EHVA Project Overview

Transcription

1 EHVA Project Overview This project has received funding from the European Union s horizon 2020 research and innovation programme under grant agreement No

2 EHVA Consortium 39 partners 11 countries 3 continents Infinite enthusiasm spanning basic, clinical, biostatistical and community disciplines 2

3 EHVA Consortium 3

4 EHVA Jan2016-Dec million Euros 22 million Euros from the European Commission (Grant nr ) 6 million Euros from the Swiss government for the Swiss partners (Grant nr ). 4

5 Primary Goals To Develop a Multidisciplinary Vaccine Platform (MVP) in the fields of Prophylactic and Therapeutic HIV Vaccines To move at least two novel prophylactic vaccine candidates to clinical development To identify immune correlates associated with the control of HIV replication following immunological intervention To establish a strong scientific basis for further development of EHVA vaccine candidates in larger clinical trials 5

6 EHVA Principals and process 6

7 EHVA Principals and process EHVA-PT-1 Experimental medicine Prime RNA dosing Boost NYVAC + CN54 EHVA-PT-2 Adaptive trials Prime RNA, DNA GTU-DNA, NYVAC Boost NYVAC + CN54 EHVA PT-3 Phase II Prime Selected in EHVA-PT-2 Boost NYVAC + CN54 NYVAC + new env 7

8 EHVA T01 Trial EHVA-T-1/2 parallel clinical trials with different vaccines strategies in patients who started ART during primary infection or during chronic infection A sophisticated set of immune and virologic profiling assays EHVA-T-3 A clinical trial evaluating therapeutic vaccination in combination with other interventions Find correlates of vaccine efficacy, and establish innovative, specific and sensitive signatures for HIV therapeutic vaccine evaluation. RESULTS FROM TRIAL 1/2 USED TO DESIGN TRIAL #3 Obtain indications on combinations to inform design/strategy for HIV remission or cure 8

9 EHVA T01 Trial A Phase I/II randomised therapeutic HIV vaccine trial in individuals who started antiretrovirals during primary or chronic infection 9

10 EHVA T01 Trial 10

11 EHVA T01 Trial A= ART and a4b7 B=ART and IgG 11

12 EHVA T01 Trial A Phase I/II randomised therapeutic HIV vaccine trial, alone and in combination with vedolizumab, in individuals who started antiretrovirals during primary or chronic infection 12

13 Multi-arm, multi-stage design Multi-arm Test many relevant approaches Multi-arm, Multi-stage C T1 T2 T3 T4 Phase II Use fewer resources Cost per comparison is much less Less bureaucracy Phase III 13

14 EVHA T01 Hypothesis Therapeutic vaccination will induce de novo immune responses and boost existing responses to improve the control of HIV replication A clinically relevant viral load response to vaccine is defined as a delay to rebound of at least 10,000 copies/ml, confirmed Vedolizumab acts through a different mechanism to limit the viral replication and it is very likely that these two interventions will be synergistic 14

15 Primary outcome measures Efficacy: Confirmation of HIV RNA 10,000 copies/ml on a separate sample Resuming antiretroviral therapy for any reason over a period of 24 weeks Safety: A clinical decision to discontinue the regimen for an adverse event that is considered related to product. 15

16 Secondary outcome measures Virological: Level of HIV total DNA Cell Associated (CA) HIV RNA Quantification Immunological: Response rate, magnitude and polyfunctionality of vaccine induced CD4 and CD8 T-cell responses Safety: severe solicited AEs; AEs leading to interruption AE leading to resuming treatment during the ATI Time to VL suppression after restarting ART SAEs, other AEs 16

17 Selected inclusion criteria HIV-1-infected, aged at screening, >50kg Nadir CD4 count > 300 CD4 count > 600, Viral load <50 at screening Started cart after 2009 and on cart for at least one year prior to screening Willing to take precautions to prevent onward transmission during ATI Willing to avoid pregnancy 17

18 Selected exclusion criteria HIV-2 infection (either isolated or associated with HIV-1) or receipt of previous HIV vaccines VL >200 copies/ml on 2 occasions in the 12 months prior to screening, previous interruptions in cart or virological failure with resistance Current medical conditions or lab abnormalities, including active infection or presence of pathogenic bacteria or parasites in the stool, active hep B or C Past history of PML, cardiac, neurological, cancer, severe reaction to vaccination Family history of rheumatoid arthritis 18

19 Trial schema 19

20 Trial schema add PIS diagram 20

21 EHVA T01 Trial Size participants will be enrolled across the 6 centers and randomised to active product or placebo in a ratio of 3:1 within each schedule 4-arm, 2-stage design with an interim analysis when 11 participants in the placebo group resume treatment Expected after 88 participants have been enrolled, so there will be a pause in enrolment when n=88 The final sample size will depend on how many arms proceed beyond the interim analysis 21

22 EHVA T01 Trial 22

23 EHVA T01 Trial Size Primary Outcome Proportion of placebo participants expected to have reached the primary outcome by 6 weeks post cart nterruption One-sided Alpha (Type I Error Probability) Power (Type II Error Probability) Critical value (Hazard Ratio compared to Control) Target HR under alternative hypothesis (H1) overall p=0.029 confers an absolute reduction of 50% Interim Analysis Final Analysis Time from treatment interruption to the earliest of reaching HIV RNA 10,000 copies/ml or resuming antiretroviral therapy for any reason 72% 72% % 92%

24 EHVA T01 Organization Trial Sponsor: Inserm-ANRS, France Clinical Centers: France: 3 Inserm-ANRS Centres, Paris Spain: Hospital Clinic de Barcelona UK: Imperial College (St Mary s and St Stephens Clinical Research/Chelsea and Westminster Hospital), London Italy: Instituto Nazionale Malattie Infettive Lazaro Spallanzani, Rome Germany: Universitätsklinikum Hamburg-Eppendorf Switzerland: CHUV, Lausanne Trial Coordinating Center: MRC CTU at UCL, London Community partner: EATG 24

25 EHVA T01 Sub-studies Leukopheresis: (Spain), Germany, Switzerland, France LN biopsy: (Spain), Germany, Switzerland GI biopsy: (Spain), Germany, France Microbiome: not flagged as substudy in the main protocol, but not all ppts/centres will take part Social Science: not yet submitted, all centres willing to take part Genital secretions: recently proposed for French centres only 25

26 EHVA T01 Enrolment per Center Country Proposed target France 18 UK 20 Italy 8 Germany 8 Spain 16 Switzerland 18 Total 88 26

27 EHVA T01 Review Status Country Reviewed Selected Comments UK Versions 1, 3, (4) Clarify risks in PIS (resistance) Italy Versions 1, (4) IDMC safety review of first 12 Switzerland* Versions 1, (4) Pregnancy Germany* Not yet (4) Spain* Not yet (4) France* Not yet (4) * These centres also seeking approval for one or more substudies leukapheresis/gi biopsy (rectal or sigmoid colon)/ln biopsy 27

28 EHVA T01 Issues ART interruption CD4 and VL eligibility criteria to mitigate against risk, but still an issue for those who started in primary? Weekly VL monitoring, monthly CD4 Resume at 10,000 copies or CD4 350 or symptomatic acceptable to EATG Need to avoid resistance, so patients may have to switch Transmission to negative partners PML and JCV antibodies Recruitment Will be challenging because of intensity 28

29 EHVA T01 Next steps Initiation Will follow approval of v4 and product release late June (if all goes to plan) Enrolment Pause 1 after 12 have been (slowly) enrolled and passed their first safety visit for IDMC to review local and systemic reactogenicity o 1 individual/week for the first 4 weeks o 2 individuals/week for 4 weeks Pause 2 after 88 have been enrolled at 4 or more per week for interim analysis Enrolment will be competitive, if necessary 29

30 EHVA T01 Acknowledgments MRC CTU at UCL: Nafisah Atako, Liz Brodnicki, Silvia Forcat, Sue Fleck, Denise Ward, Mary Rauchenberger, Cecilia Moore, Wolfgang Stohr INSERM-ANRS: Mireille Centlivre, Veronique Rieux, Laure Bourdery, Alpha Diallo, Imane Amri, Yves Levy, Jean-Daniel Lelievre, Laurence Weiss, Jean-Michel Molina, Christel Protiere, Bruno Spire, Rodolphe Thiebault, Fabien Barbier, Laura Richert, Christine Lacabaratz, Hakim Hocini, Christianne Moog EuroVacc Foundation: Song Ding, Gepi Pantaleo CHUV: Gepi Patnaleo, Matthias Cavassini, Deolinda Alves, Sandra Bettinelli-Riccardi, Dolon Das, Fabio Candotti, Craig Fenwick, Gonzalo Tapia, Francesco Procopio IDIBAPS: Felipe Garcia, Florencia Etcheverry, Jose Gatel ISS/INMI: Stefano Vella, Giuseppe Ippolito, Alessandra Mallano, Andrea Antinori, Carmela Pinnetti, Adriana Ammassari, Raffaella Libertone UKE: Julian Schulze zur Wiesch, Veronika Schlicker, Olaf Degen, Johanna Eberhard, Sandra Hertling, Thomas Brehm, Janne Rathjens, Sindy Bartel Imperial College including IAVI: Alan Winston, Ken Legg, Michael Wood, Cherry Kingsley, Jonathan Weber, Sarah Joseph, Debbie King, Fran Lala, Jill Gilmour Chelsea and Westminster (SSAT): Marta Boffito, Tom Morrish, Carl Fletcher ULVI: Bill Paxton, Georgios Pollakis HPI: Marcus Altfield Erasmus: Rob Gruters, Charles Boucher EATG: Giulio Maria Corbelli, Giorgio Barbareschi, Maria Dutarte, Mariana Vicente, Simon Collins, Richard Jefferys Fit Biotech: Kalevi Reijonen, Matti Lahde, Andres Mannik, Jussi Seitsonen, Santtu Kiviluoto 30