Summary of Industry Responses and Regulatory Perspective

1
Summary of Industry Responses and Regulatory
Perspective

• William Tauber, M.D.
• Division of Antiviral Products
• Food and Drug Administration
• October 19, 2006

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Presentation Outline

• Introduction
• Consensus Definitions
• Summary of responses re
• Study Populations-Inclusions and Definitions
• Selection of Controls
• Study Endpoints Compensated liver disease
• Study Endpoints Decompensated liver disease
• Study Design Options
• Long Term Follow-up
• Concluding Remarks

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Introduction

• Chronic Hepatitis C is a global problem
• est. 170M infected worldwide and 3.2M USA
• Incidence infection USA decreasing but HCV
  related disease cirrhosis, ESLD, HCC increasing
• long latency,
• lack of spontaneous resolution,
• aging of infected population liver related
  complications will increase in the next
  10-20years
• CHC already the most common reason for transplant

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Introduction (cont.)

• Current SOC treatment is interferon based
• Duration 48 weeks for G1/4 , 24 weeks G2/3
• SVR endpoint measured 24 weeks after end of
  therapy
• Expensive with safety issues
• Effective for 30 to 80 based on genotype and
  patient characteristics
• New treatment strategies and/or novel agents
  needed

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Respondents (IND Holders)

• Achillion Pharmaceuticals
• Bristol-Myers Squibb
• Coley Pharmaceutical Grp
• Hoffmann-La Roche
• Human Genome Sciences
• Idenix Pharmaceuticals
• National Institutes Health
• NIDDK, NIAID

• Peregrine Pharmaceuticals
• Schering-Plough
• SciClone Pharmaceuticals
• Vertex Pharmaceuticals
• Wyeth Pharmaceuticals
• XTL Biopharmaceuticals

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Consensus Definitions
All CHC pts including compensated cirrhosis
Evidence of ongoing liver damage and hepatitis C
viral replication during at least 6 months of
observation
Chronic Hepatitis C (CHC)
Compensated Liver Disease
Decompensated Liver Disease
Compensated cirrhosis
Absence of clinical consequences of liver disease
(ascites, variceal bleeding, encephalopathy) and
preserved hepatic synthetic function (albumin
3.5g/dL, total bilirubin 1.5mg/dL and
prothrombin time INR 1.5)
Decompensated cirrhosis
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Study Population Initial Clinical Development
Program

• Stage of disease- Compensated/Decompensated
• Treatment naïve or experienced
• Genotype 1or 4 vs 2 or 3
• Co-infection with either HIV or HBV
• Pre or post liver transplantation
• Pediatrics
• Racial or Ethnic Groups

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Candidates Initial Clinical Development Trials
Preferred Populations
Greatest Need Treatment-Experienced,
non-responder (fasted growing group, more
advanced histology, more urgent need for
effective treatment)
Ideal Treatment-Naïve with early stage histologic
changes, high baseline viral load and genotype 1
(largest group, homogeneous, current treatment
response 40-50)
Compensated liver disease to include cirrhosis,
no cofactors, adults, genotypes 1, 2, 3 and 4
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Candidates-Initial Clinical Development Trials

• Most favored inclusion of African Americans and
  Hispanics
• Registrational trials
• Also suggested investigator trials or phase 4
  post-marketing due to historically difficult
  enrollment in these groups

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Inclusion Candidates Post Approval
Pediatric post-approval studies and access
programs during phase 2-3 development of
promising agents
CHC pts co-infected with HIV or HBV

Historically difficult to enroll
Decompensated cirrhosis or in the immediate post
liver transplant period
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Definition Non-Responder
General agreement with the following components
as inclusion criteria in clinical development
studies of treatment experienced non- responder
patients
Previously treated with 1 or more IFN-containing
regimens that include PEG-IFN and RBV
Failure to achieve a 2 log10 reduction in HCV
RNA at Week 12, or HCV detectability at Week 24
or beyond while on therapy (confirmed by a repeat
test)
AND
Compliance documented over the first 12 weeks of
previous therapy to confirm receipt of at least
80 of the prescribed RBV and PEG-IFN dose
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Non-Responder Populations

• Non-responders to prior interferon based
  therapy can refer to a heterogeneous population.
  
• patients with no significant response (true
  nonresponder)
• patients with partial response ( 2 log10
  reduction HCV RNA at Week 12 but detectable at
  Week 24 and beyond)
• relapsers- undetectable during treatment but
  unable to maintain undetectable during follow-up
• relapsers/rebounders- temporarily undetectable
  during treatment

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Selection of Controls

• Treatment naïve compensated CHC patients
• consensus most appropriate comparator control is
  parenteral pegylated interferon alfa and oral
  ribavirin for 24 or 48 weeks based on genotype
• placebo or deferred administration could be
  acceptable if cross over to active treatment
  assured
• an acceptable delay duration varied between 4 to
  12 wks
• no parenteral placebo was endorsed

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Selection of Controls

• For treatment-experienced compensated CHC pts
• longer durations of placebo controls or Rx delay
  (up to 24 months) were acceptable.
• For both populations novel drug monotherapy
  acceptable for short periods, typically 2 weeks
  but longer periods suggested by some IND holders
• Few commented on patients with decompensated
  liver disease but one ventured placebo
  controlled or treatment delay might be possible

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Summary of ResponsesEndpoints Compensated Liver
Disease

• Primary Endpoints Viral Clearance Goal
• Primary Endpoints Viral Suppression Goal
• Secondary Endpoints

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Sustained Virologic Response (SVR)

• Defined as
• HCV RNA undetectable (lt 100 copies/mL) by RT-PCR
  after 24 weeks of untreated follow-up
• Preferred endpoint for all patient populations,
  surrogate for viral clearance
• Definition problematic with differing treatment
  durations leading to measurements at multiple
  timepoints leading to statistical chaos
• Timing of SVR measurement more controversial
• Some noted that 98 of relapses occur within 12
  weeks after treatment discontinued and offered
  SVR 12 as alternative
• SVR only currently validated for IFN treatment,
  some suggested SVR demonstration for novel drugs
  needed

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Endpoints Compensated Liver Disease

• Primary Endpoints Viral Clearance Goal
• Primary Endpoints Viral Suppression Goal
• Secondary Endpoints

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Primary Endpoints
Viral Clearance Goal

• Treatment-Naïve
• Consensus for Sustained Virologic Response (SVR)
• Potential co-primary Rapid Virologic Response
  (RVR4) defined as undetectable HCV RNA (lt100
  copies/mL) at 4 weeks of therapy

• Treatment-Experience
• SVR preferred where reasonably attainable
• Early Virologic Response (EVR12) defined as gt 2
  log10 decrease in HCV RNA 12 weeks recommended as
  futility endpoint for INF based Rx
• Novel Agents viral clearance may be slower

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Endpoints Compensated Liver Disease

• Primary Endpoints Viral Clearance Goal
• Primary Endpoints Viral Suppression Goal
• Secondary Endpoints

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Primary Endpoints Viral Suppression Goal

• Hypothesis Suppression will decrease
  development of ESLD, HCC

• Non-Responder population with lack of response
  or intolerance to PEG-IFN/RBV
• Histologic improvement- usually 2 HAI K/I
• Biochemical Improvement- normalization of liver
  transaminases
• Viral Suppression (similar to goals of HIV Rx)
  actual clinically meaningful levels not
  suggested -RVR4 might be applicable in this
  situation

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Endpoints Compensated Liver Disease

• Primary Endpoints Viral Clearance Goal
• Primary Endpoints Viral Suppression Goal
• Secondary Endpoints

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Secondary Endpoints

• For both treatment-naïve and non-responders
  except as noted above, histologic and biochemical
  endpoints were considered appropriate secondary
  endpoints due to their lack of specificity and
  sensitivity

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Endpoints Decompensated Liver Disease 1

• Few IND holders responded to this question
• Without transplantation, 5 year survival 50
• Primary Goals (transplant avoidance)
• Slowing progression, improving hepatic function,
  reversing complications, reduced transplant need
• Secondary Goals (preparation for transplant)
• Clearance of HCV RNA to prevent recurrence of HCV
  viremia post transplant (nearly universal)
• Reduction of HCV RNA to reduce severity post
  transplant liver disease

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Endpoints Decompensated Liver Disease 2

• Major concern regarding IFN safety with increased
  risk bone marrow toxicity and worsening liver
  function
• SVR remains favored primary endpoint.
• Up to 22 SVR prior to transplantation,
  virus-free post transplant
• SVR post transplant, 36 with decreased fibrosis
  in one study
• Other studies not as favorable

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Endpoints Decompensated Liver Disease 3

• Scoring systems used to prioritize
  transplantation list include
• Child Turcotte Pugh (CTP)
• Model for Endstage Liver Disease (MELD)
• Consider improvements in CTP and MELD scores as
  endpoints. However, threshold values not
  established nor validated for this purpose
• One suggested composite endpoint
• Serum HCV RNA reduction of gt1 Log10 WITH
• Histologic response of (2 points of Knodell HAI
  with no worsening fibrosis)

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Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding Investigational agent to SOC
Ribavirin substitution
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Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding Investigational agent to SOC
Ribavirin substitution
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Study Design OptionsAdding Agent to SOC

• General agreement adding a third agent to
  PEG-IFN/RBV is the preferred clinical design for
  treatment naïve pts.
• Other suggestions
• For the treatment experienced, use RVR4 and EVR12
  to prevent extended monotherapy
• If investigational agent is oral, an oral placebo
  could be used
• Depending on efficacy/safety characteristics of
  novel agent, a) triple Rx maintained throughout
  treatment course b) administered for
  defined period followed by consolidation with SOC
  
  c) administered for
  defined period followed by off-treatment F/U

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Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
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Study Design OptionsUse of Non-SOC
PEG-IFN/Novel Agent

• Consensus decreased dosage and/or duration of
  PEG-IFN with acceptable or improved efficacy
  might be possible with co-administration of novel
  agents
• However, pivotal studies should include SOC
  comparator arms with and without novel agent

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Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
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Study Design OptionsRibavirin Substitution

• Ribavirins mechanism of improving
  interferon-alfa SVR rates for CHC is unknown
• Many were reluctant to study a novel agent as
  substitution for RBV until activity as third
  agent to SOC is demonstrated
• In the presence of such data, a novel agent could
  be combined with PEG-IFN vs SOC and might be
  approvable if non-inferior and comparable or
  better safety/tolerability
• To test additive or synergistic effects novel
  agent, administration as monotherapy prior to
  PEG-IFN suggested up to 12 weeks (DAVP Concerned)

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Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
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Study Design OptionsUse of two or more Novel
Agents 1

• Ideally, differing mechanisms of action
• Prior to combination studies, a novel agent would
  need to demonstrate anti-HCV activity over
  specified period up to 14 days, longer if viral
  resistance issues satisfied
• Drug-Drug interaction studies might be considered
  if metabolism profile of drugs suggests
  interaction potential
• Novel investigational regimens with 2 novel
  agents with complementary mechanisms considered
  important for difficult to treat CHC populations

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Study Design OptionsUse of two or more Novel
Agents 2

• Patient populations to benefit from use of two or
  more agents
• SOC Non-Responders
• Multi-drug regimens compared with retreatment SOC
  or deferred treatment with novel regimen to
  establish placebo-like control period
• A concurrent PEG-IFN/RBV treatment period with
  EVR12 should be incorporated to confirm non
  responder
• Patients for whom IFN/RBV contraindicated such as
  decompensated liver disease or severe anemia
• To minimize safety concerns, RVR4 could be used
  depending on viral kinetics of products

36
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
37
Study Design OptionsMonotherapy

• Agreement for limited monotherapy treatment
  periods in clinical trials
• The major concern is high daily turnover of HCV
  RNA and low fidelity of the HCV replicase result
  in development of viral resistance with longer
  durations of monotherapy
• No support expressed for more than short duration
  of interferon monotherapy except in special
  populations such as those with ESRD

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Long-Term Follow-up
Confidence with durability of SVR for INF based
treatment
SVR following non interferon based treatment
needs validation with F/U HCV RNA, ALT x 3 years

• No further follow-up
• 5-10 Year follow-up

For cirrhotics, transplant recipients, HIV/HCV
coinfected and immune deficit patients, more
frequent follow-up of HCV RNA after SVR suggested
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Long-Term Follow-up
For patients who fail to achieve SVR, and
continuous treatment not elected
Semi-annual follow-up to monitor the state of
liver function was recommended
For situations where viral suppression is the
goal and histologic and or biochemical endpoints
used
Every 4-5 years to determine if study agent
should be continued
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Concluding RemarksStudy Populations

• Inclusion Candidates Initial Approval
• Adult, compensated liver dz, including
  cirrhotics, minority participation, genotypes 1,
  2, 3 and 4, no co-infections
• Treatment naïve most homogeneous
• Treatment experienced heterogeneous, fastest
  growing, greatest need
• Inclusion Candidates Post Approval
• Pediatrics, decompensated/transplanted,
  co-infected, minority focused
• Agency needs representative population to support
  labeling

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Study Populations/Controls

• The Non-Responder population
• Important challenge
• Substantial opportunity for the development of
  novel drugs or new treatment regimens utilizing
  currently approved products
• Issues
• Heterogeneity
• Proposed inclusion criteria definition appeared
  acceptable but additional advice on increasing
  interpretability is sought
• Controls
• SOC comparator recommended whenever possible
• Placebo or deferred treatment possible with
  shorter durations for treatment naïve

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Concluding Remarks-Endpoints

• Consensus primary endpoint SVR problems
• SVR currently only validated for IFN treatment
• Timing of endpoint measurement-
• IND holders recommended set number of weeks after
  treatment stopped
• Agency prefers standard comparable testing times
• EVR12 and RVR4 (IFN Study Tools)
• Histologic and Biochemical Endpoints
• Clinically meaningful levels of viral suppression
  and changes CTP/MELD not validated

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Concluding Remarks Study Design Options

• General agreements
• Adding third agent to SOC treatment naïve
  preferred
• RVR4 and EVR12 could prevent prolonged
  monotherapy in treatment experienced
• Ribavirin substitution-active novel agent
• Two or more novel agents SOC non-response or
  contraindication, SOC comparator possible
• Monotherapy limited time, special populations IFN

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Conclusions Long Term Follow-Up

• Confidence in SVR with IFN based Rx- range from
  no follow-up to 5-10years
• SVR with novel agents unknown durability,
  recommend retesting to 3 years post Rx
• Special populations more frequent follow-up
• No SVR, no treatment, F/U twice per year
• Long term suppression, Rx monitor every 4-5 years