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

Published by: Datamonitor

Published: Dec. 19, 2007 - 142 Pages

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

Abstract

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