John R. LaMontagne Memorial John R. LaMontagne Memorial SymposiumSymposium

on Pandemic Influenza Researchon Pandemic Influenza ResearchApril 4-5, 2005April 4-5, 2005

Institute of MedicineInstitute of Medicine

Working Group Four: Working Group Four: Antivirals and Non-Specific Antivirals and Non-Specific

Approaches, Treatments and Approaches, Treatments and Immunotherapies Immunotherapies

Research RecommendationsResearch Recommendations

Research Priorities: Short-term (1-2 Research Priorities: Short-term (1-2 Years)Years)

Clinical trial development for antivirals Clinical trial development for antivirals and immunotherpaeuticsand immunotherpaeutics Develop pandemic protocols nowDevelop pandemic protocols now Obtain data on virologic course, host immune Obtain data on virologic course, host immune

responses, and response to therapy following responses, and response to therapy following human H5 infections and other potential human H5 infections and other potential pandemic infectionspandemic infections

Safety and tolerability of available drugs:Safety and tolerability of available drugs: Oseltamivir PK + tolerance in infants <1 yrOseltamivir PK + tolerance in infants <1 yr Determine PK and tolerability of IV/IM Determine PK and tolerability of IV/IM

peramivir (parenteral drug)peramivir (parenteral drug) Assess long-term (12-20 weeks) tolerability of Assess long-term (12-20 weeks) tolerability of

oseltamivir and inhaled zanamivir prophylaxisoseltamivir and inhaled zanamivir prophylaxis High risk patient populations: pregnant High risk patient populations: pregnant

women, IC Hostswomen, IC Hosts

Research Priorities: Short-term (1-2 Research Priorities: Short-term (1-2 Years)Years)

Study H5N1 resistance emergence Study H5N1 resistance emergence in animal models and strategies for in animal models and strategies for prevention prevention

Assess probability of licensure for Assess probability of licensure for orally inhaled zanamivir for disease orally inhaled zanamivir for disease prophylaxis (because of oseltamivir prophylaxis (because of oseltamivir resistance and two well controlled resistance and two well controlled published studies) published studies)

Research Priorities: Short Term Research Priorities: Short Term (Years 1-2)(Years 1-2)

Accelerate drug development and Accelerate drug development and discovery programs, including assessment discovery programs, including assessment of orphan drugs of orphan drugs

Support ‘Operational Infrastructure Support ‘Operational Infrastructure Research’:Research’: Clinical trials of drugs administered > Clinical trials of drugs administered >

48 hours48 hours Site of careSite of care Drug deployment and response timesDrug deployment and response times Research on physician use of antiviral Research on physician use of antiviral

agentsagents Test systematic approaches to influencing Test systematic approaches to influencing

inflammatory cytokine expression in inflammatory cytokine expression in diseasedisease

Research Priorities: Mid-term (2-5 Research Priorities: Mid-term (2-5 Years)Years)

Accelerated clinical trials of antivirals:Accelerated clinical trials of antivirals: Test oseltamivir monotherapy vs combination with M2 Test oseltamivir monotherapy vs combination with M2

or ribavirin or other novel therapies in high-risk or ribavirin or other novel therapies in high-risk populationpopulation

Test therapeutic efficacy of parenteral peramivir in Test therapeutic efficacy of parenteral peramivir in hospitalized influenza patientshospitalized influenza patients

Test prophylactic efficacy and tolerability of topical Test prophylactic efficacy and tolerability of topical LANILANI

Develop contemporary virus challenge pools for Develop contemporary virus challenge pools for studies of experimental human influenzastudies of experimental human influenza Test candidate immunomodulators and antiviralsTest candidate immunomodulators and antivirals

Development of immune based therapies (mab’s, Development of immune based therapies (mab’s, polyclonal antibodies, etc.) for therapy and polyclonal antibodies, etc.) for therapy and prophylaxisprophylaxis

Inhibitors of Influenza A Inhibitors of Influenza A and B Virus and B Virus

NeuraminidasesNeuraminidases Potent and specific inhibitors Potent and specific inhibitors

of influenza NAs in nM range of influenza NAs in nM range

Varied potencies for NAs of Varied potencies for NAs of different types (A and B) and different types (A and B) and subtypessubtypes

Zanamivir (RelenzaZanamivir (RelenzaTMTM) and ) and oseltamivir (Tamifluoseltamivir (TamifluTMTM) are ) are commercially availablecommercially available

Peramivir (BCX-1812, RWJ - Peramivir (BCX-1812, RWJ - 270201) and A-315675 are 270201) and A-315675 are investigational.investigational.

Investigational Anti-Investigational Anti-Influenza AgentsInfluenza Agents

Neuraminidase (NA) inhibitorsNeuraminidase (NA) inhibitors- - Peramivir (oral/IV), A-315675 (oral)Peramivir (oral/IV), A-315675 (oral)

Long-acting NA inhibitors (LANI)Long-acting NA inhibitors (LANI) R-118958 (topical), FlunetR-118958 (topical), Flunet (topical)(topical)

Conjugated sialidaseConjugated sialidase FludaseFludase™™ (topical) (topical)

HA inhibitors- cyanovirin-NHA inhibitors- cyanovirin-N Polymerase inhibitorsPolymerase inhibitors

siRNA; ribavirin (aerosol/IV/PO)siRNA; ribavirin (aerosol/IV/PO) Protease inhibitorsProtease inhibitors

AprotininAprotinin

Research Priorities: Longer-term (5-Research Priorities: Longer-term (5-10 Years)10 Years)

Support ongoing small molecule discovery Support ongoing small molecule discovery programsprograms siRNA as a systemic or topical antiviralsiRNA as a systemic or topical antiviral New antiviral targets and agents (e.g., New antiviral targets and agents (e.g.,

polymerase) polymerase) Address incentives for industrial partnersAddress incentives for industrial partners

Support innate immune effector molecule Support innate immune effector molecule development:development: SurfactantsSurfactants Mannose-binding lectinsMannose-binding lectins Defensins Defensins

Support innate immune activation Support innate immune activation moleculesmolecules TLR-3, 4, 7, 8. 9 agonistsTLR-3, 4, 7, 8. 9 agonists NOD receptorsNOD receptors

Promote the development of modulators of Promote the development of modulators of inflammatory cascadesinflammatory cascades

What Should Be Done What Should Be Done NOW?NOW?

Clinical trial infrastructure for therapeuticsClinical trial infrastructure for therapeutics Conduct studies in SE Asia nowConduct studies in SE Asia now Protocol development, data captureProtocol development, data capture

Research on transmission and treatment Research on transmission and treatment factors to develop public health policy factors to develop public health policy

Operational research to define the optimal Operational research to define the optimal infrastructure for distribution of drug, etc.infrastructure for distribution of drug, etc.

Stockpile oseltamivir or other efficacious Stockpile oseltamivir or other efficacious agentsagents

Develop antiviral agents as quickly as Develop antiviral agents as quickly as possiblepossible