Pipeline Insight: Hepatitis C - Protease inhibitors to drive market expansion
Scope
Report Highlights
Reasons to Purchase
Table of Contents
- ABOUT DATAMONITOR HEALTHCARE - page 2
- About the Infectious Diseases & Respiratory pharmaceutical analysis team - page 2
- CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Scope of the analysis - page 3
- Contributing experts - page 4
- Datamonitor insight into the HCV market - page 5
- The HCV market is expected to grow from $2.2 billion in 2005 to $4.4 billion in 2010 and $8.8 billion in 2015. Growth will be driven mainly by the rapid uptake of new drugs and potentially the use of multiple drugs in the same treatment regime, the premium pricing these will be able to command and the increase in the number of patients seeking treatment - page 5
- Vertex' protease inhibitor VX-950, the most potent drug in the late-stage HCV pipeline, is anticipated to be the key growth driver, overshadowing Schering-Plough's protease inhibitor SCH-503034 and Idenix/Novartis's polymerase inhibitor NM283. VX-950's success will be conditional on the drug confirming superior efficacy rates and favorable long-term toxicity - page 6
- HCV trial design is becoming increasingly complex. The heterogeneity of the overall patient pool requires stratification by treatment status, HCV genotype and comorbidities. The exploration of multidrug therapy, weight-based dosing and ideal treatment duration has increased overall trial sizes. Current therapy trial design reflects uncertainty about the future face of HCV therapy - page 7
- With only half of all HCV patients benefiting from current therapy, medical unmet needs are high. Higher efficacy with regard to the ability to achieve SVR remains the key, followed by better tolerability. SVR rates are particularly low in difficult-to-treat patients - page 8
- Key metrics - page 9
- CHAPTER 2 HCV PIPELINE ANALYSIS - page 23
- Pipeline overview - page 23
- Small molecule antivirals dominate the HCV pipeline - page 23
- The HCV pipeline contains drugs with various mechanisms of action - page 25
- Double-digit growth driven by the launch of potent HCV inhibitors will lead to a doubling of the HCV market by 2010 - page 30
- Small molecule antivirals dominate the HCV pipeline - page 23
- Key companies involved in the HCV pipeline - page 32
- Established players are losing market share to newcomers - page 32
- Roche - Pegasys still growing strong - page 33
- Schering-Plough - SCH-503034 to fill the gap - page 36
- Vertex - expanding the market with VX-950 - page 38
- Novartis - building a broad arsenal of antivirals - page 39
- Pipeline overview - page 23
- CHAPTER 3 PATIENT POTENTIAL - page 41
- Hepatitis C disease definition and progression - page 41
- HCV genotype 1 currently accounts for the majority of chronic infections - page 42
- Genotype frequency: new infections may not mirror the current chronic patient pool - page 43
- While past HCV transmission occurred mainly through contaminated blood products, most new infections currently occur via injection drug use - page 45
- HCV readily establishes a chronic infection that can progress to liver cirrhosis and cancer - page 46
- As a result of the silent nature of chronic HCV, patients are usually diagnosed at advanced stages of liver fibrosis - page 48
- The number of patients presenting with HCV-related complications is set to rise - page 50
- HCV genotype 1 currently accounts for the majority of chronic infections - page 42
- HCV epidemiology and patient segmentation - page 52
- Chronic HCV is widespread on a global basis, with prevalence varying significantly by geographical region - page 52
- Estimates for chronic HCV prevalence in the seven major markets - page 53
- Chronic HCV is more prevalent among men, in older age groups, and individuals of African origin - page 58
- Significantly higher rates of HCV prevalence are found in IDUs, HIV patients, and individuals receiving renal replacement therapy - page 60
- Patient segmentation takes into account both patient and virus-specific factors - page 62
- Drug development focuses on HCV genotype 1 - page 62
- Nonresponders and relapsers currently left without treatment options - page 63
- HCV/HIV co-infection - a notoriously difficult-to-treat patient subgroup - page 64
- Recurrent HCV post-transplant - current treatment options suffer from major limitations - page 67
- Chronic HCV is widespread on a global basis, with prevalence varying significantly by geographical region - page 52
- The HCV market is characterized by high unmet need - page 68
- Higher efficacy remains the most important product-specific unmet need - page 68
- Higher efficacy, in particular in HCV genotype 1 - page 69
- Better tolerability - page 70
- Shorter treatment duration - page 72
- Less frequent dosing - page 73
- Other product-specific unmet needs - page 74
- Patient-specific unmet needs - page 74
- Diagnosis and treatment rates are currently low, but are expected to increase concomitant with market entry of new drugs - page 74
- Certain population subgroups achieve moderate or limited success with current treatment options - page 77
- Higher efficacy remains the most important product-specific unmet need - page 68
- Hepatitis C disease definition and progression - page 41
- CHAPTER 4 R&D APPROACH - page 80
- Effective treatment of chronic HCV requires combination therapy - page 80
- From interferon monotherapy to pegylated interferon plus ribavirin combination therapy - page 81
- Moderate success with interferon monotherapy - page 81
- Breakthrough with ribavirin - page 83
- Pegylation of the interferon molecule reduces dosing frequency while increasing efficacy - page 84
- Pegylated interferon plus ribavirin combination therapy is the current standard of care - page 85
- Both pegylated interferon and ribavirin have broad mechanisms of action - page 85
- Little differentiation between the two available combination therapies - page 86
- The future of Peg-IFN-based therapy lies in tailoring therapy to the patient - page 88
- From interferon monotherapy to pegylated interferon plus ribavirin combination therapy - page 81
- HCV pipeline drugs fall into five major drug classes - page 91
- Small molecule antivirals directly inhibit key steps in the viral lifecycle - page 92
- NS3 protease inhibitors are the most promising drug class - page 93
- NS5B polymerase inhibitors are less potent than the protease inhibitors but might have an important role as part of multidrug therapy - page 95
- Other direct HCV inhibitors - page 95
- Interferons act by inducing a local and systemic immune response - page 96
- Interferons with reduced dosing frequency may lower the incidence of side effects - page 97
- Immunomodulators - page 97
- Will Toll-Like Receptor (TLR) agonists live up to the expectations? - page 98
- Other immunomodulators - page 99
- Therapeutic vaccines have been difficult to develop - page 99
- Small molecule antivirals directly inhibit key steps in the viral lifecycle - page 92
- Clinical trial design in HCV is becoming increasingly complex - page 101
- Patient stratification according to genotype and treatment experience is a must - page 103
- Further levels of patient stratification require ever larger studies - page 104
- Moving toward multidrug therapy - page 105
- Patient stratification according to genotype and treatment experience is a must - page 103
- Clinical trial endpoints in HCV focus on antiviral efficacy - page 107
- Virologic response is the key measure of antiviral efficacy - page 108
- RVR, EVR, ETR and the all-important SVR - page 108
- Viramidine trials have included the incidence of anemia as a co-primary endpoint - page 110
- Study endpoints other than virologic response rates will become increasingly important - page 110
- Virologic response is the key measure of antiviral efficacy - page 108
- Effective treatment of chronic HCV requires combination therapy - page 80
- CHAPTER 5 INTERFERONS LATE-STAGE DRUG ANALYSIS - page 112
- Overview for interferons in late-stage development for HCV - page 112
- Pipeline summary - page 112
- Definition of current comparator therapy - page 113
- Pegylated interferon has limited efficacy in HCV genotype 1 and is associated with adverse events - page 113
- Long acting interferons - page 114
- Albuferon - albumin fusion to interferon reduces dosing frequency - page 114
- Drug overview - page 114
- Key clinical trial data - page 116
- Patient potential - page 119
- Marketing factors - page 120
- Datamonitor comments - page 120
- Forecast to 2015 - page 121
- Omega interferon & Omega DUROS - page 123
- Drug overview - page 123
- Key clinical trial data - page 124
- Datamonitor comments - page 125
- Albuferon - albumin fusion to interferon reduces dosing frequency - page 114
- Overview for interferons in late-stage development for HCV - page 112
- CHAPTER 6 SMALL MOLECULE ANTIVIRALS LATE-STAGE DRUG ANALYSIS - page 126
- Overview for small molecule antivirals in late-stage development for HCV - page 126
- Pipeline summary - page 126
- Definition of current comparator therapy - page 127
- RBV has limited antiviral efficacy and causes hemolytic anemia - page 127
- IMPDH inhibitors - page 129
- Viramidine - less toxic than RBV, but doubts regarding non-inferiority still prevail - page 129
- Drug overview - page 129
- Key clinical trial data - page 130
- Patient potential - page 135
- Marketing factors - page 136
- Datamonitor comments - page 137
- Forecasts to 2015 - page 139
- Viramidine - less toxic than RBV, but doubts regarding non-inferiority still prevail - page 129
- NS5B RNA-dependent RNA polymerase inhibitors - page 140
- Valopicitabine (NM-283) - commercial success relies on combination therapy with protease inhibitors - page 140
- Drug overview - page 140
- Key clinical trial data - page 142
- Patient potential - page 146
- Marketing factors - page 146
- Datamonitor comments - page 146
- Forecasts to 2015 - page 148
- Valopicitabine (NM-283) - commercial success relies on combination therapy with protease inhibitors - page 140
- NS3 protease inhibitors - page 149
- VX-950 - unprecedented high potency and potential for shorter treatment duration - page 149
- Drug overview - page 149
- Key clinical trial data - page 151
- Pharmacokinetic boosting with ritonavir may improve dosing - page 157
- Patient potential - page 157
- Marketing factors - page 158
- Datamonitor comments - page 158
- Forecasts to 2015 - page 162
- SCH-503034 - overshadowed by VX-950? - page 163
- Drug overview - page 163
- Key clinical trial data - page 165
- Patient potential - page 167
- Marketing factors - page 168
- Datamonitor comments - page 168
- Forecasts to 2015 - page 169
- VX-950 - unprecedented high potency and potential for shorter treatment duration - page 149
- Other small molecule antivirals - page 170
- Celgosivir (MX-3253) - antiviral effect through inhibition of a cellular enzyme - page 170
- Drug overview - page 170
- Key clinical trial data - page 172
- Patient potential - page 174
- Marketing factors - page 174
- Datamonitor comments - page 174
- Forecasts to 2015 - page 175
- Celgosivir (MX-3253) - antiviral effect through inhibition of a cellular enzyme - page 170
- Comparison of small molecule antivirals in late-stage development - page 176
- Late-stage developmental compounds recently discontinued - page 177
- Merimepodib (VX-497) - development post-METRO unlikely - page 178
- UT-231B - page 179
- JTK-003 - page 180
- HCV-086 - page 180
- Ciluprevir (BILN-2061) - page 181
- Unexpected toxicity in animals - page 181
- R803 - page 182
- Levovirin - page 183
- Overview for small molecule antivirals in late-stage development for HCV - page 126
- CHAPTER 7 IMMUNOMODULATORS LATE-STAGE DRUG ANALYSIS - page 184
- Overview for immunomodulators in late-stage development for HCV - page 184
- Pipeline summary - page 184
- Definition of current comparator therapy - page 185
- Toll-like receptor agonists - page 185
- CpG 10101 (Actilon) - a TLR9 agonist with a dual mode of action - page 185
- Drug overview - page 185
- Key clinical trial data - page 187
- Patient potential - page 188
- Marketing factors - page 188
- Datamonitor comments - page 189
- Forecasts to 2015 - page 190
- CpG 10101 (Actilon) - a TLR9 agonist with a dual mode of action - page 185
- Late-stage developmental compounds recently discontinued - page 191
- Histamine dihydrochloride (Ceplene) - page 191
- FK778 - page 192
- Overview for immunomodulators in late-stage development for HCV - page 184
- CHAPTER 8 DEVELOPMENTAL HCV THERAPEUTICS EXCLUDED FROM THE FORECAST - page 193
- Developmental HCV drugs in Phase I - page 193
- ANA-975 - Anadys's TLR7 agonist - page 194
- R1626 - Roche's polymerase inhibitor - page 194
- HCV-796 - ViroPharma's polymerase inhibitor - page 195
- XTL-2125 - XTL's polymerase inhibitor - page 196
- GS-9132 (ACH-806) - Achillion's & Gilead's protease inhibitor - page 197
- Developmental HCV therapeutics excluded for other reasons - page 197
- Therapeutic vaccines - page 197
- INNO101 (InnoVac-C, HCV-E1 vaccine) - page 198
- IC-41 - page 199
- Novartis's HCV vaccines - page 199
- Drugs in development for recurrent HCV post-transplant and HCV-related liver disease - page 200
- IDN-6556 - page 200
- Civacir - page 201
- XTL-6865 (XTL-002) - page 201
- Drugs with uncertain commercial potential - page 202
- Interferon beta - page 202
- Zadaxin - page 203
- IFN alfa-2b XL - page 206
- Peg-IFN alfacon-1 (consensus IFN) - page 206
- Virostat - page 206
- EMZ-702 - page 208
- AVI-4065 - page 209
- EHC-18 - page 211
- Therapeutic vaccines - page 197
- Developmental HCV drugs in Phase I - page 193
- APPENDIX - page 212
- Methodology & bibliography - page 212
- Forecasting methodology - page 212
- Chronic HCV prevalence - page 212
- HCV treatment rates - page 212
- Product penetration rates - page 213
- Product pricing - page 214
- Pricing of marketed drugs - page 214
- Average duration of HCV therapy - page 214
- Summary of HCV epidemiology forecast - page 215
- Estimation of product launch dates - page 215
- Estimation of pegylated and standard interferon sales accounted for by chronic HCV - page 216
- Developmental product patent expiry dates - page 217
- Report methodology - page 218
- Bibliography - page 218
- Journals - page 218
- Conference abstracts - page 223
- Press releases - page 225
- Datamonitor products - page 228
- Miscellaneous - page 228
- Websites - page 229
- Forecasting methodology - page 212
- About Datamonitor - page 229
- About Datamonitor Healthcare - page 229
- Datamonitor Healthcare's therapy area capabilities - page 230
- About the Infectious Diseases & Respiratory analysis team - page 231
- Disclaimer - page 232
- Methodology & bibliography - page 212
- List of Tables
- Table 1: HCV pipeline overview - page 26
- Table 2: Commercially attractive late-stage developmental HCV drugs included in the sales forecast - page 28
- Table 3: HCV drug sales by class, 2005-2015 - page 31
- Table 4: Geographical distribution of HCV genotypes - page 42
- Table 5: Adjusted prevalence of HCV RNA positive individuals in the seven major markets, 2006 - page 54
- Table 6: HIV/HCV co-infection in the seven major markets - page 61
- Table 7: The efficacy of the current standard of care is genotype-dependent, being lowest for HCV genotypes 1 and 4 - page 83
- Table 8: Dosing schedule for Peg-Intron and Rebetol combination therapy - page 87
- Table 9: Dosing schedule for Pegasys and Copegus combination therapy - page 87
- Table 10: Patients who achieve RVR and EVR are more likely to achieve SVR - page 110
- Table 11: Key late-stage interferons - page 112
- Table 12: The median half-life of Albuferon is significantly higher than that of both Pegasys and PEG-Intron - page 115
- Table 13: Albuferon: key facts - page 116
- Table 14: 48-week and 24-week results for US Albuferon combination trial in nonresponders show dose-dependent antiviral activity - page 118
- Table 15: 12-week results for the Phase II Albuferon combination trial in HCV genotype 1 treatment-naïve patients - page 119
- Table 16: Global sales forecast for Albuferon, 2010-2015 - page 123
- Table 17: Omega DUROS: key facts, 2006 - page 124
- Table 18: EVR data for Phase II trial of Omega IFN in combination with RBV, November 2005 - page 125
- Table 19: Key late-stage small molecule antivirals, 2006 - page 127
- Table 20: Viramidine: key facts,2006 - page 130
- Table 21: Efficacy results for VISER 1 - page 132
- Table 22: Stratification of patients supports weight-based viramidine dosing - page 132
- Table 23: The accumulation of viramidine in plasma and red blood cells (RBCs) is lower than that of RBV - page 135
- Table 24: Global sales forecast for viramidine, 2009-2015 - page 140
- Table 25: Valopicitabine (NM283): key facts, 2006 - page 142
- Table 26: Partial 24-week data for the NM283 Phase IIb trial in HCV genotype 1 nonresponders - page 143
- Table 27: Following the incidence of dose-dependent GI effects, the maximum dose for HCV genotype 1 nonresponders was reduced to 400mg from the original 800mg - page 144
- Table 28: Partial 4-week results for the Phase IIb NM283 trial in treatment-naïve HCV genotype 1 infected patients - page 145
- Table 29: Global sales forecast for NM283, 2009-2015 - page 149
- Table 30: VX-950: key facts, 2006 - page 151
- Table 31: Preliminary 4-week results of VX-950's triple combination Phase II study in treatment-naïve, genotype-1 infected HCV patients - page 155
- Table 32: Results of the US Phase Ib trial in HCV nonresponders - page 156
- Table 33: Global sales forecast for VX-950, 2009-2015 - page 163
- Table 34: SCH-503034: key facts, 2006 - page 165
- Table 35: Phase I open-label combination study results - page 167
- Table 36: Global sales forecast for SCH-503034, 2009-2015 - page 170
- Table 37: Celgosivir: key facts, 2006 - page 172
- Table 38: Global sales forecast for celgosivir, 2009-2015 - page 176
- Table 39: Comparative global sales forecasts for small molecule antivirals, 2009-2015 - page 177
- Table 40: Recently discontinued small molecule HCV antivirals - page 178
- Table 41: UT-231B Phase II clinical trial design - page 180
- Table 42: Key late-stage immunomodulators, 2006 - page 184
- Table 43: CpG 10101: key facts - page 186
- Table 44: 12-week data of a CpG 10101 Phase Ib trial suggest that triple combination therapy together with Peg-IFN and RBV is the most effective treatment strategy - page 188
- Table 45: Global sales forecast for CpG 10101, 2009-2015 - page 191
- Table 46: Recently discontinued small molecule HCV antivirals - page 191
- Table 47: Developmental HCV drugs in Phase I, June 2006 - page 193
- Table 48: Therapeutic vaccines in development for the treatment of chronic HCV, 2006 - page 198
- Table 49: Drugs in development for the prevention of HCV re-infection post-transplant and HCV-related liver disease, 2006 - page 200
- Table 50: Developmental HCV drugs with uncertain commercial potential, 2006 - page 202
- Table 51: Zadaxin: key facts - page 204
- Table 52: Virostat: key facts - page 207
- Table 53: AVI-4065: key facts - page 210
- Table 54: Treatment rates in the seven major markets - page 213
- Table 55: Estimations of price premiums - page 214
- Table 56: Forecast for viramidine in the US, 2009-2015 - page 215
- Table 57: Average clinical development times for developmental HCV drugs - page 216
- Table 58: US patent expiry dates for HCV pipeline drugs - page 217
- List of Figures
- Figure 1: The global HCV market, 2002-2015 - page 9
- Figure 2: HCV market share by company, 2005, 2010 and 2015 - page 10
- Figure 3: Key unmet needs in HCV - page 10
- Figure 4: Performance of key late-stage developmental drugs against key unmet needs - page 11
- Figure 5: The number of possible combinations for commercially attractive developmental drug classes are numerous - page 11
- Figure 6: Small molecule antivirals dominate the HCV pipeline - page 24
- Figure 7: HCV pipeline: number of compounds per class and phase of clinical development, 2006 - page 25
- Figure 8: Estimated US launches of forecast HCV pipeline drugs, 2006-11 - page 29
- Figure 9: Performance of key late-stage developmental drugs against the three most important unmet needs - page 30
- Figure 10: The global HCV market 2005, 2010 and 2015 - page 31
- Figure 11: HCV market share by company, 2005, 2010 and 2015 - page 33
- Figure 12: Roche has rapidly established itself in the chronic HCV market in 2002-05 - page 34
- Figure 13: Pegasys has been approved for six viral hepatitis indications - page 34
- Figure 14: Pegasys is being used in most late-stage combination trials - page 36
- Figure 15: Peg-Intron sales, US, M5EU and Japan, 2002-05 - page 37
- Figure 16: Vertex product pipeline, June 2006 - page 39
- Figure 17: Genotypes 1a and 1b combined account for over 70% of HCV infections in the US, 2006 - page 43
- Figure 18: The HCV genotype distribution in France has changed, mainly due to an increase in intravenous drug use - page 44
- Figure 19: Injection drug use accounts for the majority of recent HCV infections - page 46
- Figure 20: Over decades, HCV silently progresses to liver cirrhosis and cancer - page 47
- Figure 21: Most chronic HCV patients present with significant fibrosis at first diagnosis - page 48
- Figure 22: In the US, demand for liver transplantation far outstrips supply, 1993-2004 - page 51
- Figure 23: Estimated HCV prevalence by WHO region, 1999 - page 52
- Figure 24: Geographic differences and temporal trends of HCV epidemiology - page 58
- Figure 25: Chronic HCV is more common in males and individuals of African origin - page 60
- Figure 26: Chronic HCV patients can be segmented by treatment status, HCV genotype, viral co-infection and the stage of the underlying liver disease - page 62
- Figure 27: Factors favoring and complicating HCV therapy in HIV/HCV co-infected patients - page 66
- Figure 28: Higher efficacy clearly remains the most important unmet need, followed by better tolerability - page 69
- Figure 29: New drug development needs to focus on patient subgroups other than white patients infected with HCV genotypes 2 or 3 - page 78
- Figure 30: Evolution of chronic HCV therapy in the US since the launch of Intron A in 1991 - page 82
- Figure 31: Strategies for tailoring HCV therapy to the individual patient - page 88
- Figure 32: HCV genome organization - page 93
- Figure 33: Key factors increasing the complexity of HCV trial design - page 102
- Figure 34: Stratification of patients for clinical trial enrollment - page 103
- Figure 35: Nonresponders and relapsers, predominantly those infected with HCV genotype 1, are now commonly enrolled in early-stage clinical trials - page 104
- Figure 36: The number of possible combinations for commercially attractive developmental drug classes are numerous - page 106
- Figure 37: Virological response: timepoints and definitions - page 109
- Figure 38: Global sales forecast for Albuferon, 2010-2015 - page 122
- Figure 39: US Phase II trial design - page 133
- Figure 40: Viramidine Phase II trial results - page 134
- Figure 41: Global sales forecast for viramidine, 2009-2015 - page 140
- Figure 42: Global sales forecast for NM283, 2009-2015 - page 149
- Figure 43: PROVE 1 is designed to assess the ability of VX-950 to achieve SVR in 260 treatment-naïve patients receiving VX-950 therapy for 12 weeks - page 153
- Figure 44: PROVE 2 is designed to assess the ability of VX-950 to achieve SVR in 320 treatment-naïve patients receiving VX-950 therapy for 12 weeks, with or without RBV - page 154
- Figure 45: Global sales forecast for VX-950, 2009-2015 - page 163
- Figure 46: Global sales forecast for SCH-503034, 2009-2015 - page 170
- Figure 47: Global sales forecast for celgosivir, 2009-2015 - page 176
- Figure 48: Comparative global sales forecasts for small molecule antivirals, 2009-2015 - page 177
- Figure 49: Global sales forecast for CpG 10101, 2009-2015 - page 190
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