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Ford von Reyn MD Geisel School of Medicine at Dartmouth

DAR-901 A polyantigenic , inactivated, whole-cell mycobacterial vaccine for the prevention of tuberculosis. Ford von Reyn MD Geisel School of Medicine at Dartmouth. Clinical development plan.

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Ford von Reyn MD Geisel School of Medicine at Dartmouth

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  1. DAR-901A polyantigenic, inactivated, whole-cell mycobacterial vaccine for the prevention of tuberculosis Ford von Reyn MD Geisel School of Medicine at Dartmouth

  2. Clinical development plan Goal: Develop a booster vaccine to prevent tuberculosis in adolescents and adults who have previously been immunized with BCG Strategy: • Chose a polyantigenic reagent to mimic infections and vaccines known to prevent TB in humans • Conduct initial efficacy trials in HIV-infected adults in setting of endemic disease • Represent population with the highest risk of TB • Permits smaller sample size for efficacy trial • A vaccine that is effective in HIV-infected persons, is likely to be more effective in healthy subjects

  3. Polyantigenic exposures induce protection against TB in humans • Mycobacterial infections (natural) • M. tuberculosis (Heimbeck, Norway; Stead, US) • Non-tuberculous mycobacteria (NTM; Edwards, US) • Mycobacterial vaccines • Single-dose, live organism • M. bovis BCG • M. microti (vole bacillus) • Multiple-dose, inactivated whole cell organisms • M. bovis/MAC/MTB combination (VIP, VDS, Italy) • M. bovis (Jamaica) • Common features: • Whole organism, polyantigenic • Cross protection within genus

  4. SRL 172: An Inactivated NTM vaccine • Heat-inactivated, whole-cell preparation derived from rough variant of an environmental non-tuberculous mycobacterium (NTM) • designated M. vaccae (MV) by J. Stanford & G. Rook • originally targeted for therapyof TB • Animal studies • immunogenic and effective in preventingTB (Skinner, Hernandez-Pando, Abou-Zeid) • GMP product manufactured by SR Pharma • Demonstrated safe and well-tolerated in humans • 0.1 mL intradermal dose contained estimated 109 CFU

  5. DAR-901: Overview • Heat-killed environmental NTM vaccine for prevention ofTB • SRL 172 (1994-2008) • Agar-grown vaccine, limited size of production lots • Studies conducted: Phase I, II, III • Sites used: US, Zambia, Finland, Tanzania (NIH) • Broth-grown DAR-901 (2011- ) • Product development in collaboration with Aeras • Established MCB from seed lot used for SRL 172 • Developed high yield, scalable GMP broth mfg process • Animal immunogenicity studies: nearing completion • Phase I/IIa human studies: Q4 2013, US and Tanzania

  6. Dartmouth Phase I, II and III Trials with SRL 172 • All studies investigator-initiated (funding: NIH, EGPAF, Sigrid Juselius Foundation) • All safety, immunogenicity and efficacy studies conducted by the Dartmouth group as a new product – no support, involvement or reference to work by Stanford, Rook, SR Pharma, Silence Therapeutics, or Immodulon • All results presented in peer-reviewed publications

  7. Finland Phase II: Immunogenicity in HIV-positive IFN-γ responses toSRL 172 sonicate Study population: HIV pos, BCG pos; 70% on ART CV = control (hep B)MV = SRL 172 Vuola et al, AIDS, 2003 * P = 0.001 §p = 0.02 † p = 0.008

  8. Finland Phase II: Immunogenicity in 10 HIV-negative Lymphocyte proliferation responses toSRL 172 sonicate Study population: Healthy BCG positive adults Response to SRL-172 sonicate: Baseline vs dose 3: p = 0.04 Baseline vs dose 5: p = 0.01 Baseline vs 1 year: p = 0.001 Median LPA response to SRL-172 sonicate after 5 doses: HIV pos: 12,560 cpm HIV neg: 22,547 cpm (p = 0.170)

  9. DarDar Study – Design • Study design: • randomized (1:1), double-blind, placebo-controlled • eligibility: HIV with CD4≥200, BCG scar • follow-up Q3 mos • immune assays: baseline and post-dose 5 • Intervention: • 5 intradermal doses of SRL 172 (or placebo) SRL-172 (0, 2, 4, 6, 12 mo) Placebo randomize (1:1) 2000 subjects

  10. DarDar 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. DarDar Study – Vaccine-induced responses Lahey T et al. Vaccine 2010; 28:2652-8

  12. DAR-901 Development Program • Scalable production method • SRL-172 was agar-grown – a procedure that scales poorly • Aeras has developed a scalable, broth-grown production method • That product is now designated DAR-901. • Master Cell Bank prepared • 268 cryovials (5 mL) • Drug product release assays validated • Potency: IL-12 induction in human macrophage cell line • Quantitation: qPCR of 16S RNA • Bulk product manufactured • Yield from 20L Fermenter: 4.5 L at 49.2 g/L • Achieved greater dispersion and higher consistency than SRL 172 • Estimated to represent 2,000 doses of final product

  13. DAR-901: IFNγ dose-response in B57BL/6 mice Protocol: intradermal DAR-901 at week 0, 2, 4; dose range 0.01 to 2.5 mg Assay: IFN-γ spot forming units from splenocytes stimulated in vitro Results shown for optimal dose = 0.3 mg Among control (saline) animals, median SPU/10^6 cells was 35 for DAR-901 (sonicate) and <10 for the other antigens

  14. DAR-901 Summary A multiple dose series of agar-grown SRL 172 was safe, immunogenic and 39% effective in preventing definite TB in HIV-positive subjects primed with BCG. • It was also immunogenic in HIV-negative subjects primed with BCG Protection from SRL 172 is consistent with classically demonstrated human protection against TB (natural infection and vaccines) induced by polyantigenic exposure (including secreted, cell wall and cytosolic Ags) • Whole cell vaccine like DAR-901 is likely to stimulate both innate and acquired immunity Homologous broth-grown DAR-901 (Aeras) has greater bacterial dispersion and consistency than agar-grown SRL 172 and has the potential for higher efficacy in both HIV-positive and HIV-negative subjects Phase I and IIa human safety and immunogenicity studies to begin Q4 2013 in US and Tanzania

  15. Acknowledgements

  16. END Thank you

  17. DarDar Study: Safety • Koch reactions: • none, including 312 MV subjects with TST>5 mm • Vaccine site: • Induration: average 5-6 mm • Desquamation: 37-58% • Local drainage: 22-49% • Sterile abscesses: 3 (0.3% of subjects, 0.06% of doses) • HIV safety substudy in 150 subjects • Viral load and CD4 after each dose • No pattern of adverse changes

  18. DAR-901 – Nonclinical Animal Studies - I • Mouse Dose-Ranging & Immunogenicity Study • Species: both C57BL/6 and BALB/c mice • Intradermal immunization with heat-killed DAR-901 • Three dose schedule: 0, 2, 4 weeks • Doses (mg): 0, 0.01, 0.03, 0.1, 0.3, 1, 2.5 • Tolerability • observed physical / behavioral changes • Immunogenicity • collect samples at weeks 2, 4 and 6 • stimulate cells in vitro using several antigen preparations • assay cytokine responses: Elispot of cells; multiplex of culture supernatants

  19. DAR-901 – Nonclinical Animal Studies - II • GLP Repeat-dose Toxicology Study • Mouse strain and dose selected based on above • Note: mouse is only species in which immunogenicity has been demonstrated • Dosing schedule • Total 6 immunizations (one more than maximum proposed human exposure) • Expected timeline • ~6 months from first dose to delivery of final report • Proposed subcontractor • Spring Valley Laboratories, Sykesville, MD

  20. DAR-901 – Proposed Phase I/IIa Trials • DarDar trial used 5 dose regimen • 4 doses over 6 months plus booster at 1 year • highly desirable to shorten and simplify as supported by prior work • Goals of Phase I/IIa Trials • confirm safety, tolerability, and immunogenicity of regimen of 2 vs 3 doses over 2-4 months plus booster at 1 year • expand immunologic assessments • include both HIV-neg and HIV-pos subjects

  21. DAR-901: Phase I in US

  22. DAR-901: Phase IIa in Tanzania

  23. Immune assays in I/IIb • Assays previously used: • IFNg to DAR-901 sonicate, MTB WCL, ESAT • Additional assays under discussion • Mycobacterial growth inhibition (performed at Aeras) • Transcriptome (using stored PBMCs) • Final panel to be determined thru discussions with • Aeras CSO • NIH Vaccine Trials Network • DAR-901 Scientific Advisory Committee

  24. DAR-901 Scientific Advisory Committee

  25. DAR-901 Development Timeline - I

  26. Baseline Subject Characteristics

  27. Prevention of TB by 5 doses of inactivated M. bovis TB disease rates vaccine: 11% (23/210) control: 19% (39/206) efficacy = 42% despite inability to segregate until immunization complete Opie, Freund et al. 1939, psychiatric hospital in Jamaica Multiple dose inactive whole cell vaccines effective against other intracellular bacterial pathogens: plague, typhoid -Opie, 1939

  28. Natural Protection Against TB Risk of TB among student nurses, Oslo, 1924-26 PPD TST Status at Enrollment Number Cases of TB (%) Negative 185 62 (34) Positive 152 3 (2) Heimbeck, Br J Tuberc 1938;32:154-66.

  29. Target product profile • Indication and application • Booster vaccine for the prevention of tuberculosis in adolescents and adults primed with childhood BCG • Safe, well-tolerated (heat-inactivated, no adjuvant) • Effective both pre- and post-infection • HIV-negative: booster for all adolescents and adults • HIV-positive: immunize at first diagnosis of HIV

  30. Finland Phase II: Immunogenicity in HIV-positive Lymphocyte proliferation responses toSRL 172 sonicate Study population: HIV pos, BCG pos; 70% on ART CV = control (hep B)MV = SRL 172 * P <0.001 § P = 0.003 † P = 0.02

  31. DarDar Study 2001-2008 (Dartmouth / Dar es Salaam, Tanzania) A prime-boost strategy to prevent TB in persons with HIV infection • Hypothesis: • SRL 172 (boost) of childhood BCG (prime) will reduce disseminated TB by 50% and definite TB by 50% • Enrollment criteria: • HIV-positive, CD4 >200 • BCG scar • no active TB (smear, culture, CXR – all negative) • Sponsor: Division of AIDS (DAIDS), NIH • Cost: $8 million

  32. DarDar Study – Immunologic Assessment • Tuberculin skin testing • INH x 6 mos for subjects with TST >5 mm • LPA and IFN-γ assays in response to • SRL-172 sonicate • ESAT-6 • Ag85 • MTB WCL (whole cell lysate) • Ab to lipoarabinomannan (LAM) • Assays done at baseline and after dose 5 of vaccine • CD4 – annually

  33. DarDar DSMB

  34. DarDar Study: Compliance and Follow-up • Doses administered • MV: 4616 (84% completed 5 doses) • Placebo: 4603 (83% completed 5 doses) • All subjects seen every 3 months or if symptomatic • routine HIV care • active evaluation for new cases of TB (sputum and blood cultures for TB, CXR) • Loss to follow-up: 3% per year • Median follow-up: 3.3 years

  35. DarDar Study Endpoint Definitions and Outcomes

  36. Clinical Endpoints in TB Vaccine Trials Requirements for valid clinical endpoints • Pre-specified endpoint definitions • Blinded review of all potential endpoints by expert panel

  37. DarDar Study – Endpoint Definitions • Disseminated Tuberculosis • Positive blood culture • Definite Tuberculosis • Positive sterile site culture (other than blood) • or1 sputum culture with >10 cfu • or2 sputum cultures each with 1-9 cfu • or 2 positive sputum smears • Probable Tuberculosis • {1 positive sputum smear or 1 sputum culture with 1-9 cfu}plus{a positive CSR orpositive symptoms} • ORpositive CXR plussymptoms plusclinicalresponse to treatment von Reyn et al. AIDS 2010; 24:675-85

  38. DarDar Study Endpoints • Primary Endpoint • Time to Disseminated TB • Secondary Endpoints • Time to first episode of Definite TB • Time to first episode of Probable TB • Time to first episode of Definite / Probable TB von Reyn et al. AIDS 2010; 24:675-85

  39. DarDar Study – Disseminated TB (ITT)

  40. DarDar Study – Definite TB (ITT)

  41. Molecular epidemiology (IS6110 typing) • Clustering • represents patients with recently acquired TB infection • 25/74 (74%) vaccine recipients • 31/47 (66%) placebo recipients • Polyclonal disease • represents patients with two different strains isolated • 15 subjects had isolates available from 2 different cultures • Overall, 7 (40%) had polyclonal disease • 3/7 (43%) subjects with 2 sputum isolates • 3/8 (38%) subjects with 1 sputum and 1 blood isolate • Evidence for concurrent reactivation and recent infection • 4/6 (67%) polyclonal cases had 1 clustered and 1 unique isolate Adams, Kreiswirth, Arbeit et al. J Clin Micro 2012; 50:2645-50

  42. DarDar Study Immunology Vaccine responses and predictors of TB risk

  43. DarDar Study: Baseline Immunology Baseline positive responses among 888 DarDar subjects IFN-γ, LPA (lymphocyte proliferation) to SRL-172 sonicate; LAM: antibody to lipoarabinomannin; MAS: M. avium sensitin Matee M et al. J Infect Dis 2007;195:118-123

  44. Immunologic Predictors of TB risk - I Among Placebo subjects, those who developed TB had, at baseline, weaker IFN-γ and lymphocyte proliferation responses. Lahey et al. J Infect Dis 2010; 205: 1265-1272

  45. Immunologic Predictors of TB risk - II Conversely, the risk of TB was decreased among the Placebo subjects who at baseline had positive IFN-γ responses to multiple antigen preparations (“polyantigenic” responses). Antigen preparations: Ag85, ESAT-6 and WCL (whole cell lysate) Lahey et al. PLoS ONE 2011; 6 (7): e22074

  46. SRL-172: Phase II in HIV-positives with CD4>200 1. Waddell et al, Clin Infect Dis 2000; 30: S309-15 2. Vuola et al, AIDS 2003; 17: 2351-2355

  47. Immunologic Predictors of TB risk - III • 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 (for those with data). Number of antigen preparations eliciting positive IFN-Υ responses Lahey et al PLoS ONE 2011; 6(7): e22074

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