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Inactivated whole cell NTM vaccine for the prevention of tuberculosis SRL 172 DAR-901 2016 TBVI Symposium Les Diablerets Switzerland Ford von Reyn MD Geisel School of Medicine at Dartmouth

Investigational TB vaccines that have completed human efficacy trials Vaccine Subjects Location Dates Ref SRL 172 2013 HIV-pos Tanzania Phase III von Reyn et al (whole cell NTM) adults with prior 2001-2008 AIDS 2010 BCG MVA 85A 2797 HIV-neg South Africa Phase IIb Tameris et al (subunit) infants with prior 2009-2013 Lancet 2013 BCG

Inactivated whole cell NTM booster vaccine Target Product Profile • Booster vaccine for the prevention of TB and MDR-TB – in adolescents & adults primed with childhood BCG • Safe, well-tolerated – heat-inactivated, no adjuvant – safe in HIV and latent TB • Polyantigenic and broadly immunogenic – cell wall, secreted and cytosolic Ags – theoretical advantage for both human and pathogen diversity – stimulates both cellular and humoral immunity • Effective both pre- and post-infection • Timing of administration – Healthy persons: immunize all adolescents and adults primed with BCG – HIV infected persons: immunize at time of diagnosis of HIV 3

SRL 172: an inactivated NTM vaccine • Heat-inactivated, whole-cell preparation derived from rough variant of an environmental non-tuberculous mycobacterium – originally designated M. vaccae (phenotypic methods) by J. Stanford & G. Rook (now identified as M. obuense based on 16S RNA sequencing) – originally targeted for therapy of TB • Animal studies – immunogenic and effective in preventing TB (Skinner, Hernandez-Pando, Abou-Zeid) • GMP product manufactured by SR Pharma (agar-based method) – 0.1 mL intradermal dose contained estimated 10 9 CFU – Demonstrated safe and well-tolerated in humans 4

SRL 172 – Dartmouth Phase I, II and III Trials (multiple dose) Phase Site SRL172 Control (N) (N) US HIV - 9 0 US HIV+ 23 12 1 US HIV+ 11 0 Zambia 22 22 2 Finland 19 20 3 Tanzania ~1000 ~1000 1995 2000 2005 2010 • All studies investigator-initiated (funding: NIH, EGPAF, Sigrid Juselius Foundation) • Dartmouth group conducted an entirely independent development program (safety, immunogenicity, and efficacy) – no direct support, involvement or reference to work by Stanford, Rook, SR Pharma, Silence Therapeutics, or Immodulon • All results presented in peer-reviewed publications 5

Finland Phase II: Immunogenicity in HIV-positives IFN- γ responses to SRL 172 sonicate Study population: HIV pos, BCG pos; 70% on ART CV = control (Hep B) MV = SRL 172 * P = 0.001 § p = 0.02 † p = 0.008 6

DarDar SRL-172 Trial 2001-2008 ( Dartmouth / Dar es Salaam, Tanzania ) • “Prime - Boost” Hypothesis – In persons who had childhood BCG (prime), SRL 172 inactivated whole cell NTM (boost) will reduce incident disseminated TB by 50% and definite TB by 50% • Study Population – Residents of Tanzania – HIV-positive, CD4 >200 – BCG scar • Rationale – High-risk group provides most expeditious, efficient population in which to demonstrate efficacy • Sponsor – Division of AIDS (DAIDS), NIH 7

DarDar SRL 172 Study Placebo-controlled, randomized (1:1), double-blind SRL-172 randomize 2000 (0, 2, 4, 6, 12 mo) subjects (1:1) Placebo Safe and well tolerated Doses administered: - SRl-172: 4616 (84% completed 5 doses) - Placebo: 4603 (83% completed 5 doses) -Vaccine site reactions: - Induration: average 5-6 - Desquamation: 37-58% - Local drainage: 22-49% - Sterile abscesses: 3 (0.06% of doses) HIV viral load and CD4 after each dose in 150 subject safety substudy - No difference in SRL-172 vs placebo 8

DarDar SRL-172 Study – Outcome At year 7, DSMB recommended the trial be stopped based on efficacy in preventing definite TB Median f/u = 3.3 years von Reyn et al. AIDS 2010; 24:675-85 9

DarDar SRL-172 Study – Outcome At year 7, DSMB recommended the trial be stopped based on efficacy in preventing definite TB Median f/u = 3.3 years von Reyn et al. AIDS 2010; 24:675-85 10

DarDar SRL-172 Study – Outcome At year 7, DSMB recommended the trial be stopped based on efficacy in preventing definite TB Median f/u = 3.3 years von Reyn et al. AIDS 2010; 24:675-85 11

Immunogenicity of SRL-172 in DarDar Trial IFN- γ response to SRL-172 LPA response to SRL-172 Anti-LAM Ab response • Significant IFN- γ and lymphocyte proliferative responses to SRL-172 vaccine sonicate • Significant antibody responses to LAM Lahey et al Vaccine 2010

Risk of TB among placebo recipients in DarDar trial was lowest if they had polyantigenic IFN- γ responses at baseline = to 3 mycobacterial antigens (ESAT-6, Ag 85, MTB whole cell lysate) Number of antigen preparations eliciting positive IFN- Υ responses • Results are adjusted for age, baseline CD4 count, previous TB treatment and a positive TST. Results were similar among TST-pos and TST-neg, and across HIV viral loads. 13 Lahey et al PLoS ONE 2011

SRL-172 to DAR-901 • Agar-grown SRL 172 (1994-2008) – Limited size of production lots, not scalable – Identified as M. vaccae based on phenotypic methods • Broth-grown DAR-901 (2011- ) – Product development in collaboration with Aeras • Established MCB from seed lot used for SRL 172 • GMP broth manufacturing process – high yield, scalable • SRL 172 and DAR-901 identity confirmed by sequencing – 16sRNA indicates 99.6% homology with M. obuense (first isolated in Obu, Japan;Tsakamura J Gen Micro 1971) • Animal toxicology and immunogenicity completed – Feb 2014: Phase I IND accepted by FDA – April 2014: multiple injection, dose-escalation study initiated 14

DAR-901 booster - Phase I Dose Escalation US Study among adults BCG primed at birth ID administration at 0, 2, 4 months; f/u to 10 months after last dose Dose HIV IGRA DAR-901 DAR-901 x3 Saline x2 Saline x3 Total Group Status status dose BCG x1 (N) (N) (N) A1 Neg Neg 0.1 mg 10 3 3 16 A2 Neg Neg 0.3 mg 10 3 3 16 A3 Neg Neg 1 mg 10 3 3 16 – – A4 Neg Pos 1 mg 6 6 – – B1+B2 Pos Neg+Pos 1 mg 5 5 Total 41 9 9 59 Safe, well-tolerated, dose of 1 mg selected for further clinical trials Immune assays pending: - IFN- γ response to vaccine Ag and MTB - 13-color ICS assay and modified Ki-67/gamma delta TCR ICS assay Support: Dartmouth, Aeras

Median injection site reactions at 7 days (mm) Cohort Injection 1 Injection 2 Injection 3 DAR-901 dose (N=30) (N=30) (N=28) Erythema Induration Erythema Induration Erythema Induration A1, 0.1 mg 5 6.5 6 4 7 3.5 A2, 0.3 mg 6 4 6 6.5 7.5 3 A3, 1 mg 10 4.5 8 6 8 5 Note: • Excludes subjects with 0 reactions for all 3 doses; • Excludes subjects with 0 reactions at dose 1 & dose 2, and large reactions at dose 3. • Measurement for erythema more reliable than for induration.

DAR-901 Phase II prevention of infection trial in adolescents (DAR-PIA) • Hypothesis: DAR-901 will reduce new TB infection by 50% – Defined as conversion of IGRA from negative to positive • Design: Placebo-controlled, randomized (1:1), blinded • Study population: Tanzania, 650 adolescents, age 13-15 • Eligibility: BCG, positive; baseline IGRA, negative • Intervention: intradermal DAR-901 or placebo at 0, 2, 4 mo. • Duration: Feb 2016- Feb 2018 • Follow-up: repeat IGRA at 2, 12, and 24 months – Repeat IGRA in new positives to confirm “persistent Infection” • Funded by GHIT - Japan

DAR-901 Summary • Inactivated whole cell NTM booster remains the only investigational TB vaccine shown effective in preventing TB disease in humans • Extensive prior safety data • DAR-901 – High-yield, scalable, broth-based product – Phase I multiple dose escalation – complete – Phase II Prevention of Infection trial • Funded by GHIT • Starting in Tanzania, February 2016

Acknowledgements Richard Waddell Dartmouth Lisa Adams Tim Lahey Todd Mackenzie Sue Tvaroha Mark Carey Wendy Wieland-Alter Chip Cole Ruth Connor Peter Wright Leway Kailani Brenda Haynes Tanzania Lillian Mtei Isaac Maro Kisali Pallangyo Sajida Kimambo Muhammad Bakari Johnson Lyimo Mecky Matee Betty Mchaki Boston Robert D. Arbeit C. Robert Horsburgh Finland Jenni Vuola Matti Ristola Juhani Eskola Hanna Soini New York Barry Kreiswirth Aeras Tom Evans Veerabadran Dheenadhayalan Eric Tsao Dominick Laddy Ann Ginsberg Bernard Landry 20

SRL-172: Phase II in HIV-positives with CD4>200 Study Design Assays Comment Zambia 1 5 doses (0, 2, 4 mo LPA to MV Responses greater in and 6, 12 mo) BCG pos N: 22 SRL, 22 PLA Immunogenicity data BCG pos & BCG neg limited to 5 doses Included 10 HIV-neg Finland 2 5 doses LPA to MV controls – had N: 19 SRL, 20 PLA LPA to MTB greater LPA IFN g to MV BCG pos only responses 1. Waddell et al, Clin Infect Dis 2000; 30: S309-15 2. Vuola et al, AIDS 2003; 17: 2351-2355 21

Conclusions from Phase II trials • Zambia (BCG neg and BCG pos; all HIV pos) – SRL 172 immunogenic in both BCG-positive and BCG-negative – Immunogenicity greater in BCG-positive • Finland (all BCG pos; HIV neg and HIV pos) – SRL-172 immunogenic after 3 doses – Immunogenicity greater in HIV-negatives 22