Pipeline Insight: Hepatitis B - New Kids on the Block

Published by: Datamonitor

Published: Apr. 21, 2005 - 211 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 B market

CHAPTER 2 PIPELINE DYNAMICS

The future HBV market is expected to consist mainly of NRTIs, with pipeline drugs expected to dominate the market

Pipeline overview

With the launch of up to eight compounds between 2005-2013, the NRTI class dominate in the future HBV market

As a consequence of the immaturity of the current HBV market, new HBV drugs might dominate the market by 2006

New drugs lead to new players in the HBV market

CHAPTER 3 PATIENT POTENTIAL

HBV infection leads to a complex chronic disease associated with progressive liver damage

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

Acute and chronic infection

The role of ccc HBV DNA

Chronic hepatitis B is a complex and highly dynamic disease consisting of different stages marked by both viral and host-specific markers

Active CHB versus inactive carrier state

HBeAg+ and HBeAg- hepatitis

HBV persistence prevents disease resolution

Although the incidence of new HBV infections has been decreasing, there is a large pool of chronically infected carriers

The introduction of HBV vaccination has led to a significant decrease in new HBV infections

Screening of blood and pregnant women has also contributed to a drop in new HBV infections

Globally, 350-400 million people are believed to be chronically infected with HBV

In the West, HBV is predominantly transmitted by sexual contact

Patient segmentation by age and gender

Estimated chronic HBV patient pool in the seven major markets

Different forms of HBV disease require tailored therapies

HBeAg- hepatitis B-associated with poor treatment outcomes-is increasing

Geographic variability

Long-term therapy with specific HBV antivirals is associated with the development of drug-resistant HBV strains

Lamivudine resistance

Adefovir resistance

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

There are currently few therapeutic options and these fail to achieve sustained suppression of viral replication

Only two HBV polymerase inhibitors and one interferon are currently available for the treatment of CHB

The key unmet needs in HBV therapy are the achievement of sustained virus suppression and the management of resistant viral strains

The low rate of HBs seroconversion and the difficulty in ccc HBV clearance preclude the achievement of a sustained antiviral response

Of the currently marketed drugs, only Pegasys has demonstrated significant induction of HBsAg loss and anti-HBs seroconversion in HBeAg+ patients

Several drug developers are now addressing the elimination of ccc HBV DNA, but, so far, little progress has been made

Loss of HBeAg and HBeAg seroconversion increases the chance of achieving sustained viral suppression

The emergence of resistant virus strains due to the long duration of therapy reduces drug efficacy

Summary of key unmet needs for NRTIs, currently the most active developmental drug class

CHAPTER 4 R&D APPROACH

Current hepatitis B pipeline activity is driven manly by HBV polymerase inhibitors, raising the possibility of future combination therapy

Most HBV polymerase inhibitors are derived from the HIV pipeline and are still the main focus of drug development due to effective proof of concept

With several polymerase inhibitors in the late-stage pipeline, the building blocks for combination therapy could soon be available

The increasing competition of the HBV drug market demands a higher level of sophistication in clinical trial design

The choice of the comparator is no longer clear-cut

Placebo-controlled trials provide valuable data

In the future, entecavir might be preferred over lamivudine and adefovir as a comparator if it demonstrates a better resistance profile than adefovir

The complete assessment of a drug, in terms of resistance development, seroconversion rates and toxicity, requires long-term follow-up, beyond 48 weeks

Resistance mutation development increases with time

Anti-HBe and anti-HBs seroconversion are slow to develop

Potential drug toxicity following prolonged drug use

In addition to patient stratification according to HBeAg status, effective clinical trial design needs to focus on ethnic groups, HBV genotypes and the stage of the liver disease

Both patient-specific and viral factors govern the treatment response

Despite the variety of current endpoints currently used, virus suppression is key to demonstrating drug efficacy

The clinical endpoints used in CHB therapy differ between patients with compensated and those with decompensated CHB

Endpoints for compensated CHB

Endpoints for decompensated CHB

CHAPTER 5 NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS

Most HBV polymerase inhibitors were originally being developed for HIV prior to the identification of their activity against HBV

Mode of action

It is currently unclear which drug is the qualified gold standard HBV therapy

Lamivudine has traditionally been considered the gold standard HBV therapy

Zeffix's strengths and weaknesses

Hepsera, with its superior resistance profile, could be perceived as a challenger for the HBV gold standard

Hepsera's strengths and weaknesses

The lack of head-to-head data between lamivudine and adefovir means there is no definitive quantification of the HBV gold-standard therapy

The NRTI pipeline is relatively active, with two drugs in Phase III and one, entecavir, recently approved in the US

NRTI pipeline summary

Novel HBV polymerase inhibitors are competing in terms of higher potency and favorable resistance profiles

With the conclusion of several favorable trials, BMS has clinical support for Baraclude (entecavir) positioning across all lines of therapy

Profile

Key clinical trials overview

Datamonitor analysis

With effective HBV suppression alone not sufficient to achieve a durable response, several pipeline drugs are addressing indicators for sustained viral suppression

Telbivudine achieves potent early viral suppression

Profile

Key clinical trial overview

Datamonitor analysis

Clevudine - prolonged post-treatment suppression of HBV DNA even after short treatment periods

Profile

Key clinical trial overview

Datamonitor analysis

The potential for combination therapy, already a standard of care in other chronic viral diseases, is being investigated for HBV

Valtorcitabine has shown synergistic efficacy in combination with telbivudine

Profile

Key clinical trial overview

Datamonitor analysis

Despite the availability of adefovir, lamivudine resistance is still a key unmet need being targeted by pipeline drugs

LB80380 (ANA380), targeting LVD-resistant patients

Profile

Key clinical trials overview

Datamonitor analysis

Remofovir, an oral prodrug of adefovir, is being developed to challenge Hepsera

Profile

Key clinical trial overview

Datamonitor analysis

Tenofovir, first choice for HIV/HBV coinfected patients despite absence of official development for HBV monoinfection

Widely used for HIV but also active against the HBV polymerase

Drug of choice for HIV/HBV coinfected patients, in particular those harboring LVD-resistant HBV variants

Datamonitor analysis

Others

Alamifovir

MIV-210 is active against LVD-resistant HBV strains in vitro

Three late-stage developmental compounds have recently been suspended or discontinued due to poor resistance profiles

Emtricitabine - high rate of resistance precludes further development despite antiviral efficacy

Elvucitabine, Phase II clinical data awaited

Although active against HBV, amdoxovir is no longer being developed for this indication

Profile

In the duck HBV infection model, amdoxovir failed to demonstrate ccc DNA suppression and clearance of infected cells

Comparative NRTI forecasts

CHAPTER 6 IMMUNOMODULATORS AND OTHERS

The recent approval of Pegasys for the treatment of HBV might lead to a revival of interferon-based therapy

Pegasys requires less frequent administration than standard IFN and has equal or superior efficacy to lamivudine

Profile

Key clinical trial overview

With Pegasys setting a high benchmark, the entry barrier for immunomodulators is high, leading to very few companies developing compounds in this class

Immunomodulator and others pipeline summary

The adverse events associated with IFN therapy have instigated the search for alternative immunomodulators with better tolerability profiles

Although Zadaxin has the potential to benefit patients when administered as combination therapy, past and current trial design has failed to support the drug's real value

Profile

Key clinical trial overview

Datamonitor analysis

The increase of liver transplant patients chronically infected with HBV has created a market for products that prevent HBV reinfection post transplant

HepeX-B (XTL-001) is undergoing Phase IIb trials for HBV-associated liver transplant patients

Profile

Key clinical trial overview

Datamonitor analysis

Other immunomodulators

EHT899 is an oral viral protein with both immune suppressing and enhancing activity

SpecifEx-HepB, antigen-specific T cell transfer

Other developmental drugs

NOV-205 (BAM-205)

Comparative class forecasts

CHAPTER 7 OPINION LEADER TRANSCRIPTS

Discussion guide

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profiles and assessment

Section 4 - Future of HBV therapy

Key opinion leader 1

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profiles and assessment

Section 4 - Future of HBV therapy

Key opinion leader 2

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profiles and assessment

Section 4 - Future of HBV therapy

Key opinion leader 3

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profiles and assessment

Section 4 - Future of HBV therapy

Key opinion leader 4

Section 1 - Unmet needs

Section 2 - Clinical trial design

Section 3 - Developmental drug profiles and assessment

Section 4 - Future of HBV therapy

APPENDIX A

Bibliography

Epidemiology

Journal articles

Conference abstracts

Useful websites

PowerPoint Presentations

Press releases

Datamonitor reports

Miscellaneous

Report methodology

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

About the Infectious Disease analysis team

Disclaimer

List of Tables

Table 1: HBV pipeline overview

Table 2: Total HBV market sales forecasts, 2005-2015, US, EU and Pacific Rim

Table 3: Geographical distribution of HBV genotypes

Table 4: Forms of chronic hepatitis B according to serologic, biochemical and histological markers

Table 5: Deaths caused by hepatitis B infection worldwide, by geographical area, 2002

Table 6: HBV prevalence and total patient population in the seven major markets, 2004

Table 7: Treatment response to currently approved regimens for HBeAg+ versus HBeAg- patients

Table 8: Most common patterns of LVD-resistance mutations

Table 9: HIV monoinfected and HIV/HBV coinfected populations in the seven major markets, 2003

Table 10: Approved drug classes for HBV treatment

Table 11: Endpoints for clinical trials involving CHB patients with compensated liver disease

Table 12: Approved drugs for the treatment of chronic HBV infection

Table 13: Zeffix: key facts

Table 14: Hepsera: key facts

Table 15: Lamivudine versus adefovir: comparison of key performance attributes

Table 16: HBV polymerase inhibitors (nucleoside and nucleotide reverse transcriptase inhibitors) in clinical development

Table 17: Clevudine's developmental history

Table 18: In vitro, LB80380 is active against common LVD-resistant strains, similar to ADV

Table 19: Discontinued late-stage HBV polymerase inhibitors

Table 20: Phase III clinical trial summary for Pegasys

Table 21: HBV immunomodulators in clinical development

Table 22: Zadaxin's ranking with respect to the ability to achieve anti-HBe seroconversion

Table 23: Zadaxin has a delayed onset of efficacy

Table 24: Zadaxin + IFN combination therapy is more effective than placebo

Table 25: EHT-899 demonstrated antiviral activity in a Phase II clinical trial conducted in Israel

List of Figures

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

Figure 2: Estimated launch dates for developmental HBV drugs

Figure 3: HBV market sales forecasts by class, 2005-2015, US, EU and Pacific Rim

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

Figure 5: HBV disease progression

Figure 6: Outcome of hepatitis B virus infection by age at the time of infection

Figure 7: Stages of HBV disease remission

Figure 8: Geographic distribution of HBV immunization policies, 1996 and 2001

Figure 9: The incidence of acute hepatitis in the US has declined steadily between 1990-2002, in particular in children and adolescents

Figure 10: Geographic distribution of HBV prevalence

Figure 11: Reported cases of HBV in England and Wales, 1993 and 2003

Figure 12: Reported HBV incidence in England and Wales, 1993 and 2003

Figure 13: Diagnosed HBV patient population, seven major markets, 2004

Figure 14: Out of the diagnosed HBV patient population, only an average of 53% receive pharmacological treatment, seven major markets, 2004

Figure 15: Key HBV patient populations

Figure 16: The prevalence of HBeAg- CHB varies geographically and is related to the infecting HBV genotype

Figure 17: Proportion of CHB patients receiving each line of therapy in the seven major markets

Figure 18: The development of drug resistance counteracts the antiviral immune response in the achievement of a sustained antiviral response

Figure 19: While a few unmet needs in HBV therapy have been satisfied, most are either partially or unsatisfactorily achieved

Figure 20: Compensated versus decompensated CHB-associated liver disease

Figure 21: Goals and markers of CHB therapy are the basis for clinical trial endpoints

Figure 22: Zeffix's strengths and weaknesses

Figure 23: Hepsera's strengths and weaknesses

Figure 24: In two multinational, randomized, double-blind, randomized Phase III trials, ETV-022 and ETV-027, ETV 0.5mg once daily was a potent inhibitor in HBeAg- patients

Figure 25: In a multinational, double-blind, comparative, randomized Phase III trial (ETV-022) against LVD 100mg QD, ETV 0.5mg QD was effective in patients with both high and low ALT levels

Figure 26: In a multinational, randomized, double-blind Phase III clinical trial, ETV-026, ETV at 1mg QD was a potent inhibitor of LVD-resistant HBV strains

Figure 27: Entecavir sales forecasts, 2005-15

Figure 28: A randomized, multicenter Phase IIb study demonstrated that L-dT is more potent than LVD and combination of L-dT and LVD does not improve the treatment response to L-dT monotherapy

Figure 29: Telbivudine sales forecasts, 2005-15

Figure 30: In a Phase II, multicenter, dose-escalation study, CLV for only four weeks achieved lasting viral suppression and unprecedented loss of HBeAg

Figure 31: Clevudine sales forecasts, 2005-15

Figure 32: Following a Phase I/II, randomized, dose-escalation study, valtorcitabine was not considered potent enough to be developed as monotherapy

Figure 33: Valtorcitabine sales forecasts, 2005-15

Figure 34: In a Phase I/II double-blind, randomized, placebo-controlled multiple ascending-dose trial, LB80380 was shown to effectively inhibit HBV DNA replication

Figure 35: In a Phase II open-label, multicenter, sequential group dose escalation study, LB80380 has shown activity in patients infected with LVD-resistant HBV strains

Figure 36: LB80380 sales forecasts, 2005-15

Figure 37: In a double-blind, placebo-controlled, parallel group, multiple-dose Phase I/II study, remofovir was effective in reducing HBV DNA load at all doses tested

Figure 38: Design of the Phase II head-to-head trial of remofovir mesylate against adefovir dipivoxil

Figure 39: Remofovir's sales forecasts, 2005-15

Figure 40: TFV is significantly more potent than ADV in HBV suppression in HIV/HBV coinfected patients with LVD-resistant HBV variants

Figure 41: Addition of TFV to LVD in LVD-resistant patients greatly enhances the antiviral response

Figure 42: Alamifovir sales forecasts, 2005-15

Figure 43: MIV-210 sales forecasts, 2005-15

Figure 44: In a randomized, double-blind, placebo-controlled Phase III trial FTC led to development of the YMDD mutation in 12.6% of patients after 48 weeks of treatment

Figure 45: NRTI comparative sales forecasts, 2005-2013

Figure 46: Pegasys sales forecasts, 2005-15

Figure 47: Zadaxin sales forecasts, 2005-15

Figure 48: HepeX-B sales forecasts, 2005-15

Figure 49: EHT899 sales forecasts, 2005-15

Figure 50: Immunomodulators comparative sales forecasts, 2005-2013

Abstract

• Comprehensive overview of HBV pipeline nucleosides, nucleotides and immunomodulators
• Opinion leader appraisal of HBV clinical trial design, comparators and endpoint definition
• Detailed analysis of entecavir first year market share and peak sales forecast
• Expert outlook on evolution of HBV therapy and discussing of opposing views

• Gain the latest understanding on the long term outlook for HBV treatments
• Assess the potential impact of entecavir on lamivudine and adefovir
• Quantify present and future split between antiviral and immunomodulator segments

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