Abstract
Overview
Introduction
Research and Development activity in the Hepatitis C arena continue to be
high. The market still holds many areas of unmet medical needs: while existing
therapies provide good efficacy for about half of the patient population, side
effects and limited efficacy in other patients offer much room for
improvement. Several development setbacks over the past 18 months highlight
the obstacles in R&D.
Scope
- In-depth analysis of hepatitis C patient potential and dynamics across the
major Western markets
- Thorough assessment of unmet needs and shortfalls of current HCV therapy
- Review of current clinical trial practice and key drug classes in
development for hepatitis C
- In-depth discussion of novel hepatitis C pipeline candidates and
assessment of their potential in HCV therapy
Highlights
Due to the suboptimal efficacy and safety profile of current standard HCV
therapy, there is a large unmet need for drugs with an improved clinical
profile. Experts agree that add-on therapy currently seems more promising than
interferon or ribavirin replacement approaches.
Recent clinical data on small-molecule polymerase and protease inhibitors has
sparked high hopes for improving SVR rates through triple therapy. Vertex' s
telaprevir, Schering Plough' s boceprevir and Roche' s R-1626 currently show the
most promising profiles.
Further strategies in HCV drug development include host enzyme inhibitors and
non-interferon immunomodulators. However, although theoretically highly
promising, most candidates are in very early stages of development and not
expected to reach the market soon.
Reasons to Purchase
- Review the epidemiological and clinical factors driving new product
decisions in hepatitis C as well as unmet needs with current treatment options.
- Gain insight through a detailed discussion of key pipeline candidates in
late-stage development for hepatitis C.
- Understand where concerns and future opportunities lie by learning about
the views of key hepatitis B opinion leaders.
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
- 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
- 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
- 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
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