FDA Hepatitis C Hearing Oct 19, 2006

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FDA Hepatitis C Hearing Oct 19, 2006

• Jules Levin
• Executive Director/Founder, NATAP
• National AIDS Treatment Advocacy Project

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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

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NATAP

• www.NATAP.org 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

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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
• Multiple Investigational Drug Studies are
  important in HCV companies need to collaborate
  FDA needs to streamline process
• HIV Drug Development Model
• Fast Track
• Accelerated Approval for advanced disease
• Expanded Access

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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

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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

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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

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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

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Endpoints

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

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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

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Study design

• Problem if VX950 looks good who will want to
  enroll in new drug studies
• Standard of Care will be VX950Peg/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

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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??

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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