Pipeline Insight: Hepatitis C - Small Molecules, Big Revolution

Published by: Datamonitor

Published: Apr. 25, 2005 - 237 Pages

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

About the Infectious Disease pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

Scope of the analysis

Datamonitor insight into the Hepatitis C market

CHAPTER 2 PIPELINE DYNAMICS

The changing hepatitis C market - minor changes in the short-term, potential new treatment paradigm in the long-term

Pipeline overview

With most pipeline drugs in early phases of clinical development, new drug launches are expected to cluster in the period 2011-2013

Pegylated interferon and ribavirin replacement drugs in the short term, small molecule antivirals in the long term

The value of the HCV pharmaceutical market is expected to double between 2004-2012

Factors of both clinical and commercial nature are expected to fuel the future growth of the HCV market

As a consequence of their early stage in clinical development, new drugs are expected to account for only one-third of total sales in 2013

New players are expected to enter a market traditionally dominated by Schering-Plough and Roche

Although several new players are expected to enter the HCV market, the two members of the traditional duopoly are expected to hold their positions

In-licensing could provide the opportunity for companies lacking an HCV antivirals portfolio to enter a rapidly growing infectious disease market

CHAPTER 3 PATIENT POTENTIAL

Due to the silent nature and slow disease progression of chronic HCV infection, the pool of chronically infected patients seeking treatment is expected to peak within the next 10-20 years

Globally, 170-200m people are believed to be chronically infected with HCV

Japan and the US account for 75% of hepatitis C patients in the seven major markets

While past infections occurred through contaminated blood, present infections occur predominantly due to the use of shared needles

Chronic HCV infection silently progresses to liver cirrhosis and cancer over prolonged periods of time

The number of CHC patients seeking treatment is expected to peak within the next 10-20 years

HCV genotype 1, liver transplant and HIV-coinfected patients are the key patient populations requiring improved treatment options

HCV genotype 1 mono-infected patients constitute the majority of both the naïve and treatment-experienced chronic HCV patient pool

Nonresponders and relapsers, most of whom are infected with HCV genotype 1, are accumulating due to the lack of alternative therapies

The high incidence of post-transplant HCV reinfection has created an important niche market

Due to the prolongation of life expectancy associated with HAART therapy, HIV/HCV coinfection is becoming an increasingly important indication

Clinical limitations associated with the current standard of care have led to suboptimal diagnosis and treatment rates

Peg-IFN alfa plus RBV combination therapy is current standard of care but not gold standard

Both therapy components have individual limitations

Due to the immaturity of the HCV pharmaceutical market, new product development might increase both diagnosis and treatment rates

The key unmet needs are HCV genotype 1 infection, non-response to current therapy and improved drug tolerability

HCV genotype 1 infection is the most common but also the least responsive to available therapy

Up to 90% of nonresponders are infected with HCV genotype 1

Increased drug tolerability-related issues are also key to increasing market uptake

CHAPTER 4 R&D APPROACH

HCV protease inhibitors are perceived as the most promising antivirals in the HCV pipeline, but interferon and ribavirin replacement drugs are closer to approval

The highly active HCV pipeline is driven by several different drug classes and sub-classes

Strategies for HCV drug development focus on 'add-on' therapy or replacement of either component of the current standard of care and pave the way for a potential new treatment paradigm

Developmental drug strategies

Specific HCV antivirals are not expected to reach the market before the end of the decade

Late discovery and drug research patents have slowed the development of HCV-specific small molecule antivirals

Current clinical trial design requires careful evaluation of various trial components

Comparison against Peg-IFN plus ribavirin is a must, although, in some cases, valuable data can also be gained from a placebo arm

Treatment remains sub-optimal for HCV genotype 1-infected patients, leading to a large pool of nonresponders that is now increasingly being enrolled in clinical trials

Lack of differentiation between male and female coinfected patients also a factor

The achievement of a sustained virological response (SVR) is the key endpoint in both HCV clinical trials and therapy

Since HCV therapy leads to durable viral suppression, the key goal of HCV therapy is the reduction of the HCV viral load to undetectable levels

The achievement of an early virological response is often a prognostic factor for the achievement of a sustained virological response

Additional endpoints include the incidence of anemia for ribavirin replacement drug viramidine and the histological and biochemical response

CHAPTER 5 IMMUNOMODULATORS (NON-INTERFERON)

The immunomodulator pipeline is relatively active, with companies focusing on 'add-on' therapy, IFN replacement or reinfection following liver transplant

Pipeline summary

The low success rate associated with Peg-IFN plus RBV retreatment has led to the development of 'add-on' therapies for HCV nonresponders

The immune enhancer Zadaxin has shown efficacy in HCV nonresponders when added to the current standard of care

Profile

Key clinical trial overview

Datamonitor analysis

Ceplene, an antioxidant and immunomodulant, is in development as 'add-on' therapy for HCV nonresponders

Profile

Key clinical trial overview

Datamonitor analysis

IFN alfa-inducing drugs with improved tolerability have the potential to replace Peg-IFN alfa

Isatoribine (ANA245) and its oral prodrugs, ANA971 and ANA975 are being developed for potential IFN replacement or 'add-on' therapy

Profile

Key clinical trial overview

Datamonitor analysis

Actilon (CPG 10101) induces endogenous IFN alfa but only targets patients relapsing from, or intolerant to, previous IFN-based therapy

Profile

Datamonitor analysis

Therapeutic HCV vaccines have been finding their niche in the growing pool of nonresponders to IFN-based therapy

InnoVac-C improves liver histology in HCV genotype 1-infected nonresponders with active liver disease

Profile

Datamonitor analysis

Intercell's HCV therapeutic vaccine - from the nonresponder & relapser niche to treatment-naïve patients

Profile

Key clinical trial overview

Datamonitor analysis

Chiron is developing several HCV vaccines, including one for nonresponders

Profiles

Datamonitor analysis

The increase in HCV post-liver transplant patients has created a niche for products that address HCV reinfection

HepeX-C - a dual human monoclonal antibody therapy to prevent HCV reinfection post transplant

Profile

Key clinical trial overview

Trial results

Datamonitor analysis

Civacir - a preparation of human polyclonal antibodies - has received orphan drug status for the prevention of HCV reinfection in liver transplant patients

Profile

Datamonitor analysis

Late-stage development compounds potentially discontinued recently

EHC-18, broad-spectrum immunomodulator for HCV infection and HCV-related hepatocellular carcinoma

FK778, an immunomodulator in development for HCV nonresponders

Comparative class forecasts

CHAPTER 6 INTERFERONS

Unmodified interferons were the gold standard for HCV until they were displaced from their pedestal by pegylated interferons

Interferons have a non-specific, broad antiviral activity

The mechanism of IFN alfa against HCV infection has not been elucidated

Standard interferons were first in class but have poor efficacy as monotherapy

Although the longer-acting pegylated IFNs improved IFN efficacy...

...it was primarily the addition of RBV that significantly boosted the IFN-based treatment response

Few companies have attempted to replace Peg-IFN, with main drivers in this class including more favorable dosing, delivery and tolerability, and further efficacy against HCV genotype 1

Pipeline summary

Long-acting interferons requiring less frequent dosing might challenge pegylated interferons for first-line therapy

Due to its improved bioavailability, Albuferon is undergoing clinical trials in naïve patients of all genotypes

Profile

Key clinical trial overview

Datamonitor analysis

Omega interferon - progress on improved delivery system justifies testing in naïve patients for Peg-IFN replacement

Profile

Key clinical trial overview

Datamonitor analysis

Other interferons

Viragen seeks to expand Multiferon use from second- to first-line therapy and enter the US market

IFN-beta 1 for Asian nonresponders and relapsers

Strategic issues have led to the discontinuation of two developmental compounds

PEG-Alfacon-1 - seeking a partner for future development

As part of a strategic decision, Viragen abandoned development of Omniferon in favor of Multiferon

Comparative class forecasts

CHAPTER 7 SMALL MOLECULE ANTIVIRALS

Most specific HCV antivirals are at early stages of clinical development, therefore, their potential efficacy is surrounded by uncertainty

Pipeline summary

RBV dose reduction due to drug-related anemia has led to the development of second-generation ribavirin with reduced toxicity

Several factors of predominantly clinical nature preclude the wider use of ribavirin

RBV has no effect when administered on its own

RBV's four hypothetical mechanisms of action

Dose-limiting anemia leads to dose-reduction or supplementation with growth factors

For several years, Schering-Plough dominated the HCV ribavirin market

Fierce generic competition since loss of patent protection in 2003

Viramidine, a ribavirin prodrug, has significant potential to replace ribavirin based on its favorable toxicity profile

Profile

Key clinical trial overview

Datamonitor analysis

The lack of efficacy of the current standard of care in the growing pool of genotype 1-infected patients has triggered the race for specific HCV inhibitors

BILN 2061 provided proof-of-concept for HCV protease inhibitors, but development has been suspended due to toxicity

Profile

Clinical trials showed an early and potent decrease in HCV viral load in genotype 1-infected patients

HCV NS5B polymerase inhibitors follow the rationale used for the HBV and HIV reverse transcriptase inhibitors and have the potential to revolutionize HCV therapy

Rationale for HCV NS5B polymerase inhibitors

Inhibition of the NS5B polymerase specifically blocks HCV replication at an early stage

The RdRp can be targeted with both active and allosteric site inhibitors

The rationale for RdRp inhibitors is similar to that of HBV and HIV RT inhibitors

Valopicitabine (NM283) - potential for ribavirin replacement

Profile

Key clinical trial overview

Datamonitor analysis

Other HCV polymerase inhibitors

JTK-003 - ongoing Phase II trials but little published data

ViroPharma's HCV-086 and HCV-796

Despite being the most promising class among HCV antivirals, the development of HVC NS3 protease inhibitors has taken off slowly

Rationale for HCV NS3 protease inhibitors

The NS3 protease is essential for viral replication

The HCV protease as a drug target: ideal in theory, difficult in practice

Since viral resistance to PIs might develop, combination treatment-initially with Peg-IFN alfa-could be the preferred strategy

VX-950 - potential to become first-in-class HCV PI

Profile

Key clinical trial overview

Datamonitor analysis

Other HCV protease inhibitors

Little data available for Schering-Plough's SCH 6 and SCH7

Other small molecule antivirals with unknown function

KPE02003002

UT 231B

Discontinued small molecule antivirals

Most small molecule antivirals are discontinued due to the lack of activity in the clinic

BILN 2061 - unexpected cardiac toxicity

VP-50406 - poor antiviral activity

R803 - insignificant effects in Phase I/II clinical trial despite potent anti-HCV activity in vitro led to the removal of the drug from Rigel's pipeline

Levovirin - lack of antiviral activity

JTK-109 - discontinued for unknown reasons

R1479 - discontinued for unknown reasons

Comparative class forecasts

CHAPTER 8 HOST ENZYME INHIBITORS

Limited R&D attention has been paid to the inhibition of host enzyme inhibitors, with only three compounds in this class currently undergoing Phase II trials

Pipeline summary

Host enzyme inhibitors are in development for 'add-on' therapy in patients who fail to respond to the current standard of care

IMPDH inhibitor merimepodib (VX-497) for 'add-on' therapy in nonresponders

Profile

Key clinical trial overview

Datamonitor analysis

Caspase inhibitor IDN-6556 is primarily being developed to prevent liver damage in nonresponders

Profile

Key clinical trial overview

Datamonitor analysis

Other host enzyme inhibitors

Alfa-glucosidase inhibitor Celgosivir - potential as monotherapy but ultimately to be positioned as 'add-on' therapy

Comparative class forecasts

CHAPTER 9 OPINION LEADER TRANSCRIPTS

Discussion Guide

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profile and assessment

Section 4 - Future of HCV therapy

Opinion leader 1

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profile and assessment

Section 4 - Future of HCV therapy

Opinion leader 2

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profile and assessment

Section 4 - Future of HCV therapy

Opinion leader 3

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profile and assessment

Section 4 - Future of HCV therapy

Opinion leader 4

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profile and assessment

Section 4 - Future of HCV therapy

APPENDIX A

Bibliography

Epidemiology

Journal articles

Conference abstracts

Useful websites

Power Point Presentations

Press releases

Datamonitor reports

Miscellaneous

Report methodology

APPENDIX B

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

About the Infectious Disease analysis team

Disclaimer

List of Tables

Table 1: HCV pipeline overview

Table 2: Total HCV market sakes forecasts, 2005-2013, US, EU and Pacific Rim

Table 3: Deaths caused by HCV infection, by geographical area, 2002

Table 4: Reported HCV cases in England and Wales, 2003

Table 5: HCV prevalence and total patient population in the seven major markets, 2004

Table 6: Geographical distribution of HCV genotypes

Table 7: Relative distribution of HCV genotypes in the West

Table 8: HIV mono-infected and HIV/HCV coinfected populations in the seven major markets, 2003

Table 9: Interferons and ribavirin are the only marketed HCV antivirals

Table 10: Historically, HCV therapy has failed to address patients interferon-resistant HCV-genotypes 1 and 4

Table 11: Estimated HCV genotype 1-infected CHC patient -population

Table 12: Mode of action of developmental immunomodulators (non-IFN)

Table 13: Mode of action of developmental interferons

Table 14: Mode of action of developmental small molecule antivirals

Table 15: Mode of action of developmental host enzyme inhibitors

Table 16: Several developmental drugs are specifically enrolling genotype 1-infected patients and nonresponders

Table 17: The four key endpoints used for clinical trials involving CHC patients with compensated liver disease

Table 18: Pipeline overview for immunomodulators (non-IFN)

Table 19: In a pilot trial, Zadaxin plus Peg-IFN alfa-2a plus RBV triple combination therapy led to a significant virologic response in HCV genotype 1 infected nonresponders

Table 20: In a Phase II trial, Ceplene was found to be effective in reducing the HCV viral load and normalizing ALT levels in naïve patients when used with IFN alfa

Table 21: Phase II trial design for the study of Ceplene in nonresponders

Table 22: Isatoribine's proof-of-concept Phase Ib trial

Table 23: In two Phase I studies, Actilon has demonstrated a good safety and tolerability profile and led to HCV RNA reductions in HCV relapsers of and patients intolerant to previous IFN alfa therapy

Table 24: Intercell's Phase II European multicenter trial in HCV nonresponders and relapsers showed the induction of a significant T cell response

Table 25: Phase I and II clinical trials for HepeX-C monotherapy (AbXTL68) pave the way for dual antibody therapy

Table 26: Suspended or discontinued late-stage drugs

Table 27: Relative proportion of standard and pegylated interferon being prescribed to chronic hepatitis C versus chronic hepatitis B patients, seven major markets, 2004

Table 28: Pipeline overview for interferons

Table 29: The mean half-life of Albuferon alpha is significantly higher than that of the Peg-IFNs, supporting less frequent dosing

Table 30: In a Phase I/II study, Albuferon alfa monotherapy demonstrated antiviral activity when administered as monotherapy to genotype 1 nonresponders

Table 31: Preliminary results at treatment day 28 for 38 patients enrolled in the Canada-based Phase II trial showed that Albuferon monotherapy significantly reduced the viral load

Table 32: In a European Phase II trial, omega IFN was effective in all genotypes in treatment-naïve patients, although genotype 1-infected patients required a higher dose

Table 33: Omega IFN is currently undergoing a Phase II clinical trial in Russia involving HCV genotype 1-infected, treatment-naïve patients

Table 34: Suspended or discontinued interferons

Table 35: Pipeline overview for small molecule antivirals

Table 36: In a Phase I/II double-blind, randomized trial, NM283 led to consistent reductions of HCV RNA

Table 37: VX-950's developmental history

Table 38: VX-950 Phase Ib trial design

Table 39: UT-231B Phase II clinical trial design

Table 40: Discontinued small molecule HCV antivirals

Table 41: Host enzyme inhibitors in development for HCV

Table 42: IDN-6556 Phase II clinical trials overview

Table 43: Phase IIa clinical trial design of Celgosivir monotherapy

List of Figures

Figure 1: HCV pipeline, by phase of clinical development and drug class

Figure 2: Estimated launch dates for developmental HCV drugs

Figure 3: HCV market sales forecasts by class, 2003-2015, US, EU and Pacific Rim

Figure 4: Anticipated long-term impact of novel HCV products on marketed HCV products

Figure 5: Geographic distribution of HCV prevalence

Figure 6: Prevalence of HCV infection by age and gender, US, 1988-94

Figure 7: Reported HCV incidence in England and Wales, 1993-2003

Figure 8: Most patients infected with HCV progress to chronic HCV (CHC) infection, which can lead to liver cirrhosis and cancer within 20-50 years

Figure 9: Proportion of CHC patients receiving each line of therapy in the seven major markets, 2004

Figure 10: HCV diagnosis rates, seven major markets, 2004

Figure 11: HCV treatment rates, seven major markets, 2004

Figure 12: Key clinical HCV unmet needs

Figure 13: Drug developers follow four major strategies for HCV developmental drugs

Figure 14: One of the ongoing Phase III trials studies the efficacy of Zadaxin + Peg-IFN alfa-2a + RBV triple combination in genotype 1-infected nonresponders

Figure 15: SciClone has enrolled patients for two multicenter, randomized double-blinded Phase III studies for Zadaxin in combination with Peg-IFN alfa-2a in HCV nonresponders

Figure 16: Zadaxin sales forecasts, 2005-2013

Figure 17: Ceplene sales forecasts, 2005-2013

Figure 18: Isatoribine sales forecasts, 2005-2013

Figure 19: Actilon sales forecasts, 2005-2013

Figure 20: HepeX-C sales forecasts, 2005-2013

Figure 21: Civacir sales forecasts, 2005-2013

Figure 22: Immunomodulators (non-interferon) comparative sales forecasts, 2005-2013

Figure 23: Two Phase II trials are assessing Albuferon either as monotherapy in treatment-naïve patients (Canada study) or as combination therapy with RBV in nonresponders (US study)

Figure 24: Albuferon sales forecasts, 2005-2013

Figure 25: Omega interferon sales forecasts, 2005-2013

Figure 26: Multiferon sales forecasts, 2005-2013

Figure 27: Interferon beta sales forecasts, 2005-2013

Figure 28: Interferon comparative sales forecasts, 2005-2013

Figure 29: In a comparative, US Phase II trial involving mainly genotype 1-infected CHV patients, viramidine showed similar antiviral efficacy to RBV but significantly less anemia

Figure 30: 12-week interim data of viramidine's Phase II trials highlighted that the accumulation of viramidine in both plasma and RBCs was lower than that of RBV

Figure 31: Two global viramidine Phase III trials, VISER1 and VISER2, have completed patient enrollment

Figure 32: Initially, viramidine us likely to be the alternative to adding erythropoietin to Peg-IFN alfa plus RBV therapy

Figure 33: Viramidine sales forecasts, 2005-2015

Figure 34: Interim data from a Phase IIa trial show that combination therapy of NM283 and Peg-IFN significantly reduces the HCV viral load

Figure 35: Valopicitabine sales forecasts, 2005-2013

Figure 36: JTK-003 sales forecasts, 2005-2013

Figure 37: HCV-086 sales forecasts, 2005-2013

Figure 38: The HCV NS3-encoded serine protease cleaves the non-structural HCV proteins

Figure 39: VX-950 sales forecasts, 2005-2013

Figure 40: KPE02003002 sales forecasts, 2005-2013

Figure 41: UT 231B sales forecasts, 2005-2013

Figure 42: Small molecule antivirals comparative sales forecasts, 2005-2013

Figure 43: In a randomized, placebo-controlled European Phase IIa trial in genotype 1 nonresponders, addition of MMPD to the standard of care improved treatment success

Figure 44: In the double-blind, placebo-controlled randomized METRO (Phase II) trial, MMPD is assessed in HCV nonresponders as triple combination with the current standard of care

Figure 45: Merimepodib sales forecasts, 2005-2013

Figure 46: An estimated 1,5m patients in the seven major markets are likely to progress to liver cirrhosis and could potentially benefit from IDN-6556 therapy

Figure 47: Celgosivir sales forecasts, 2005-2013

Figure 48: Host enzyme inhibitors comparative sales forecasts, 2005-2013

Abstract

• Overview of HCV pipeline with coverage of polymerase inhibitors, protease inhibitors along with newer generation ribavirin and long acting interferons
• Opinion leader appraisal of HCV clinical trial design, comparators and endpoint definition
• Detailed analysis of new product first year market share and peak sales forecasts
• Expert outlook on evolution of HCV therapy and discussion of opposing views

• Gain the latest understanding on the long term outlook for HCV treatments
• Assess the long-term impact of new small molecules on pegylated interferon uptake
• Quantify present and future split between antiviral and immunomodulator segments

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