John R. LaMontagne Memorial Symposium on Pandemic Influenza Research April 4-5, 2005 Institute of Medicine

1. John R. LaMontagne Memorial Symposiumon Pandemic Influenza ResearchApril 4-5, 2005Institute of Medicine Working Group Four: Antivirals and Non-Specific Approaches, Treatments and Immunotherapies Research Recommendations

2. Research Priorities: Short-term (1-2 Years) • Clinical trial development for antivirals and immunotherpaeutics • Develop pandemic protocols now • Obtain data on virologic course, host immune responses, and response to therapy following human H5 infections and other potential pandemic infections • Safety and tolerability of available drugs: • Oseltamivir PK + tolerance in infants <1 yr • Determine PK and tolerability of IV/IM peramivir (parenteral drug) • Assess long-term (12-20 weeks) tolerability of oseltamivir and inhaled zanamivir prophylaxis • High risk patient populations: pregnant women, IC Hosts

3. Research Priorities: Short-term (1-2 Years) • Study H5N1 resistance emergence in animal models and strategies for prevention • Assess probability of licensure for orally inhaled zanamivir for disease prophylaxis (because of oseltamivir resistance and two well controlled published studies)

4. Research Priorities: Short Term (Years 1-2) • Accelerate drug development and discovery programs, including assessment of orphan drugs • Support ‘Operational Infrastructure Research’: • Clinical trials of drugs administered > 48 hours • Site of care • Drug deployment and response times • Research on physician use of antiviral agents • Test systematic approaches to influencing inflammatory cytokine expression in disease

5. Research Priorities: Mid-term (2-5 Years) • Accelerated clinical trials of antivirals: • Test oseltamivir monotherapy vs combination with M2 or ribavirin or other novel therapies in high-risk population • Test therapeutic efficacy of parenteral peramivir in hospitalized influenza patients • Test prophylactic efficacy and tolerability of topical LANI • Develop contemporary virus challenge pools for studies of experimental human influenza • Test candidate immunomodulators and antivirals • Development of immune based therapies (mab’s, polyclonal antibodies, etc.) for therapy and prophylaxis

6. Inhibitors of Influenza A and B Virus Neuraminidases • Potent and specific inhibitors of influenza NAs in nM range • Varied potencies for NAs of different types (A and B) and subtypes • Zanamivir (RelenzaTM) and oseltamivir (TamifluTM) are commercially available • Peramivir (BCX-1812, RWJ - 270201) and A-315675 are investigational.

7. Investigational Anti-Influenza Agents • Neuraminidase (NA) inhibitors - Peramivir (oral/IV), A-315675 (oral) • Long-acting NA inhibitors (LANI) • R-118958 (topical), Flunet (topical) • Conjugated sialidase • Fludase™ (topical) • HA inhibitors- cyanovirin-N • Polymerase inhibitors • siRNA; ribavirin (aerosol/IV/PO) • Protease inhibitors • Aprotinin

8. Research Priorities: Longer-term (5-10 Years) • Support ongoing small molecule discovery programs • siRNA as a systemic or topical antiviral • New antiviral targets and agents (e.g., polymerase) • Address incentives for industrial partners • Support innate immune effector molecule development: • Surfactants • Mannose-binding lectins • Defensins • Support innate immune activation molecules • TLR-3, 4, 7, 8. 9 agonists • NOD receptors • Promote the development of modulators of inflammatory cascades

9. What Should Be Done NOW? • Clinical trial infrastructure for therapeutics • Conduct studies in SE Asia now • Protocol development, data capture • Research on transmission and treatment factors to develop public health policy • Operational research to define the optimal infrastructure for distribution of drug, etc. • Stockpile oseltamivir or other efficacious agents • Develop antiviral agents as quickly as possible