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

Research Priorities: Short-term (1-2 Years) Clinical trial development for antivirals and immunotherpaeutics Clinical trial development for antivirals and immunotherpaeutics Develop pandemic protocols now 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 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: Safety and tolerability of available drugs: Oseltamivir PK + tolerance in infants <1 yr Oseltamivir PK + tolerance in infants <1 yr Determine PK and tolerability of IV/IM peramivir (parenteral drug) Determine PK and tolerability of IV/IM peramivir (parenteral drug) Assess long-term (12-20 weeks) tolerability of oseltamivir and inhaled zanamivir prophylaxis Assess long-term (12-20 weeks) tolerability of oseltamivir and inhaled zanamivir prophylaxis High risk patient populations: pregnant women, IC Hosts High risk patient populations: pregnant women, IC Hosts

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

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

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

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 (Relenza TM ) and oseltamivir (Tamiflu TM ) are commercially available Peramivir (BCX-1812, RWJ ) and A are investigational.

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

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

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