Antiretroviral Drug Development: Progress and Challenges

1. Antiretroviral Drug Development: Progress and Challenges Charles Knirsch, MD, MPH VP, New York Site Head, Clinical Research and Development Pfizer, Inc

2. R&D Perspective on ART’s • Progress and Future ART Research and Development • Developing World Considerations • Access and Distribution • Regulatory • Pediatrics • Planning

3. Entry Inhibitors Nucleus RNA Protease DNA Reverse transcriptase Reverse transcriptase inhibitors Protease inhibitors Antiviral Agents for HIV

4. ART approvals: 1987 through 2005

6. ARV Development • AZT 1987 • ddI 1993 • Protease Inhibitor 12/95 • HAART era begins 1996 • Good drugs made easier 1998- present Easier Regimens, Longer Lives Deaths Cases ADULT AIDS IN THE USEnd of year figures Early Steps 1987-mid-90’s The first of anti-H.I.V. drugs was AZT. It and drugs like it were found to have some impact on the virus but were often defeated as the virus developed resistance through mutations. The ‘Cocktail’ 1996-present Dr. David Ho introduced protease inhibitors, which block a protein necessary for HIV to reproduce. Used in combination with drugs like AZT, they proved more effective but required a complex and often unsustainable drug regimen. 1998-present: Good. Drugs Made Easier FINDING THE RIGHT TREATMENT CHANGING REGIMENS HIV Drug Development 1981-1999 Sources: Centers for Disease Control and Prevention: Gay Men’s Health Crisis adapted from New York Times, June 25, 2000 Jim McManus for the NY Times

8. Survival in Africa with ART • HIV+ cohort followed since 1995 • ART available since 2003 • ART impact on mortality and causes of death assessed Munden P, et al. XVI IAC Toronto, Canada Aug 13-18, 2006 Abst THLB0208

9. Class-Specific Toxicities NRTI Mitochondrial DNA toxicity NtRTI Proximal renal tubular dysfunction NNRTI Hypersensitivity, Rash PI Metabolic disorders

10. Drug-Specific Toxicities ABC Hypersensitivity reaction (3-6%) APV Rash, GI Intolerance ATZ Hyperbilirubinemia, 1st degree AVB AZT Anemia, leukopenia, pigmentation, GI intolerance ddC Oral ulceration ddl GI intolerance (formulation), pancreatitis, neuropathy d4T neuropathy, pancreatitis, lipoatrophy, lactic acidosis EFV CNS toxicity (first 3 weeks), avoid pregnancy, rash IDV Renal stones, hyperbilirubinemia NVF Diarrhea NVP Hepatotoxicity, Stevens-Johnson syndrome RTV GI intolerance, perioral paresthesias

11. Implications of Toxicities • Poor adherence/compliance • Loss of antiretroviral control of resistance • Long-term morbidity • AZT myopathy • NRTI peripheral neuropathy • IDV renal stones and renal dysfunction • PI metabolic disorders and IHD • Mortality (low but reported) • Thymidine analog NRTIs hepatic steatosis/lactic acidosis • ddI pancreatitis • ABC hypersensitivity • NNRTI Stevens-Johnson syndrome • Long-term trade-off between toxicity and efficacy unclear.

12. Risk Management Is Core Activity Across Product Lifecycle Ph IV FIM Ph I Ph II Ph III Product Life Cycle Approval Drug Discovery/Preclinical Clinical Development Post Marketing Pharmacovigilance CapabilitiesProvided • Estimate potentialbenefit • Predict potentialcandidates • Disease Mechanism of Action Studies • Studies to better understand population, risks, etc • Promote betterapproval analysis • Achieve appropriate label • Execution of defined risk management plan • Address anynew emergingsafety issues • Epidemiological studies • Signal detection using correct scientific standards

13. DRUG RESISTANCE* Method: multicenter, 10 cities, U.S. Acute HIV, 1995-2000 *Little S. NEJM 2002;347:385

14. New Agents to Treat HIV Infection

15. Combination Therapies • Goal: improve compliance by combining drugs into single pill • Examples • 3 drugs: • tenofovir + emtricitabine (FTC) + efavirenz [ = Atripla] • AZT + 3TC + abacavir [ = Trizivir] • AZT + 3TC + tenofovir • 2 drugs: • AZT + 3TC [ = Combivir] • tenofovir + emtricitibine [ = Truvada] • abacavir + lamivudine [ = Epzicom] • Next Combinations?

16. Drug development costs in relation to therapeutic areas ‘..The most striking change was in the cost of anti-infectives, which has risen from 25% below average to 6% above average [between 1970-82 and 1997]. "This increase in costs has been driven largely, but not exclusively, by HIV treatments, which weren't being developed in the previous analysis," says DiMasi….’ Nature Reviews Drug Discovery3; 466(2004); doi:10.1038/nrd1436Therapeutic area influences drug development costs

17. Innovation Across Research and Development • Efficient lead identification • Novel biological targets • Formulation innovation • Clinical science innovation • Clinical trial design innovation • Risk management • Power of collaboration • Emerging opportunities

18. Collaborations Between Regulator, Industry & Public Sector BasicResearch Biology Chemistry Development Pre-Clinical/Clinical Post MarketingStudies Ongoing efforts focused on improving R&D productivity/safety: NIH Roadmap FDA Critical Path Pharmaceutical Innovation Steering Committee (PISC) EFPIA Innovative Medicines Initiative • Improving efficiency of late-stage clinical research • SAE data-mining validation • Best regulatory practices and sponsor/regulator communication • Predictive models for safety and efficacy • Biomarkers Consortium • Novel adaptive trial design • Accelerating proof of concept • Enriched patient population trial designs • Rolling dose studies • Exploratory IND

19. Industry can play a role in strengthening healthcare systems in LDC’s… Support of pharmacovigilence in the regions Registration and ‘effectiveness’ studies to further define value of therapies in the region (HIV clade variations) Potential for industry support of wrap around services as members of Public-Private Partnerships Research Infrastructure Partnerships Technical Collaborations Infrastructure required for diagnostic testing Optimization of healthcare support for ART’s in LDC’s Infectious Diseases Institute Industry Support of Healthcare System

21. Access: Distribution and Scale Up • Forecasting of demand • Matching availability of drug with healthcare infrastructure to manage the supply • Estimating the regulatory timelines • Identification of manufacturing facilities • Sometimes within the region • Considerations: workforce; government policies towards private investment; logistical practicalities • Distribution mechanisms within the region

22. Combivir - GSK Viramune - BI Kaletra - Abbott ARV-originator # African countries(1) where registered 29 39 41 where registra-tion pending - - 9 # not registered & lowest pricing tier 22 14 2 Registered Pending reg. Not registered Access: REGISTRATIONBroad, Efficient Registration Expected by Stakeholders • What is the best registration strategy for developing countries? • For novel mechanisms, is Africa ready to accept a emerging risk/benefit profile? • Side effects to monitor? Opportunistic infection exposure? • Are all drugs of equal value in LDC’s? How does one prioritize registration efforts to match needs of the country?

23. Summary • Current ART’s effective but further innovation of dose, safety and efficacy desirable • Drug development costs in HIV rising • Developing world concentration of epidemic presents unique challenges • Clinical Trial Conduct • Regulatory • Distribution and Access • Pharmacovigilance • Learning from PPP’s to address challenges