Stakeholder Opinions Hepatitis C Smallmolecule antivirals pave the way for triple therapy

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the Hepatitis C market 3
CHAPTER 2 DISEASE BACKGROUND AND CURRENT TREATMENT 7
HCV virology 7
Chronic HCV infection silently progresses to liver cirrhosis and cancer over prolonged periods of time 8
Interferon and ribavirin are the standard treatment for HCV 10
The current standard of care therapy - Peg-IFN alfa plus ribavirin - has a suboptimal tolerability and efficacy profile 11
Depending on their response to standard therapy, patients can be divided in different groups 12
Key unmet needs include HCV genotype 1 infection, non-response to current therapy and improved drug tolerability 15
CHAPTER 3 PATIENT POTENTIAL 18
HCV is a major health concern with 180 million people infected globally 18
Intravenous drug users and people who received blood transfusions before 1990 are at highest risk of infection 20
The number of CHC patients seeking treatment is expected to peak within the next 10-20 years 22
Across the 7MM, immigration from high prevalence countries influences overall prevalence rates for HCV 22
HCV genotype 1, which is particularly hard to treat, accounts for the majority of infections in the 7MM 23
The prevalence of genotypes varies by country 23
Whereas SVR rates are high for genotypes 2 and 3, genotypes 1 and 4 are much harder to treat 25
Patients with an African background show poorer treatment outcomes if they suffer from genotype 1 25
The treatment of HIV/HCV co-infected patients is particularly challenging 26
There are few treatment options for the large population of non-responders and relapsers 28
The high incidence of post-transplant HCV re-infection has created an important niche market 32
CHAPTER 4 R&D APPROACH 33
Of the drug classes are in development for HCV, small molecule antivirals show best prospects 33
Multiple different drug classes are being developed for use in HCV 33
'Add-on' therapy to current standard treatment is the most promising approach in HCV drug development 36
Developmental drug strategies 38
Due to the late characterization of the hepatitis C virus, drug development has been slow 41
Future HCV therapy is likely to involve combinations of at least three drugs 42
Current clinical trials focus on achieving higher SVR rates in genotype-1 patients and non-responders 43
In late-stage trials, comparison with peginterferon/ribavirin is a must for new drug candidates 44
Trials are mostly conducted in genotype-1 patients 45
The achievement of a sustained virological response (SVR) is the key endpoint in both HCV clinical trials and therapy 45
CHAPTER 5 INTERFERONS 48
Interferons have a non-specific, broad antiviral activity 48
The mechanism of Interferon alfa against HCV infection has not been elucidated 48
Standard interferons were first in class but have poor efficacy as monotherapy 48
Pegylated interferons in combination with ribavirin have become established as standard therapy 49
Pipeline efforts concentrate on long-acting formulations of interferon alfa with better tolerability 49
Pipeline summary 50
Albuferon (Human Genome Sciences/Novartis) - threatening the leading position of the peginterferons 52
Profile 52
Key clinical trials 52
Datamonitor analysis 58
IFNalpha-2b XL (Flamel Technologies) - more results needed to confirm positive top-line data 59
Profile 59
Key clinical trials 60
Datamonitor analysis 61
Locteron (OctoPlus/Biolex Therapeutics) - high EVR rates and good safety profile raise high hopes 61
Profile 61
Key clinical trials 61
Datamonitor analysis 63
Omega Interferon (Intarcia) - potential only lies in sustained release formulation 63
CHAPTER 6 SMALL MOLECULE ANTIVIRALS 64
Due to the insufficient efficacy of current HCV therapy, targeted antivirals are a popular approach for new HCV therapies 64
Pipeline summary 65
HCV NS5B polymerase inhibitors - R-1626 leading the way following late-stage pipeline failures 67
Rationale for HCV NS5B polymerase inhibitors 67
Inhibition of the NS5B polymerase specifically blocks HCV replication at an early stage 67
Nucleoside and non-nucleoside inhibitors block polymerase activity by different mechanisms 67
Pipeline overview 68
R-1626 (Roche) - positive interim Phase II results sparking high hopes 70
Profile 70
Key clinical trials 70
Datamonitor analysis 73
Other HCV polymerase inhibitors - Gilead and Roche are benefiting from Novartis's and Wyeth's trial failures 74
GS-9190 (Gilead) - Phase I trial demonstrates antiviral activity and good pharmacokinetics 74
R-7128 (Roche/Pharmasset) - trials evaluating combination with standard therapy in progress following positive Phase I results 75
NS3/4A protease inhibitors - Telaprevir facing challenges 76
Rationale for HCV NS3/4A protease inhibitors 76
The NS3 protease is essential for viral replication 76
The HCV protease as a drug target: ideal in theory, difficult in practice 77
Combination therapy with pegylated interferons and/or other antivirals will be the preferred regimen for protease inhibitors to control resistances 77
Pipeline overview 78
VX-950 (telaprevir; Vertex) - handicapped by dosing and resistances 80
Profile 80
Key clinical trial overview 80
Datamonitor analysis 84
SCH 503034 (boceprevir; Schering-Plough) - emerging as competitor for VX-950 87
Product overview 87
Key clinical trial overview 87
Datamonitor analysis 91
Other HCV protease inhibitors - two promising newcomers in Phase I 92
TMC435350 (Medivir/Johnson & Johnson) 92
ITMN-191 (Roche/InterMune) 92
Other small molecule antivirals - uncertain future for taribavirin 93
Pipeline overview 93
Taribavirin (Viramidine; Valeant Pharmaceuticals) - Phase IIb results will determine fate of the drug following VISER-1 and VISER-2 failures 94
Profile 94
Key clinical trials 94
Datamonitor assessment 98
KPE02003002 (Kemin Pharma) - no updates since 2004 99
CHAPTER 7 IMMUNOMODULATORS (NON-INTERFERON) 101
Immunomodulators are mostly developed as add-ons to existing therapy, using HCV as a secondary indication 101
Pipeline summary 102
Product profiles - best outlook for civacir 104
Zadaxin (SciClone) 104
Civacir (Nabi Biopharmaceuticals/Kedrion) 104
IM-862 (Implicit Bioscience) 105
IPH 1101 (Innate Pharma) 105
KRN-7000 (Kirin) 105
SCV-07 105
Therapeutic vaccines - a long way to go 106
IC-41 (Intercell AG) - more long-term data needed 107
Profile 107
Key clinical trial overview 108
Datamonitor analysis 110
HCV vaccine (Novartis/CSL) - no progress reported since 2004 111
CHAPTER 8 HOST ENZYME INHIBITORS 112
The main role for host-enzyme inhibitors will be as add-on to standard therapy rather than as monotherapy 112
Pipeline summary 112
Product profiles - Most candidates are still in early stages 114
Celgosivir (Migenix) 114
Profile 114
Key clinical trials 114
Datamonitor assessment 116
NIM-811 (Novartis) 117
Debio-025 (Debiopharm) 117
VGX-410C (mifepristone; VGX Pharmaceuticals) 118
Alinia (nitazoxanide; Romark Laboratories) 118
APPENDIX A 119
Bibliography 119
Report methodology 131
APPENDIX B 133
About Datamonitor 133
About Datamonitor Healthcare 133
Datamonitor Healthcare's therapy area capabilities 134
About the Infectious Diseases analysis team 135
Key therapy team members 136
Holger Rovini, Head of Respiratory and Infectious Diseases 136
Hedwig Kresse, Analyst, Infectious Diseases 136
Disclaimer 136
List of Tables
Table 1: Interferons and ribavirin are the only marketed HCV antivirals, 2007 10
Table 2: HIV mono-infected and HIV/HCV co-infected populations, 7MM, 2007 27
Table 3: Key trials for therapy in nonresponders to previous treatment with peginterferon / ribavirin 30
Table 4: Mode of action of developmental immunomodulators (non-IFN), 2007 33
Table 5: Mode of action of developmental interferons, 2007 34
Table 6: Mode of action of developmental small molecule antivirals, 2007 34
Table 7: Mode of action of developmental host enzyme inhibitors, 2007 35
Table 8: Key endpoints used in clinical trial design for HCV 47
Table 9: HCV pipeline overview - late-stage interferons, 2007 51
Table 10: Albuferon - ACHIEVE 1 trial design 53
Table 11: Albuferon - ACHIEVE 2/3 trial design 54
Table 12: Albuferon - Phase IIb (treatment-naïve) trial design and results 56
Table 13: Albuferon - Phase II (nonresponder) trial design and results 58
Table 14: Locteron - Phase IIa clinical trial design and results 62
Table 15: HCV pipeline overview -- late-stage small molecule antivirals, 2007 66
Table 16: HCV pipeline overview - NS5B polymerase inhibitors, 2007 69
Table 17: R-1626 - Phase IIa clinical trial overview and interim results 71
Table 18: R-1626 - Phase IIb clinical trial overview and interim results 72
Table 19: HCV pipeline overview - NS3/4A protease inhibitors, 2007 79
Table 20: Telaprevir -PROVE 1 study design and interim results 81
Table 21: Telaprevir - PROVE 2 study design and interim results 83
Table 22: Telaprevir - PROVE 3 study design 84
Table 23: Boceprevir - SPRINT-1 study design and preliminary results 89
Table 24: Boceprevir - Phase II study design and preliminary results 91
Table 25: HCV pipeline overview - late-stage other antivirals, 2007 93
Table 26: Taribavirin - VISER-1 Phase III study design and results 95
Table 27: Taribavirin - VISER-2 Phase III study design and results 97
Table 28: Taribavirin - Phase IIb trial design 98
Table 29: HCV pipeline overview - immunomodulators (non-IFN), 2007 103
Table 30: HCV pipeline - late-stage therapeutic vaccines, 2007 107
Table 31: IC-41 - Phase II monotherapy trial overview and interim results 108
Table 32: IC-41 - Phase II combination trial overview and interim results 110
Table 33: HCV pipeline - late-stage host enzyme inhibitors, 2007 113
Table 34: Celgosivir - Phase II combination trial design and results 115
List of Figures
Figure 1: HCV - genome organisation 8
Figure 2: HCV - course of disease 9
Figure 3: Efficacy of Pegasys + Copegus by HCV genotype 11
Figure 4: HCV - patient classification by response to treatment 14
Figure 5: HCV - key unmet needs 15
Figure 6: HCV diagnosis, 7MM, 2004 17
Figure 7: HCV - global disease prevalence and infection numbers 18
Figure 8: HCV prevalence and potential patient population across the 7MM, 2007 19
Figure 9: Sources of infection for HCV patients; US, 2006 21
Figure 10: HCV genotype split by country; Europe, US and Japan, 2007 25
Figure 11: Late-stage HCV drug pipeline (Phase II and III) by class, December 2007 36
Figure 12: Strategies for HCV drug development 37
Figure 13: The HCV NS3-encoded serine protease cleaves the non-structural HCV proteins 76