M72/AS01E candidate vaccine development

Olivier Van Der Meeren, MDSenior Clinical R&D LeadGSK Vaccines

M72/AS01E : A fusion peptide and an adjuvant

Candidate vaccine

Skeiky et al, Inf and Immun 1999. Dillon et al, Inf and Immun 1999. Al-Attiyah et al, Clin Exp Immunol 2004. Garçon et al, Expert Rev Vaccines 2007.

Gey van Pittius et al, BMC Evol Biol 2006. Nair et al, J immunol 2009 and 2011. Lewinshon et al, Am J Respir 2002. J Immunol 2004;172(12):7618-28.

*QS-21: Quillaja saponaria Molina, fraction 21; Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., Lexington, MA, USA.

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Mtb32a C-term 192-323

(132aa)N-term C-term

Mtb32a N-term 1-195

(195aa)

Mtb39a full length

(391aa)

1 725

706Ser→Ala

MHH

EcoRI siteEF residues

EcoRV siteDI residues

138 528 53143 135

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

(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/NCT1669096.

Clinical phase 1/2 experience so far

Safety and immunogenicity assessed in a broad range of populations

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2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

MTB-001: Ph 1 FTIHAdults PPD-

USA(1)

TB-002: Ph I Adults PPD-Belgium(2)

TB-004: Ph I/IIAdults PPD+

Switzerland(3)

TB-010: PhIIAdults PPD +/-South Africa (6)

TB-005/008: Ph I/IIAdults PPD-Belgium (4)

TB-012: Ph II Adolescents

South Africa (8)

TB-013: Ph IIInfants (±EPI)The Gambia (9)

TB-019: Ph II Adults (BCG+ QFT-)

Belgium(12)

TB-014: Ph II Adults HIV+/- ±ART

India (10)

TB-009: Ph IIAdults PPD+ Philippines (5)

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

3,500 adult male and female subjects

aged 18-50 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

Proof of concept study TB-018 (NCT01755598)

A randomised, double-blind, placebo-control efficacy study

IGRA: Interferon Gamma Release Assay 4

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 immune-

mediated 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

Study endpoints

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Case definitions

The primary endpoint will be analysed when 21 type-1 cases are accrued

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Case Definition Localisation Culture ResultGeneXpert

MTB/RifHIV status Other

1st Case Def.

= Primary ObjectivePulmonary Either or Both Positive Negative

Sputum sample taken

before treatment

2nd Case Def. Pulmonary Any Positive Negative

3rd Case Def. Pulmonary Either or Both Positive NegativeSputum sample taken

up to 4 week after

treatment start4th Case Def. Pulmonary Either or Both Positive Any

5th Case Def. Any Any Any AnyPhysician decided to

treat for Tuberculosis

Participating centres

A total of 11 sites across South Africa, Kenya and Zambia

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Kisumu (KEMRI)

Lusaka (ZAMBART)

Lusaka (CIDRZ)

Cape Town (TASK)

Khayalitsha (CIDRI)

Paarl (BePart)

Worcester (SATVI)

Soweto (PHRU)

Tembisa (AURUM)

Soshanguve (Setshaba)

Klerksdorp (AURUM)

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

Primary results are expected in the next few months

Study status

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Collection of Biological Samples for Future Research to Evaluate Correlates of Tuberculosis

Ancillary biobank study C-041

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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.

Prevalence by region Prevalence by baseline characteristics

LTBI prevalence in the screened population

The study is ongoing and double-blind, but screening data shed light on epidemiology

Lau et al, TB2016 Conference, Durban, South Africa, Poster P34. 10

N=7,404 screened subjects with IGRA results available

%

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

Conclusions

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Investigators and teams:

Andreas Diacon

Mark Hatherill

Nduba Videlis

Malahleha Mookho

Innes Craig

Elizabeth Hellstrom

Neil Martinson

Robert Wilkinson

German Henostroza

Helen Ayles

Acknowledgments

We deeply thank all study participants and their families, as well as:

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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

IDMC Members:

Annanele Nel

Linda-Gail Bekker

Neil French

William Blackwelder

CRO and Lab partners:

Quintiles

BARC

KEMRI

CIDRZ