This project has received funding from the European Union’s horizon 2020 research and innovation programme under grant agreement No 681032.

EHVA Project Overview

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EHVA Consortium

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39 partners 11 countries3 continents

Infinite enthusiasm spanning basic, clinical, biostatistical and

community disciplines

EHVA Consortium

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EHVA Jan2016-Dec2020

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28 million Euros22 million Euros from

the European Commission(Grant nr 681032)

6 million Euros from the Swiss government for

the Swiss partners (Grant nr 15.0337).

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

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EHVA Principals and process

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EHVA Principals and process

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EHVA-PT-1

Experimental medicine

Prime RNA dosing

BoostNYVAC + CN54

EHVA-PT-2

Adaptive trials

PrimeRNA, DNA GTU-DNA,

NYVAC

BoostNYVAC + CN54

EHVA –PT-3

Phase II

PrimeSelected in EHVA-PT-2

BoostNYVAC + CN54

NYVAC + new env

EHVA T01 Trial

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A sophisticated set of immune and virologic

profiling assays

EHVA-T-1/2

parallel clinical trials with different vaccines

strategies in patients whostarted ART duringprimary infection or

during chronic infection

Find correlates of vaccine efficacy, and establish innovative, specific and sensitive

signatures for HIV therapeutic vaccine

evaluation.

EHVA-T-3

A clinical trial evaluating therapeutic

vaccination in combination with

other interventions

Obtain indications on

combinations to inform

design/strategy for HIV

remission or cure

RESULTS FROM TRIAL 1/2 USED TO DESIGN TRIAL #3

EHVA T01 Trial

A Phase I/II randomised therapeutic HIV vaccine trial in individuals who

started antiretrovirals during primary or chronic infection

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EHVA T01 Trial

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EHVA T01 Trial

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A= ART and a4b7

B=ART and IgG

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

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Multi-arm, multi-stage design

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Multi-arm

Test many relevant approaches

Use fewer resources

Cost per comparison is much less

Less bureaucracy

Multi-arm, Multi-stage

T2 T3T1C T4

Phase II

Phase III

Multi-arm, Multi-stage

T2 T3T1C T4

Phase II

Phase III

EVHA T01 Hypothesis

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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

Primary outcome measures

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• 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.

Secondary outcome measures

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• 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

Selected inclusion criteria

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HIV-1-infected, aged 18 – 65 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

Selected exclusion criteria

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• 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 virologicalfailure 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

Trial schema

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Trial schema – add PIS diagram

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EHVA T01 Trial Size

• 88-192 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

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EHVA T01 Trial

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EHVA T01 Trial Size

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Interim Analysis Final Analysis

Primary Outcome Time from treatment interruption to the earliest of

reaching HIV RNA ≥ 10,000 copies/ml or resuming

antiretroviral therapy for any reason

Proportion of placebo participants

expected to have reached the

primary outcome by 6 weeks post

cART nterruption

72% 72%

One-sided Alpha

(Type I Error Probability)0.500† 0.025†

Power

(Type II Error Probability)95% 92%

Critical value

(Hazard Ratio compared to Control)1.00 1.00

Target HR under alternative

hypothesis (H1)0.46‡ 0.46‡

†overall p=0.029‡confers an absolute reduction of 50%

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

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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 centresonly

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EHVA T01 Enrolment per Center

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Country Proposed target

France 18

UK 20

Italy 8

Germany 8

Spain 16

Switzerland 18

Total 88

EHVA T01 Review Status

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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 substudiesleukapheresis/GI biopsy (rectal or sigmoid colon)/LN biopsy

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

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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

o1 individual/week for the first 4 weeks

o2 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 necessary29

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

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