FDA Hepatitis C Hearing Oct 19, 2006 Jules Levin Executive Director/Founder, NATAP National AIDS Treatment Advocacy Project

Background NATAP founded 1995 Member of ACTG & HIV RAC Committee for 5 years as NYU/Bellevue community representative 1st Coinfection peg/rbv cure. Worked closely with FDA in 1995 for accelerated protease inhibitor access and approval

NATAP website is a leading resource on HIV, HCV & HBV Conference Coverage, Journal Publications, News HIV & Hepatitis Treatment Education; –First HIV education forums 1995 –First coinfection education forums 1999 –National HIV & Hepatitis Education Forums: 25 cities; 15,000 attendees; met with local & national government officials –HCV & HBV coinfection in the Ryan White Care Act

HCV drug development is accelerating We need to speed up drug development process: -- Animal & human safety studies should be accelerated -- Phase I/II should be abbreviated Prevent drug resistance as serial monotherapy in HIV resulted in HIV drug resistance 1.Multiple Investigational Drug Studies are important in HCV & companies need to collaborate; FDA needs to streamline process 2.HIV Drug Development Model Fast Track Accelerated Approval for advanced disease Expanded Access

We Need To Improve End Stage Liver Disease, HCV/HIV coinfection, decompensated cirrhotics are in particular need Can we accelerate animal & human safety & efficacy study timeline? Can we start multiple investigational drug studies in phase IIb/III RESISTANCE, Cross-Resistance; need Resistance Assays & databases HCV/HIV coinfection is the leading cause of death & hospitalization in HIV (except for AIDS); undetected in developing world TWO DISEASES: mono-infection & co-infection

Questions Populations: efficacy/safety studies simultaneous with Phase II/III before approval in needy populations: coinfection, liver transplant, cirrhosis, decompensated cirrhosis Control arms Endpoints Follow-up research

Study Populations HCV monoinfection HIV coinfection: PK and efficacy studies conducted before approval HBV/HCV coinfection Genotype 1; genotype 2/3; genotype 4 Cirrhosis Decompensated cirrhosis Pre and post liver transplant Naives Ethnic/racial groups: African-Americans, Latinos Null responders Partial responders Relapsers IDUs, Substance Abusers, Alcohol users, Methadone

Endpoints Primary endpoint SVR: 24 weeks after end of treatment Secondary endpoint and non-responders: improved liver histology Durability should be demonstrated with oral agents Need to look at early responses: 2, 4, 8, 12 weeks

Endpoints Correlate SVR, biopsy and non-invasive tests although these may not be necessary

Study design Study reduced dose peginteferon No ribavirin No pegIFN Establish safety and efficacy in humans Worried about Resistance using old model of adding 1 new oral agent to Peg/RBV?? Need to study 2 or 3 investigational oral agents in regimen Switch drug or class if viral failure

Study design Problem: if VX950 looks good who will want to enroll in new drug studies Standard of Care will be VX950+Peg/RBV VX950 + or another PI or potent 4 to 5 log drug in combination with 1 or 2: NM283, R1626, MK0606, HCV- 796 Substitute oral agent for ribavirin Resistance profiles SUGGEST: - 7 or 14 day monotherapy depending on resistance potential followed by - Combinations of oral agents with and without Peg & Peg/RBV - Drug-drug interaction studies conducted before combination studies - Coinfection studies

Follow-Up Although SVR is predictive with Peg/RBV I have concern about oral agents only. I think followup is way to address this concern 3 yrs SVR follow-up Long-Term Cohorts: efficacy, liver disease confirmation & safety, cancer, improved histology Hepatitis C Study Consortium: independent, not NIH nor ACTG Evaluate low level HCV found in SVRs We need resistance databases When is the next meeting??

Research Questions In coinfection, affect on CD4 response to HAART When to begin HAART & HCV therapy in coinfection; prevent hepatotoxicity Affect of HCV on metabolics in coifected