BARDA INFLUENZA PROGRAM OVERVIEW

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1 BARDA INFLUENZA PROGRAM OVERVIEW Drs. Armen Donabedian and Michael Wathen Vaccines and Therapeutics Resilient People. Healthy Communities. A Nation Prepared. 0

2 BARDA Overview 1

3 Perpetual challenge of responding to influenza 2

4 Landscape of Next Generation Influenza Vaccine Candidates 3

5 Landscape of Next Generation Influenza Vaccine Candidates Need more convincing immunological data 4

6 Immune-Landscape of Influenza Vaccines Immunological compartments Humoral Cell-mediated Mucosal Platform Responses HAI/MN Stem CD4 CD8 to HA TIV or QIV MF59, AS03 Candidate examples potential? CD8 to conserved Ag LAIV,DM2, DNS1???? IgA,Tissue resident memory cells Vectors MVA-NP,M1,????? Ad HA, IN??? Ad HA, Oral? Plant VLP??? Peptides Nucleic Acid Stem-based potential M-100 conserved Ag?? potential RNA + delivery?? chimeric, headless, polypeptides Theoretical potential Demonstrated immune response 5? Data lacking Not expected

7 Immunological compartments Immune-Landscape of Influenza Vaccines Humoral Cell-mediated Mucosal Platform Responses HAI/MN Stem CD4 CD8 to HA TIV or QIV MF59, AS03 Candidate examples potential? CD8 to conserved Ag LAIV,DM2, DNS1???? IgA,Tissue resident memory cells Need MVA-NP,M1,????? Vectors convincing immunological Ad HA, IN??? Peptides Nucleic Acid Stem-based Ad HA, Oral? Plant VLP??? potential M-100 conserved Ag?? potential RNA + delivery?? chimeric, headless, polypeptides data Theoretical potential Demonstrated immune response 6? Data lacking Not expected

8 More Effective Influenza Vaccine Development Pipeline at BARDA 7

9 The program is investing in next-generation portfolio of improved influenza vaccines Next-Generation Influenza Vaccines Leverage licensed influenza platforms Design antigenically advanced vaccines Heterologous prime-boost (HtPB) vaccination Innovative antigen delivery platforms Orally administered temperature-stable vaccine HA-stem recombinant or vectored mrna vaccines Promote industry partnerships & interagency efforts Phase 1b (human challenge) studies Leverage HHS technology pipeline 8

10 Current Development Efforts 9

11 Influenza: An Integrated Response 10

12 Influenza HA and Stalk mabs 11

13 Broad Spectrum Neutralizing Monoclonal Antibodies Target the HA stalk Highly conserved Novel target Broad spectrum Group 1 and 2 of Influenza A Unique properties Extended treatment window Long half life resulting in single dose administration Large binding surface reducing likelihood for resistance ASPR: Resilient People. Healthy Communities. A Nation Prepared. 12

14 Antibody Therapies in Development 13

15 Clinical Trial Challenges for Hospitalized Influenza Patients Trial enrollment Heterogeneous population ENDPOINTS Trial design 14 14

16 How Can We Improve Enrollment? season - 1 ED enrolled 58 subjects in BARDA sponsored study evaluating enrollment 24 hospitalized subjects 34 outpatients Recommendations Identify subjects in the ED for early enrollment and treatment Include ED clinicians on clinical site contracts Find sites that have rapid influenza PCR testing as SOC in the ED with 24/7 coverage 15 15

17 Current Endpoints FDA Guidance for Industry Influenza: Developing Drugs for Treatment and/or Prophylaxis (2011) Primary Endpoint should include: Clinical signs and symptoms Duration of hospitalization Time to normalization of vital signs Fever Respiratory status Heart rate Systolic blood pressure Supplemental oxygenation requirements Proposed endpoint [should] directly measure how a patient feels, functions, or survives 16 16

18 Clinical Endpoints Working Group Government and academic working group WG has looked at therapeutic sponsor, research and hospital databases Ordinal Scale Discrete categories for classifying hospitalized subjects over time could include: Death ICU on mechanical ventilation ICU Hospital floor receiving supplemental oxygen Hospital floor without supplemental oxygen Discharge but has not returned to normal activity Discharge returned to normal activity 17 17

19 Percentage of Ordinal Scale Relative Frequency Distribution of Ordinal Scale 48 Hours (n=58) > 48 Hours (n=157) 100% 100% 90% 90% 80% 80% 70% 70% 60% 60% 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% Day from Admission 0% Day from Admission 18 18

20 BARDA Influenza Therapeutics Program Program Goal: Reduce morbidity and mortality in all patient populations during an influenza pandemic Critical unmet medical needs: Severely ill, hospitalized influenza patients More effective treatment options, suitable for all populations Critical Properties for Target Product Profile Novel mechanism of action Superior efficacy compared to neuraminidase inhibitors (NAIs) Inhibits all Influenza A strains tested Expanded treatment window beyond 48 hours Suitable for combination therapy with existing NAI or other therapies IV formulation for seriously ill ASPR: Resilient People. Healthy Communities. A Nation Prepared. 19