizing antibodies Establish and support the infrastructure for the manufacturing and testing of novel immunogens and bnabs Develop strategies to optimize protective B-cell responses Assess correlates of immunogenicity and of protection elicited by experimental vaccines 10

11 DAIDS VRP Programmatic Focus by Area Pre-clinical/Discovery Research Long-range goals: predictive model of immune response; lab correlates of protection Design immunogens to induce NAbs, protective non-nabs, cellular responses Identify and characterize protective immune signatures of vaccines Increase breadth and durability of protective responses better immunogens, adjuvants Translational Research Identify key analytics for protein/immunogen effectiveness Access technology for cost-effective and efficient manufacture Improve product yields (e.g. higher expression, reduced loss) Sharing lessons learned through Process Development, Tech Transfer, GMP scale-up Clinical Research Design and conduct phase 1, 2 & 3 trials; pursue study correlates Study concepts to elicit and technology to assess innate, adaptive, mucosal responses Understand and modulate immune response obstacles to bnab development Actively coordinate/integrate clinical research with basic/preclinical/nhp investigators Incorporate research on behavioral & social factors in prevention and transmission CONFIDENTIAL 11

12 How does NIAID/VRP manage vaccine portfolio? Science and data-based decision-making Rely on Peer-review system Often start with basic-innovative concepts Concepts grow into platforms and candidates Staged and milestone driven processes Stronger candidates emerge with compelling data (small animals, NHP) Manufacturability, feasibility and analytics considered Defensible rationale to test in humans 12

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14 3 Novel Strategies for HIV Vaccine Development L. Correy/HVTN 14

15 HIV Efficacy Trial Landscape Enrollment Completion Anticipated Efficacy Results Anticipated 15

16 Where are we now and next steps.. 16

17 HIV-1 Vaccine Development Long term success depends on ability to: 1. Learn from the past 2. Integrate/move breakthroughs into clinic 3. Adapt to challenges through innovation How can we work together to advance more HIV protein candidates into the clinic for testing? 17

18 The End Game: An AIDS-Free Generation When asked about his 2000 failed experiments to develop a commercially-viable incandescent light bulb: Those weren t failures. This was just a 2000-step process. Thomas Edison 18

19 Acknowledgements NIAID/DAIDS Senior Management Anthony S. Fauci Carl Dieffenbach VRP- Office of the Director Kevin Ryan Barbara Cunningham Sherolyn Earle Yvette Edghill Spano Sussan Paydar Tina Tong Vaccine Clinical Research Branch Dale Hu (Branch Chief) Philip Renzullo Patricia D Souza Mary Allen Cesar Boggiano Margarita Gomez Julia Hutter Nina Kunwar James Lane Pierre Paisible Laura Polakowski Edith Swann Lynne Wu Jane Baumblatt Preclinical Research Development Branch Jim Bradac (Branch Chief) Que Dang Angela Malaspina Nancy Miller Jessica Santos Alan Schultz Stuart Shapiro Anjali Singh Jonathan Warren Vaccine Translational Research Branch Michael Pensiero (Branch Chief) Joellyn Bowser Chris Butler Jane Halpern Vijay Mehra Nandini Sane Shah Raza Becky Sheets Shyam Rele Amanda Ulloa Christoper Hamlin Maria Chiuchiolo Vernisha Greene Kevin Kampherstein Sujata Vijh NIAID funded Networks, Principal Investigators, Labs, Sites and Partners HVTN: Larry Corey, Linda Gail-Becker, Peter Gilbert, Glenda Gray, Scott Hammer, Jim Kublin, Julie McElrath, and Georgia Tomaras HPTN: Mike Cohen, Srilatha Edupuganti, Nyaradzo Mgodi VRC: John Mascola, Julie Ledgerwood, Barney Graham Janssen: Maria Pau, Frank Tomaka Pox Protein Public Private Partnership (P5): 19

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22 Strategies to Amplify RV144 Response CONFIDENTIAL AS Fauci/NIAID 22

23 P5 Vaccine Program in South Africa Underpinned by community, regulatory and government stakeholder engagement CONFIDENTIAL G. Gray/HVTN 23

24 P5 Vaccine Program: Added 12 and 18 month boosts CONFIDENTIAL G. Gray/HVTN 24

25 Go/No-Go Criteria required to move to efficacy Criterion 1: Prevalence of antibodies to gp120 vaccine antigens to be 75% 100% of HVTN 100 subjects developed Env binding antibodies to the Clade C strain. Criterion 2: Magnitude of Env antibody response to be 50% of that seen in RV144 HVTN 100 binding antibody responses were 3.5 to 8.6 fold higher than in RV144. Criterion 3: CD4 T cell response to Env will be at least equal to that seen in RV144 HVTN 100 Env specific CD4 T cell responses exceeded those in RV144 (58% vs. 41%, respectively) and showed considerably higher polyfunctionality than in RV144. The polyfunctionality score was shown to be an independent correlate of VE in RV144. Criterion 4: Prevalence of IgG antibodies to the V1V2 loop to be 63% Prevalence of IgG V1V2 to the 1086 Clade C strain in the bivalent gp120 boost was 71% in HVTN 100 which exceeds the threshold predicted for a VE=50% based upon RV144. CONFIDENTIAL 25

26 HVTN 100 Conclusions The level of immune responses to these key immune markers allows assessment of Correlates of Protection in the HVTN 702 design. The funders NIAID/BMGF, as well as the P5 Partners including Sanofi, GSK and MHRP, agree to proceed with HVTN 702 and the trial was opened in October CONFIDENTIAL 26

27 Study Schema: HVTN 702 N (total 5400) Primary Vaccine Regimen Month 0 Month 1 Month 3 Month 6 Booster Month 12 and Month 18 (?) 2700 ALVAC-HIV- C ALVAC-HIV- C ALVAC-HIV-C Bivalent Subtype C gp120/mf59 ALVAC-HIV-C Bivalent Subtype C gp120/mf59 ALVAC-HIV-C Bivalent Subtype C gp120/mf Placebo Placebo Placebo Placebo Placebo Estimated Study duration 72 months: Stage 1: Two year efficacy estimate (24 months after final vaccination) Stage 2: Additional 12 months of follow up for durability estimate CONFIDENTIAL 27

28 Prospective improvements in VE with the HVTN 702 vaccine regimen CONFIDENTIAL G. Gray/HVTN 28

29 HVTN 702 Study Design Features Evaluates Stage 1 VE to 24 months after 1 st vaccination If evidence of positive VE, evaluates VE durability to 36 months after 1 st vaccination Continuous monitoring for harm, sequential monitoring for nonefficacy and non-efficacy/efficacy futility 90% power to detect VE of 50% (enrollment through 24 months) 90% power to reject null hypothesis (VE 25%) True Average VE (0-24) Power to reject null: VE (0-24) 25% 30% 7 40% 45 50% 90 60% % % 100 CONFIDENTIAL G. Gray/HVTN 29

30 Target Product Profile Pox-Protein Public Private Partnership program and upcoming HIV vaccine efficacy trials. Russell, Nina; Marovich, Mary Current Opinion in HIV & AIDS. 11(6): , November

31 P5 Clinical Program Time Lines HVTN 111 HVTN 108 HVTN 120 HVTN 107 CONFIDENTIAL G. Gray/HVTN 31

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33 AMP Americas Trial (HVTN704/HPTN085) AMP Africa Trial (HVTN703/HPTN081) Phase 2b studies to evaluate the efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection CONFIDENTIAL 33

34 AMP (HVTN703/HPTN081) Trial Questions 1. Can the VRC01 neutralizing mab can prevent HIV infection? 2. What marker(s) correlate with protection against HIV infection? 3. What are the mechanistic correlates of protection? Objective: Help design candidate HIV vaccines and define immunogenicity study endpoints in Phase I/II trials for evaluating these candidate vaccines CONFIDENTIAL 34

35 AMP Study Schema A Phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection VRC01 Ab 10 or 30 mg/kg IV or placebo every 8 weeks, 10 doses High Risk Women N=1500 Sub-Saharan Africa MSM/TG N=2700 North and South Americas and Switzerland Primary Objectives: Safety, tolerability and reduction of HIV-1 infection Estimate efficacy of prevention of infection in each of two separate cohorts Study duration: 92 weeks CONFIDENTIAL 35

36 Rationale for the 2 Cohorts and 2 Dosing Regimens Route of acquisition and genital tract immunology and anatomy may influence the distribution of VRC01 and potential efficacy. Variation in the doses allows us to more precisely define what are the optimal concentrations of neutralizing activity associated with protection from acquisition. J. Mascola, VRC

37 AMP Study Status HVTN 704/ HPTN 085 (MSM + TG in Americas and Switzerland) Opened March 31, 2016 (n=2700) First participant enrolled April 6, 2016 Total Number Currently Enrolled: 1135 (as of May 8, 2017) 25/26 sites activated 4044 infusions administered (as of May 11, 2017): 99.9% infusion adherence Anticipated completion of enrollment: July 2018 HVTN 703/ HPTN 081 (Women in SSA) Opened May 9, 2016 (n=1500) First participant enrolled May 17, 2016 Total Number Currently Enrolled: 662 (as of May 8, 2017) 15/21 sites activated 1736 infusions administered (as of May 11, 2017): 99.1% infusion adherence Anticipated completion of enrollment: October 2017 Interim Safety Assessment successfully passed [based on 450 participants followed for 24 weeks (up to 4 infusions)] CONFIDENTIAL

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39 Janssen Collaboration: Preventive HIV Vaccine aiming for Global Coverage Barouch, D.H., et.al. Nature 482, pp (02 February 2012) ; Barouch, D.H., et.al. Cell, Volume 155, Issue 3, pp (24 October 2013) ; Barouch, D.H., et.al. Science Vol. 349, Issue 6245, pp (17 Jul 2015) CONFIDENTIAL M. Pau/Janssen 39

40 Ad26/Ad26 + gp140 HIV vaccine regimen provides substantial protection against SHIV challenges in NHPs Percent uninfected week post first challenge Regimen Ad prime / Ad boost Ad prime / gp140 boost Ad prime / Ad+gp140 boost Ad prime / MVA boost Ad prime / MVA+gp140 boost Sham Per-exposure risk reduction versus sham Full protection after 6 challenges 35% 0% 12 84%* 33% 12 94%* 66% 12 71% 8% 12 87%* 42% 12 N/A 0% 12 N *Statistically significant vs Sham in a Cox proportional hazard model and Log-rank test; Statistically significant vs Sham in a 2-sided Fisher s exact test CONFIDENTIAL M. Pau/Janssen 40

41 Heterologous Prime/Boost Regimen Prime Boost Ad26.Mos.HIV Ad26 vectors with Mosaic gag-pol or env inserts Ad26.Mos1.Gag-Pol Ad26.Mos2.Gag-Pol Ad26.Mos1.Env Ad26.Mos.HIV gag-pol-env MVA-Mosaic MVA vectors with Mosaic gag-pol-env inserts and/or OR and/or gp140 Clade C Soluble trimer gp140 env protein gp140 Clade C Soluble trimer gp140 env protein MVA-Mosaic 1 MVA-Mosaic 2 months Regimen to be selected after Phase 1/2a CONFIDENTIAL M. Pau/Janssen 41

42 Phase 2b Proof of Concept Trial HVTN705, in sub-saharan Africa (SSA), commencing Q Evaluate vaccine efficacy of a regimen including Ad26.Mos4.HIV and clade C gp140 Population: Moderate to high risk subjects in Southern Africa Limited to female subjects CONFIDENTIAL M. Pau/Janssen 42

43 Objectives of Janssen Collaboration Efficacy Program Efficacy against multiple clades for a global vaccine Efficacy in preventing HIV infection in heterosexual population and in MSM Safety and reactogenicity Persistence of protective immunity Correlates of vaccine-induced protection May include the Mosaic gp140, depending on HPX2003 results Subjects yo would be enrolled based on safety data in adults from HIV-V-A004, HPX2008, and HPX2003 (ASCENT) Immunologic bridging studies will be considered for younger adolescents CONFIDENTIAL M. Pau/Janssen 43