Pipeline Insight: Hepatitis B

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Publication Date: 2005-04-21

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According to the WHO, 350-400 million people are chronically infected with HBV progresses to liver cirrhosis and hepatocellular carcinoma. Previously HBV has been treated with lamivudine or adefovir monotherapy and ‘off label’ use of unmodified and pegylated interferon. Recent US approval of BMS’s new nucleoside entecavir (Baraclude) and EU approval of Roche’s Pegasys will change the status quo.

Scope

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

Report Highlights
The HBV market in 2004 is estimated at $551m with antivirals accounting for 2 fold more sales than the immunomodulators.

If priced between lamivudine and adefovir, entecavir will exceed the $300m barrier before patent expiry and dominate first-line HBV monotherapy.

Pegasys brings increased benefit to HBeAg+ patients over 48 weeks where further uptake will be driven by more detailed pharmacoeconomic analysis.

Reasons to Purchase

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

ABOUT DATAMONITOR HEALTHCARE - page 2
- About the Infectious Disease pharmaceutical analysis team - page 2
CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Scope of the analysis - page 3
- Datamonitor insight into the hepatitis B market - page 4
CHAPTER 2 PIPELINE DYNAMICS - page 16
- The future HBV market is expected to consist mainly of NRTIs, with pipeline drugs expected to dominate the market - page 16
  - Pipeline overview - page 16
  - With the launch of up to eight compounds between 2005-2013, the NRTI class dominate in the future HBV market - page 18
  - As a consequence of the immaturity of the current HBV market, new HBV drugs might dominate the market by 2006 - page 22
- New drugs lead to new players in the HBV market - page 22
CHAPTER 3 PATIENT POTENTIAL - page 24
- HBV infection leads to a complex chronic disease associated with progressive liver damage - page 24
  - Chronic hepatitis B infection silently progresses to liver cirrhosis and cancer over prolonged periods of time - page 24
    - Acute and chronic infection - page 25
    - The role of ccc HBV DNA - page 28
  - Chronic hepatitis B is a complex and highly dynamic disease consisting of different stages marked by both viral and host-specific markers - page 29
    - Active CHB versus inactive carrier state - page 30
    - HBeAg+ and HBeAg- hepatitis - page 30
    - HBV persistence prevents disease resolution - page 31
- Although the incidence of new HBV infections has been decreasing, there is a large pool of chronically infected carriers - page 31
  - The introduction of HBV vaccination has led to a significant decrease in new HBV infections - page 31
  - Screening of blood and pregnant women has also contributed to a drop in new HBV infections - page 33
  - Globally, 350-400 million people are believed to be chronically infected with HBV - page 34
    - In the West, HBV is predominantly transmitted by sexual contact - page 35
    - Patient segmentation by age and gender - page 36
    - Estimated chronic HBV patient pool in the seven major markets - page 38
- Different forms of HBV disease require tailored therapies - page 41
  - HBeAg- hepatitis B-associated with poor treatment outcomes-is increasing - page 42
    - Geographic variability - page 42
  - Long-term therapy with specific HBV antivirals is associated with the development of drug-resistant HBV strains - page 44
    - Lamivudine resistance - page 45
    - Adefovir resistance - page 45
  - Due to the prolongation of life expectancy associated with HAART therapy, HIV/HBV coinfection is becoming an increasingly important indication - page 46
- There are currently few therapeutic options and these fail to achieve sustained suppression of viral replication - page 48
  - Only two HBV polymerase inhibitors and one interferon are currently available for the treatment of CHB - page 48
- The key unmet needs in HBV therapy are the achievement of sustained virus suppression and the management of resistant viral strains - page 50
  - The low rate of HBs seroconversion and the difficulty in ccc HBV clearance preclude the achievement of a sustained antiviral response - page 51
    - Of the currently marketed drugs, only Pegasys has demonstrated significant induction of HBsAg loss and anti-HBs seroconversion in HBeAg+ patients - page 51
    - Several drug developers are now addressing the elimination of ccc HBV DNA, but, so far, little progress has been made - page 52
  - Loss of HBeAg and HBeAg seroconversion increases the chance of achieving sustained viral suppression - page 53
  - The emergence of resistant virus strains due to the long duration of therapy reduces drug efficacy - page 53
  - Summary of key unmet needs for NRTIs, currently the most active developmental drug class - page 54
CHAPTER 4 R&D APPROACH - page 55
- Current hepatitis B pipeline activity is driven manly by HBV polymerase inhibitors, raising the possibility of future combination therapy - page 55
  - 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 - page 55
  - With several polymerase inhibitors in the late-stage pipeline, the building blocks for combination therapy could soon be available - page 56
- The increasing competition of the HBV drug market demands a higher level of sophistication in clinical trial design - page 57
  - The choice of the comparator is no longer clear-cut - page 58
    - Placebo-controlled trials provide valuable data - page 58
    - In the future, entecavir might be preferred over lamivudine and adefovir as a comparator if it demonstrates a better resistance profile than adefovir - page 58
  - The complete assessment of a drug, in terms of resistance development, seroconversion rates and toxicity, requires long-term follow-up, beyond 48 weeks - page 59
    - Resistance mutation development increases with time - page 60
    - Anti-HBe and anti-HBs seroconversion are slow to develop - page 60
    - Potential drug toxicity following prolonged drug use - page 61
  - 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 - page 61
    - Both patient-specific and viral factors govern the treatment response - page 61
- Despite the variety of current endpoints currently used, virus suppression is key to demonstrating drug efficacy - page 63
  - The clinical endpoints used in CHB therapy differ between patients with compensated and those with decompensated CHB - page 66
    - Endpoints for compensated CHB - page 66
    - Endpoints for decompensated CHB - page 69
CHAPTER 5 NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS - page 70
- Most HBV polymerase inhibitors were originally being developed for HIV prior to the identification of their activity against HBV - page 70
  - Mode of action - page 70
- It is currently unclear which drug is the qualified gold standard HBV therapy - page 71
  - Lamivudine has traditionally been considered the gold standard HBV therapy - page 72
    - Zeffix's strengths and weaknesses - page 72
  - Hepsera, with its superior resistance profile, could be perceived as a challenger for the HBV gold standard - page 73
    - Hepsera's strengths and weaknesses - page 74
  - The lack of head-to-head data between lamivudine and adefovir means there is no definitive quantification of the HBV gold-standard therapy - page 75
- The NRTI pipeline is relatively active, with two drugs in Phase III and one, entecavir, recently approved in the US - page 77
  - NRTI pipeline summary - page 77
- Novel HBV polymerase inhibitors are competing in terms of higher potency and favorable resistance profiles - page 78
  - With the conclusion of several favorable trials, BMS has clinical support for Baraclude (entecavir) positioning across all lines of therapy - page 78
    - Profile - page 78
    - Key clinical trials overview - page 79
    - Datamonitor analysis - page 83
- With effective HBV suppression alone not sufficient to achieve a durable response, several pipeline drugs are addressing indicators for sustained viral suppression - page 86
  - Telbivudine achieves potent early viral suppression - page 86
    - Profile - page 86
    - Key clinical trial overview - page 87
    - Datamonitor analysis - page 89
  - Clevudine - prolonged post-treatment suppression of HBV DNA even after short treatment periods - page 91
    - Profile - page 91
    - Key clinical trial overview - page 93
    - Datamonitor analysis - page 95
- The potential for combination therapy, already a standard of care in other chronic viral diseases, is being investigated for HBV - page 97
  - Valtorcitabine has shown synergistic efficacy in combination with telbivudine - page 97
    - Profile - page 97
    - Key clinical trial overview - page 98
    - Datamonitor analysis - page 99
- Despite the availability of adefovir, lamivudine resistance is still a key unmet need being targeted by pipeline drugs - page 101
  - LB80380 (ANA380), targeting LVD-resistant patients - page 101
    - Profile - page 101
    - Key clinical trials overview - page 101
    - Datamonitor analysis - page 103
  - Remofovir, an oral prodrug of adefovir, is being developed to challenge Hepsera - page 105
    - Profile - page 105
    - Key clinical trial overview - page 105
    - Datamonitor analysis - page 106
  - Tenofovir, first choice for HIV/HBV coinfected patients despite absence of official development for HBV monoinfection - page 109
    - Widely used for HIV but also active against the HBV polymerase - page 109
    - Drug of choice for HIV/HBV coinfected patients, in particular those harboring LVD-resistant HBV variants - page 109
    - Datamonitor analysis - page 111
  - Others - page 112
    - Alamifovir - page 112
    - MIV-210 is active against LVD-resistant HBV strains in vitro - page 114
- Three late-stage developmental compounds have recently been suspended or discontinued due to poor resistance profiles - page 115
  - Emtricitabine - high rate of resistance precludes further development despite antiviral efficacy - page 116
  - Elvucitabine, Phase II clinical data awaited - page 117
  - Although active against HBV, amdoxovir is no longer being developed for this indication - page 118
    - Profile - page 118
    - In the duck HBV infection model, amdoxovir failed to demonstrate ccc DNA suppression and clearance of infected cells - page 118
- Comparative NRTI forecasts - page 119
CHAPTER 6 IMMUNOMODULATORS AND OTHERS - page 120
- The recent approval of Pegasys for the treatment of HBV might lead to a revival of interferon-based therapy - page 120
  - Pegasys requires less frequent administration than standard IFN and has equal or superior efficacy to lamivudine - page 120
    - Profile - page 120
    - Key clinical trial overview - page 121
- With Pegasys setting a high benchmark, the entry barrier for immunomodulators is high, leading to very few companies developing compounds in this class - page 125
  - Immunomodulator and others pipeline summary - page 126
- The adverse events associated with IFN therapy have instigated the search for alternative immunomodulators with better tolerability profiles - page 127
  - 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 - page 127
    - Profile - page 127
    - Key clinical trial overview - page 129
    - Datamonitor analysis - page 130
- The increase of liver transplant patients chronically infected with HBV has created a market for products that prevent HBV reinfection post transplant - page 132
  - HepeX-B (XTL-001) is undergoing Phase IIb trials for HBV-associated liver transplant patients - page 132
    - Profile - page 132
    - Key clinical trial overview - page 133
    - Datamonitor analysis - page 133
  - Other immunomodulators - page 135
    - EHT899 is an oral viral protein with both immune suppressing and enhancing activity - page 135
    - SpecifEx-HepB, antigen-specific T cell transfer - page 137
  - Other developmental drugs - page 138
    - NOV-205 (BAM-205) - page 138
- Comparative class forecasts - page 138
CHAPTER 7 OPINION LEADER TRANSCRIPTS - page 139
- Discussion guide - page 139
  - Section 1 - Unmet needs - page 139
  - Section 2 - Clinical trial design - page 140
  - Section 3 - Developmental drug profiles and assessment - page 141
  - Section 4 - Future of HBV therapy - page 145
- Key opinion leader 1 - page 146
  - Section 1 - Unmet needs - page 146
  - Section 2 - Clinical trial design - page 147
  - Section 3 - Developmental drug profiles and assessment - page 151
  - Section 4 - Future of HBV therapy - page 157
- Key opinion leader 2 - page 160
  - Section 1 - Unmet needs - page 160
  - Section 2 - Clinical trial design - page 161
  - Section 3 - Developmental drug profiles and assessment - page 165
  - Section 4 - Future of HBV therapy - page 174
- Key opinion leader 3 - page 177
  - Section 1 - Unmet needs - page 177
  - Section 2 - Clinical trial design - page 177
  - Section 3 - Developmental drug profiles and assessment - page 179
  - Section 4 - Future of HBV therapy - page 183
- Key opinion leader 4 - page 184
  - Section 1 - Unmet needs - page 184
  - Section 2 - Clinical trial design - page 185
  - Section 3 - Developmental drug profiles and assessment - page 187
  - Section 4 - Future of HBV therapy - page 194
APPENDIX A - page 196
- Bibliography - page 196
  - Epidemiology - page 196
  - Journal articles - page 196
  - Conference abstracts - page 200
  - Useful websites - page 204
  - PowerPoint Presentations - page 204
  - Press releases - page 204
  - Datamonitor reports - page 206
  - Miscellaneous - page 206
- Report methodology - page 207
APPENDIX B - page 208
- About Datamonitor - page 208
  - About Datamonitor Healthcare - page 208
- Datamonitor Healthcare's therapy area capabilities - page 209
  - About the Infectious Disease analysis team - page 210
  - Disclaimer - page 211

List of Tables
Table 1: HBV pipeline overview - page 17
Table 2: Total HBV market sales forecasts, 2005-2015, US, EU and Pacific Rim - page 21
Table 3: Geographical distribution of HBV genotypes - page 25
Table 4: Forms of chronic hepatitis B according to serologic, biochemical and histological markers - page 29
Table 5: Deaths caused by hepatitis B infection worldwide, by geographical area, 2002 - page 35
Table 6: HBV prevalence and total patient population in the seven major markets, 2004 - page 38
Table 7: Treatment response to currently approved regimens for HBeAg+ versus HBeAg- patients - page 43
Table 8: Most common patterns of LVD-resistance mutations - page 45
Table 9: HIV monoinfected and HIV/HBV coinfected populations in the seven major markets, 2003 - page 47
Table 10: Approved drug classes for HBV treatment - page 49
Table 11: Endpoints for clinical trials involving CHB patients with compensated liver disease - page 65
Table 12: Approved drugs for the treatment of chronic HBV infection - page 70
Table 13: Zeffix: key facts - page 72
Table 14: Hepsera: key facts - page 74
Table 15: Lamivudine versus adefovir: comparison of key performance attributes - page 76
Table 16: HBV polymerase inhibitors (nucleoside and nucleotide reverse transcriptase inhibitors) in clinical development - page 77
Table 17: Clevudine's developmental history - page 92
Table 18: In vitro, LB80380 is active against common LVD-resistant strains, similar to ADV - page 102
Table 19: Discontinued late-stage HBV polymerase inhibitors - page 116
Table 20: Phase III clinical trial summary for Pegasys - page 123
Table 21: HBV immunomodulators in clinical development - page 126
Table 22: Zadaxin's ranking with respect to the ability to achieve anti-HBe seroconversion - page 128
Table 23: Zadaxin has a delayed onset of efficacy - page 129
Table 24: Zadaxin + IFN combination therapy is more effective than placebo - page 130
Table 25: EHT-899 demonstrated antiviral activity in a Phase II clinical trial conducted in Israel - page 136

List of Figures
Figure 1: HBV pipeline, by phase of clinical development and drug class - page 18
Figure 2: Estimated launch dates for developmental HBV drugs - page 19
Figure 3: HBV market sales forecasts by class, 2005-2015, US, EU and Pacific Rim - page 20
Figure 4: Anticipated long-term impact of novel HBV products on marketed HBV products - page 22
Figure 5: HBV disease progression - page 27
Figure 6: Outcome of hepatitis B virus infection by age at the time of infection - page 28
Figure 7: Stages of HBV disease remission - page 31
Figure 8: Geographic distribution of HBV immunization policies, 1996 and 2001 - page 32
Figure 9: The incidence of acute hepatitis in the US has declined steadily between 1990-2002, in particular in children and adolescents - page 33
Figure 10: Geographic distribution of HBV prevalence - page 34
Figure 11: Reported cases of HBV in England and Wales, 1993 and 2003 - page 36
Figure 12: Reported HBV incidence in England and Wales, 1993 and 2003 - page 37
Figure 13: Diagnosed HBV patient population, seven major markets, 2004 - page 39
Figure 14: Out of the diagnosed HBV patient population, only an average of 53% receive pharmacological treatment, seven major markets, 2004 - page 39
Figure 15: Key HBV patient populations - page 41
Figure 16: The prevalence of HBeAg- CHB varies geographically and is related to the infecting HBV genotype - page 43
Figure 17: Proportion of CHB patients receiving each line of therapy in the seven major markets - page 46
Figure 18: The development of drug resistance counteracts the antiviral immune response in the achievement of a sustained antiviral response - page 50
Figure 19: While a few unmet needs in HBV therapy have been satisfied, most are either partially or unsatisfactorily achieved - page 54
Figure 20: Compensated versus decompensated CHB-associated liver disease - page 63
Figure 21: Goals and markers of CHB therapy are the basis for clinical trial endpoints - page 64
Figure 22: Zeffix's strengths and weaknesses - page 73
Figure 23: Hepsera's strengths and weaknesses - page 75
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 - page 79
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 - page 80
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 - page 81
Figure 27: Entecavir sales forecasts, 2005-15 - page 86
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 - page 88
Figure 29: Telbivudine sales forecasts, 2005-15 - page 91
Figure 30: In a Phase II, multicenter, dose-escalation study, CLV for only four weeks achieved lasting viral suppression and unprecedented loss of HBeAg - page 94
Figure 31: Clevudine sales forecasts, 2005-15 - page 96
Figure 32: Following a Phase I/II, randomized, dose-escalation study, valtorcitabine was not considered potent enough to be developed as monotherapy - page 98
Figure 33: Valtorcitabine sales forecasts, 2005-15 - page 100
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 - page 102
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 - page 103
Figure 36: LB80380 sales forecasts, 2005-15 - page 104
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 - page 106
Figure 38: Design of the Phase II head-to-head trial of remofovir mesylate against adefovir dipivoxil - page 107
Figure 39: Remofovir's sales forecasts, 2005-15 - page 108
Figure 40: TFV is significantly more potent than ADV in HBV suppression in HIV/HBV coinfected patients with LVD-resistant HBV variants - page 110
Figure 41: Addition of TFV to LVD in LVD-resistant patients greatly enhances the antiviral response - page 111
Figure 42: Alamifovir sales forecasts, 2005-15 - page 113
Figure 43: MIV-210 sales forecasts, 2005-15 - page 115
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 - page 117
Figure 45: NRTI comparative sales forecasts, 2005-2013 - page 119
Figure 46: Pegasys sales forecasts, 2005-15 - page 125
Figure 47: Zadaxin sales forecasts, 2005-15 - page 132
Figure 48: HepeX-B sales forecasts, 2005-15 - page 135
Figure 49: EHT899 sales forecasts, 2005-15 - page 137
Figure 50: Immunomodulators comparative sales forecasts, 2005-2013 - page 138

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Pipeline Insight: Hepatitis B

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