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