Stakeholder Opinions: Hepatitis C - Small-molecule antivirals pave the way for triple therapy

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE
  • About the Infectious Diseases pharmaceutical analysis team
• CHAPTER 1 EXECUTIVE SUMMARY
  • Scope of the analysis
  • Datamonitor insight into the Hepatitis C market
• CHAPTER 2 DISEASE BACKGROUND AND CURRENT TREATMENT
  • HCV virology
  • Chronic HCV infection silently progresses to liver cirrhosis and cancer over prolonged periods of time
  • Interferon and ribavirin are the standard treatment for HCV
  • The current standard of care therapy - Peg-IFN alfa plus ribavirin - has a suboptimal tolerability and efficacy profile
  • Depending on their response to standard therapy, patients can be divided in different groups
  • Key unmet needs include HCV genotype 1 infection, non-response to current therapy and improved drug tolerability
• CHAPTER 3 PATIENT POTENTIAL
  • HCV is a major health concern with 180 million people infected globally
  • Intravenous drug users and people who received blood transfusions before 1990 are at highest risk of infection
  • The number of CHC patients seeking treatment is expected to peak within the next 10-20 years
  • Across the 7MM, immigration from high prevalence countries influences overall prevalence rates for HCV
  • HCV genotype 1, which is particularly hard to treat, accounts for the majority of infections in the 7MM
    • The prevalence of genotypes varies by country
    • Whereas SVR rates are high for genotypes 2 and 3, genotypes 1 and 4 are much harder to treat
  • Patients with an African background show poorer treatment outcomes if they suffer from genotype 1
  • The treatment of HIV/HCV co-infected patients is particularly challenging
  • There are few treatment options for the large population of non-responders and relapsers
  • The high incidence of post-transplant HCV re-infection has created an important niche market
• CHAPTER 4 R&D APPROACH
  • Of the drug classes are in development for HCV, small molecule antivirals show best prospects
    • Multiple different drug classes are being developed for use in HCV
    • ' Add-on' therapy to current standard treatment is the most promising approach in HCV drug development
      • Developmental drug strategies
    • Due to the late characterization of the hepatitis C virus, drug development has been slow
    • Future HCV therapy is likely to involve combinations of at least three drugs
  • Current clinical trials focus on achieving higher SVR rates in genotype-1 patients and non-responders
    • In late-stage trials, comparison with peginterferon/ribavirin is a must for new drug candidates
    • Trials are mostly conducted in genotype-1 patients
    • The achievement of a sustained virological response (SVR) is the key endpoint in both HCV clinical trials and therapy
• CHAPTER 5 INTERFERONS
  • Interferons have a non-specific, broad antiviral activity
    • The mechanism of Interferon alfa against HCV infection has not been elucidated
    • Standard interferons were first in class but have poor efficacy as monotherapy
    • Pegylated interferons in combination with ribavirin have become established as standard therapy
  • Pipeline efforts concentrate on long-acting formulations of interferon alfa with better tolerability
    • Pipeline summary
    • Albuferon (Human Genome Sciences/Novartis) - threatening the leading position of the peginterferons
      • Profile
      • Key clinical trials
      • Datamonitor analysis
    • IFNalpha-2b XL (Flamel Technologies) - more results needed to confirm positive top-line data
      • Profile
      • Key clinical trials
      • Datamonitor analysis
    • Locteron (OctoPlus/Biolex Therapeutics) - high EVR rates and good safety profile raise high hopes
      • Profile
      • Key clinical trials
      • Datamonitor analysis
    • Omega Interferon (Intarcia) - potential only lies in sustained release formulation
• CHAPTER 6 SMALL MOLECULE ANTIVIRALS
  • Due to the insufficient efficacy of current HCV therapy, targeted antivirals are a popular approach for new HCV therapies
    • Pipeline summary
  • HCV NS5B polymerase inhibitors - R-1626 leading the way following late-stage pipeline failures
    • Rationale for HCV NS5B polymerase inhibitors
      • Inhibition of the NS5B polymerase specifically blocks HCV replication at an early stage
      • Nucleoside and non-nucleoside inhibitors block polymerase activity by different mechanisms
    • Pipeline overview
    • R-1626 (Roche) - positive interim Phase II results sparking high hopes
      • Profile
      • Key clinical trials
      • Datamonitor analysis
    • Other HCV polymerase inhibitors - Gilead and Roche are benefiting from Novartis' s and Wyeth' s trial failures
      • GS-9190 (Gilead) - Phase I trial demonstrates antiviral activity and good pharmacokinetics
      • R-7128 (Roche/Pharmasset) - trials evaluating combination with standard therapy in progress following positive Phase I results
  • NS3/4A protease inhibitors - Telaprevir facing challenges
    • Rationale for HCV NS3/4A protease inhibitors
      • The NS3 protease is essential for viral replication
      • The HCV protease as a drug target: ideal in theory, difficult in practice
      • Combination therapy with pegylated interferons and/or other antivirals will be the preferred regimen for protease inhibitors to control resistances
    • Pipeline overview
    • VX-950 (telaprevir; Vertex) - handicapped by dosing and resistances
      • Profile
      • Key clinical trial overview
      • Datamonitor analysis
    • SCH 503034 (boceprevir; Schering-Plough) - emerging as competitor for VX-950
      • Product overview
      • Key clinical trial overview
      • Datamonitor analysis
    • Other HCV protease inhibitors - two promising newcomers in Phase I
      • TMC435350 (Medivir/Johnson & Johnson)
      • ITMN-191 (Roche/InterMune)
  • Other small molecule antivirals - uncertain future for taribavirin
    • Pipeline overview
    • Taribavirin (Viramidine; Valeant Pharmaceuticals) - Phase IIb results will determine fate of the drug following VISER-1 and VISER-2 failures
      • Profile
      • Key clinical trials
      • Datamonitor assessment
    • KPE02003002 (Kemin Pharma) - no updates since 2004
• CHAPTER 7 IMMUNOMODULATORS (NON-INTERFERON)
  • Immunomodulators are mostly developed as add-ons to existing therapy, using HCV as a secondary indication
    • Pipeline summary
  • Product profiles - best outlook for civacir
    • Zadaxin (SciClone)
    • Civacir (Nabi Biopharmaceuticals/Kedrion)
    • IM-862 (Implicit Bioscience)
    • IPH 1101 (Innate Pharma)
    • KRN-7000 (Kirin)
    • SCV-07
  • Therapeutic vaccines - a long way to go
    • IC-41 (Intercell AG) - more long-term data needed
      • Profile
      • Key clinical trial overview
      • Datamonitor analysis
    • HCV vaccine (Novartis/CSL) - no progress reported since 2004
• CHAPTER 8 HOST ENZYME INHIBITORS
  • The main role for host-enzyme inhibitors will be as add-on to standard therapy rather than as monotherapy
    • Pipeline summary
  • Product profiles - Most candidates are still in early stages
    • Celgosivir (Migenix)
      • Profile
      • Key clinical trials
      • Datamonitor assessment
    • NIM-811 (Novartis)
    • Debio-025 (Debiopharm)
    • VGX-410C (mifepristone; VGX Pharmaceuticals)
    • Alinia (nitazoxanide; Romark Laboratories)
• APPENDIX A
  • Bibliography
  • Report methodology
• APPENDIX B
  • About Datamonitor
  • About Datamonitor Healthcare
  • Datamonitor Healthcare' s therapy area capabilities
    • About the Infectious Diseases analysis team
    • Key therapy team members
      • Holger Rovini, Head of Respiratory and Infectious Diseases
      • Hedwig Kresse, Analyst, Infectious Diseases
    • Disclaimer
  • List of Tables
    • Table 1: Interferons and ribavirin are the only marketed HCV antivirals, 2007
    • Table 2: HIV mono-infected and HIV/HCV co-infected populations, 7MM, 2007
    • Table 3: Key trials for therapy in nonresponders to previous treatment with peginterferon / ribavirin
    • Table 4: Mode of action of developmental immunomodulators (non-IFN), 2007
    • Table 5: Mode of action of developmental interferons, 2007
    • Table 6: Mode of action of developmental small molecule antivirals, 2007
    • Table 7: Mode of action of developmental host enzyme inhibitors, 2007
    • Table 8: Key endpoints used in clinical trial design for HCV
    • Table 9: HCV pipeline overview - late-stage interferons, 2007
    • Table 10: Albuferon - ACHIEVE 1 trial design
    • Table 11: Albuferon - ACHIEVE 2/3 trial design
    • Table 12: Albuferon - Phase IIb (treatment-naïve) trial design and results
    • Table 13: Albuferon - Phase II (nonresponder) trial design and results
    • Table 14: Locteron - Phase IIa clinical trial design and results
    • Table 15: HCV pipeline overview -- late-stage small molecule antivirals, 2007
    • Table 16: HCV pipeline overview - NS5B polymerase inhibitors, 2007
    • Table 17: R-1626 - Phase IIa clinical trial overview and interim results
    • Table 18: R-1626 - Phase IIb clinical trial overview and interim results
    • Table 19: HCV pipeline overview - NS3/4A protease inhibitors, 2007
    • Table 20: Telaprevir -PROVE 1 study design and interim results
    • Table 21: Telaprevir - PROVE 2 study design and interim results
    • Table 22: Telaprevir - PROVE 3 study design
    • Table 23: Boceprevir - SPRINT-1 study design and preliminary results
    • Table 24: Boceprevir - Phase II study design and preliminary results
    • Table 25: HCV pipeline overview - late-stage other antivirals, 2007
    • Table 26: Taribavirin - VISER-1 Phase III study design and results
    • Table 27: Taribavirin - VISER-2 Phase III study design and results
    • Table 28: Taribavirin - Phase IIb trial design
    • Table 29: HCV pipeline overview - immunomodulators (non-IFN), 2007
    • Table 30: HCV pipeline - late-stage therapeutic vaccines, 2007
    • Table 31: IC-41 - Phase II monotherapy trial overview and interim results
    • Table 32: IC-41 - Phase II combination trial overview and interim results
    • Table 33: HCV pipeline - late-stage host enzyme inhibitors, 2007
    • Table 34: Celgosivir - Phase II combination trial design and results
  • List of Figures
    • Figure 1: HCV - genome organisation
    • Figure 2: HCV - course of disease
    • Figure 3: Efficacy of Pegasys + Copegus by HCV genotype
    • Figure 4: HCV - patient classification by response to treatment
    • Figure 5: HCV - key unmet needs
    • Figure 6: HCV diagnosis, 7MM, 2004
    • Figure 7: HCV - global disease prevalence and infection numbers
    • Figure 8: HCV prevalence and potential patient population across the 7MM, 2007
    • Figure 9: Sources of infection for HCV patients; US, 2006
    • Figure 10: HCV genotype split by country; Europe, US and Japan, 2007
    • Figure 11: Late-stage HCV drug pipeline (Phase II and III) by class, December 2007
    • Figure 12: Strategies for HCV drug development
    • Figure 13: The HCV NS3-encoded serine protease cleaves the non-structural HCV proteins