M72/AS01E candidate vaccine development. Olivier Van Der Meeren, MD Senior Clinical R&D Lead GSK Vaccines

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1 M72/AS01E candidate vaccine development Olivier Van Der Meeren, MD Senior Clinical R&D Lead GSK Vaccines

2 Candidate vaccine M72/AS01E : A fusion peptide and an adjuvant EcoRI site EF residues EcoRV site DI residues 706 Ser Ala N-term MHH Mtb32a C-term (132aa) Mtb39a full length (391aa) Mtb32a N-term (195aa) C-term Mtb39A (PPE18, TbH9, Rv1196) Mtb32A (PepA, Rv0125) Membrane-associated protein Secreted protein Putative evasion factor Putative Serine protease Early expression Constitutive expression Induces proliferation and production of IFN- by T cells Expressed in BCG strains and M. tuberculosis GSK Proprietary Adjuvant System : AS01E Liposomes + MPL + QS-21* = Promotes Th1 response Skeiky et al, Inf and Immun Dillon et al, Inf and Immun Al-Attiyah et al, Clin Exp Immunol Garçon et al, Expert Rev Vaccines Gey van Pittius et al, BMC Evol Biol Nair et al, J immunol 2009 and Lewinshon et al, Am J Respir J Immunol 2004;172(12): *QS-21: Quillaja saponaria Molina, fraction 21; Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., Lexington, MA, USA. 2

3 Clinical phase 1/2 experience so far Safety and immunogenicity assessed in a broad range of populations MTB-001: Ph 1 FTIH Adults PPD- USA (1) TB-005/008: Ph I/II Adults PPD- Belgium (4) TB-009: Ph II Adults PPD+ Philippines (5) TB-012: Ph II Adolescents South Africa (8) TB-014: Ph II Adults HIV+/- ±ART India (10) TB-002: Ph I Adults PPD- Belgium (2) TB-010: PhII Adults PPD +/- South Africa (6) TB-013: Ph II Infants (±EPI) The Gambia (9) TB-019: Ph II Adults (BCG+ QFT-) Belgium (12) TB-004: Ph I/II Adults PPD+ Switzerland (3) TB-011: Ph I/II Adults HIV+/ART+ Switzerland (7) TB-017: Ph II Adults with TB disease Taiwan & Estonia (11) Safe and well tolerated in the tested populations; more reactogenic in subjects with active TB disease Induce a high-magnitude M72-specific CD4 polyfunctional response (IFNγ, IL2, TNFα, CD40L) that persists >1 year (1) Von Eschen et al, 2009; (2) Leroux-Roels et al, 2010; (3) Spertini et al, 2012; (4) Leroux-Roels et al, 2012; (5) Montaya et al, 2013; (6) Day et al, 2013; (7) Tacher et al, 2014 ; (8) Penn-Nicholson et al, 2015; (9) Idoko et al, 2014; (10) Kumarasamy et al, 2016; (11) Gillard et al, 2016; (12) TB-019/NCT

4 Proof of concept study TB-018 (NCT ) A randomised, double-blind, placebo-control efficacy study 3,500 adult male and female subjects aged years, who at baseline have: o IGRA + o HIV - o Negative clinical screening questionnaire o Negative sputum sample Randomised 50/50 to receive, 2 intramuscular injections one month apart of either: o M72(10µg)/AS01E o Placebo Follow-up of 3 years for occurrence of TB disease With this sample size, assuming a mean yearly attack rate of 0.55% in the control group, the study has 80% power to detect vaccine efficacy when 21 cases of tuberculosis disease are accrued Sub-cohort (n=450) provided blood samples for immunogenicity, and filled out diary cards for reactogenicity IGRA: Interferon Gamma Release Assay 4

5 Study endpoints Primary Outcome Measure Incident cases of definite pulmonary TB disease not associated with HIV-infection meeting the first case definition Secondary Outcome Measures Incident cases of TB disease meeting the secondary case definitions Occurrence of SAEs, unsolicited AEs, solicited local and general AEs, and potential immunemediated diseases Evaluation of CMI responses in terms of frequency of M72-specific CD4+/CD8+ T cells expressing TNFα and/or IFNγ and/or IL-2 and/or CD40L after in vitro stimulation Evaluation of humoral responses with respect to components of the study vaccine in terms of M72-specific antibody titres and seropositivity rates Occurrence of grade 2 haematological and biochemical levels 5

6 Case definitions The primary endpoint will be analysed when 21 type-1 cases are accrued Case Definition Localisation Culture Result GeneXpert MTB/Rif HIV status Other 1 st Case Def. = Primary Objective Pulmonary Either or Both Positive Negative 2 nd Case Def. Pulmonary Any Positive Negative Sputum sample taken before treatment 3 rd Case Def. Pulmonary Either or Both Positive Negative 4 th Case Def. Pulmonary Either or Both Positive Any Sputum sample taken up to 4 week after treatment start 5 th Case Def. Any Any Any Any Physician decided to treat for Tuberculosis 6

7 Participating centres A total of 11 sites across South Africa, Kenya and Zambia Kisumu (KEMRI) Lusaka (ZAMBART) Lusaka (CIDRZ) Cape Town (TASK) Khayalitsha (CIDRI) Paarl (BePart) Worcester (SATVI) Soweto (PHRU) Tembisa (AURUM) Soshanguve (Setshaba) Klerksdorp (AURUM) 7

8 Study status Primary results are expected in the next few months 8,336 subjects were screened and 3,573 were vaccinated between August 2014 and October 2015 All subjects have now completed 15 months of follow-up An independent safety review committee had regular unblinded access to safety data, and allowed the study to continue unchanged Accrual of clinical cases is ongoing, follow-up expected to end by 4Q2018 Primary analysis will be triggered earlier, as soon as 21 clinical endpoints have been observed 8

9 Ancillary biobank study C-041 Collection of Biological Samples for Future Research to Evaluate Correlates of Tuberculosis Samples collected at regular intervals from subjects in TB-018 could provide valuable information on the immune profiles of subjects who develop TB disease correlates of risk, and, if the vaccine is efficacious correlates of protection. Plasma, peripheral blood mononuclear cells (PBMCs) and blood for RNA transcriptomics are collected and stored pre-vaccination, Day 37, Month 6 and Month 12 (not PBMCs). Samples have been obtained from 99% of TB-018 participants. Immune assays to be conducted are not pre-specified. Once study is completed, these samples will be made available to the scientific community under a peer review process after a request for proposals. These will be evaluated and selected based on best scientific rationale and knowledge at the time. 9

10 LTBI prevalence in the screened population The study is ongoing and double-blind, but screening data shed light on epidemiology Prevalence by region Prevalence by baseline characteristics % N=7,404 screened subjects with IGRA results available Lau et al, TB2016 Conference, Durban, South Africa, Poster P34. 10

11 Conclusions TB-018 is a double-blind randomised controlled trial assessing the efficacy of M72/AS01E at preventing the occurrence of TB disease in HIV negative IGRA+ adults More than 3,500 subjects were vaccinated in South Africa, Kenya and Zambia An independent safety review committee had regular access to safety data and allowed the study to continue unchanged Primary analysis will be triggered in the next few months, when 21 cases are accrued Study follow-up is planned to complete by the end of 2018 An AERAS-sponsored ancillary biobank study is ongoing that could provide additional information on correlates of protection and risks 11

12 Acknowledgments We deeply thank all study participants and their families, as well as: Investigators and teams: Andreas Diacon Mark Hatherill Nduba Videlis Malahleha Mookho Innes Craig Elizabeth Hellstrom Neil Martinson Robert Wilkinson German Henostroza Helen Ayles IDMC Members: Annanele Nel Linda-Gail Bekker Neil French William Blackwelder CRO and Lab partners: Quintiles BARC KEMRI CIDRZ AERAS: Dereck Tait Maria Lempicki Maureen Lambrick Tom Evans Cadwill Pillay Gretta Blatner GSK: Paul Gillard Marie-Ange Demoitié Nadia Ouaked Anne Bollaerts Christina Caporaso Pramod Dhoke Neela Kumar Erik Jongert Hildegarde Lemaire Jacqueline Akite François Roman 12