Pipeline Insight: Hepatitis C - Protease inhibitors to drive market expansion

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE
  • About the Infectious Diseases & Respiratory pharmaceutical analysis team
• CHAPTER 1 EXECUTIVE SUMMARY
  • Scope of the analysis
  • Contributing experts
  • Datamonitor insight into the HCV market
    • 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
    • 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
    • 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
    • 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
  • Key metrics
• CHAPTER 2 HCV PIPELINE ANALYSIS
  • Pipeline overview
    • Small molecule antivirals dominate the HCV pipeline
      • The HCV pipeline contains drugs with various mechanisms of action
    • Double-digit growth driven by the launch of potent HCV inhibitors will lead to a doubling of the HCV market by 2010
  • Key companies involved in the HCV pipeline
    • Established players are losing market share to newcomers
    • Roche - Pegasys still growing strong
    • Schering-Plough - SCH-503034 to fill the gap
    • Vertex - expanding the market with VX-950
    • Novartis - building a broad arsenal of antivirals
• CHAPTER 3 PATIENT POTENTIAL
  • Hepatitis C disease definition and progression
    • HCV genotype 1 currently accounts for the majority of chronic infections
      • Genotype frequency: new infections may not mirror the current chronic patient pool
    • While past HCV transmission occurred mainly through contaminated blood products, most new infections currently occur via injection drug use
    • HCV readily establishes a chronic infection that can progress to liver cirrhosis and cancer
      • As a result of the silent nature of chronic HCV, patients are usually diagnosed at advanced stages of liver fibrosis
      • The number of patients presenting with HCV-related complications is set to rise
  • HCV epidemiology and patient segmentation
    • Chronic HCV is widespread on a global basis, with prevalence varying significantly by geographical region
      • Estimates for chronic HCV prevalence in the seven major markets
      • Chronic HCV is more prevalent among men, in older age groups, and individuals of African origin
      • Significantly higher rates of HCV prevalence are found in IDUs, HIV patients, and individuals receiving renal replacement therapy
    • Patient segmentation takes into account both patient and virus-specific factors
      • Drug development focuses on HCV genotype 1
      • Nonresponders and relapsers currently left without treatment options
      • HCV/HIV co-infection - a notoriously difficult-to-treat patient subgroup
      • Recurrent HCV post-transplant - current treatment options suffer from major limitations
  • The HCV market is characterized by high unmet need
    • Higher efficacy remains the most important product-specific unmet need
      • Higher efficacy, in particular in HCV genotype 1
      • Better tolerability
      • Shorter treatment duration
      • Less frequent dosing
      • Other product-specific unmet needs
    • Patient-specific unmet needs
      • Diagnosis and treatment rates are currently low, but are expected to increase concomitant with market entry of new drugs
      • Certain population subgroups achieve moderate or limited success with current treatment options
• CHAPTER 4 R&D APPROACH
  • Effective treatment of chronic HCV requires combination therapy
    • From interferon monotherapy to pegylated interferon plus ribavirin combination therapy
      • Moderate success with interferon monotherapy
      • Breakthrough with ribavirin
      • Pegylation of the interferon molecule reduces dosing frequency while increasing efficacy
    • Pegylated interferon plus ribavirin combination therapy is the current standard of care
      • Both pegylated interferon and ribavirin have broad mechanisms of action
      • Little differentiation between the two available combination therapies
      • The future of Peg-IFN-based therapy lies in tailoring therapy to the patient
  • HCV pipeline drugs fall into five major drug classes
    • Small molecule antivirals directly inhibit key steps in the viral lifecycle
      • NS3 protease inhibitors are the most promising drug class
      • NS5B polymerase inhibitors are less potent than the protease inhibitors but might have an important role as part of multidrug therapy
      • Other direct HCV inhibitors
    • Interferons act by inducing a local and systemic immune response
      • Interferons with reduced dosing frequency may lower the incidence of side effects
    • Immunomodulators
      • Will Toll-Like Receptor (TLR) agonists live up to the expectations?
      • Other immunomodulators
    • Therapeutic vaccines have been difficult to develop
  • Clinical trial design in HCV is becoming increasingly complex
    • Patient stratification according to genotype and treatment experience is a must
      • Further levels of patient stratification require ever larger studies
    • Moving toward multidrug therapy
  • Clinical trial endpoints in HCV focus on antiviral efficacy
    • Virologic response is the key measure of antiviral efficacy
      • RVR, EVR, ETR and the all-important SVR
      • Viramidine trials have included the incidence of anemia as a co-primary endpoint
      • Study endpoints other than virologic response rates will become increasingly important
• CHAPTER 5 INTERFERONS LATE-STAGE DRUG ANALYSIS
  • Overview for interferons in late-stage development for HCV
    • Pipeline summary
    • Definition of current comparator therapy
      • Pegylated interferon has limited efficacy in HCV genotype 1 and is associated with adverse events
  • Long acting interferons
    • Albuferon - albumin fusion to interferon reduces dosing frequency
      • Drug overview
      • Key clinical trial data
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecast to 2015
    • Omega interferon & Omega DUROS
      • Drug overview
      • Key clinical trial data
      • Datamonitor comments
• CHAPTER 6 SMALL MOLECULE ANTIVIRALS LATE-STAGE DRUG ANALYSIS
  • Overview for small molecule antivirals in late-stage development for HCV
    • Pipeline summary
    • Definition of current comparator therapy
      • RBV has limited antiviral efficacy and causes hemolytic anemia
  • IMPDH inhibitors
    • Viramidine - less toxic than RBV, but doubts regarding non-inferiority still prevail
      • Drug overview
      • Key clinical trial data
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecasts to 2015
  • NS5B RNA-dependent RNA polymerase inhibitors
    • Valopicitabine (NM-283) - commercial success relies on combination therapy with protease inhibitors
      • Drug overview
      • Key clinical trial data
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecasts to 2015
  • NS3 protease inhibitors
    • VX-950 - unprecedented high potency and potential for shorter treatment duration
      • Drug overview
      • Key clinical trial data
      • Pharmacokinetic boosting with ritonavir may improve dosing
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecasts to 2015
    • SCH-503034 - overshadowed by VX-950?
      • Drug overview
      • Key clinical trial data
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecasts to 2015
  • Other small molecule antivirals
    • Celgosivir (MX-3253) - antiviral effect through inhibition of a cellular enzyme
      • Drug overview
      • Key clinical trial data
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecasts to 2015
  • Comparison of small molecule antivirals in late-stage development
  • Late-stage developmental compounds recently discontinued
    • Merimepodib (VX-497) - development post-METRO unlikely
    • UT-231B
    • JTK-003
    • HCV-086
    • Ciluprevir (BILN-2061)
      • Unexpected toxicity in animals
    • R803
    • Levovirin
• CHAPTER 7 IMMUNOMODULATORS LATE-STAGE DRUG ANALYSIS
  • Overview for immunomodulators in late-stage development for HCV
    • Pipeline summary
    • Definition of current comparator therapy
  • Toll-like receptor agonists
    • CpG 10101 (Actilon) - a TLR9 agonist with a dual mode of action
      • Drug overview
      • Key clinical trial data
      • Patient potential
      • Marketing factors
      • Datamonitor comments
      • Forecasts to 2015
  • Late-stage developmental compounds recently discontinued
    • Histamine dihydrochloride (Ceplene)
    • FK778
• CHAPTER 8 DEVELOPMENTAL HCV THERAPEUTICS EXCLUDED FROM THE FORECAST
  • Developmental HCV drugs in Phase I
    • ANA-975 - Anadys's TLR7 agonist
    • R1626 - Roche's polymerase inhibitor
    • HCV-796 - ViroPharma's polymerase inhibitor
    • XTL-2125 - XTL's polymerase inhibitor
    • GS-9132 (ACH-806) - Achillion's & Gilead's protease inhibitor
  • Developmental HCV therapeutics excluded for other reasons
    • Therapeutic vaccines
      • INNO101 (InnoVac-C, HCV-E1 vaccine)
      • IC-41
      • Novartis's HCV vaccines
    • Drugs in development for recurrent HCV post-transplant and HCV-related liver disease
      • IDN-6556
      • Civacir
      • XTL-6865 (XTL-002)
    • Drugs with uncertain commercial potential
      • Interferon beta
      • Zadaxin
      • IFN alfa-2b XL
      • Peg-IFN alfacon-1 (consensus IFN)
      • Virostat
      • EMZ-702
      • AVI-4065
      • EHC-18
• APPENDIX
  • Methodology & bibliography
    • Forecasting methodology
      • Chronic HCV prevalence
      • HCV treatment rates
      • Product penetration rates
      • Product pricing
      • Pricing of marketed drugs
      • Average duration of HCV therapy
      • Summary of HCV epidemiology forecast
      • Estimation of product launch dates
      • Estimation of pegylated and standard interferon sales accounted for by chronic HCV
      • Developmental product patent expiry dates
    • Report methodology
    • Bibliography
      • Journals
      • Conference abstracts
      • Press releases
      • Datamonitor products
      • Miscellaneous
      • Websites
  • About Datamonitor
    • About Datamonitor Healthcare
    • Datamonitor Healthcare's therapy area capabilities
    • About the Infectious Diseases & Respiratory analysis team
    • Disclaimer
  • List of Tables
    • Table 1: HCV pipeline overview
    • Table 2: Commercially attractive late-stage developmental HCV drugs included in the sales forecast
    • Table 3: HCV drug sales by class, 2005-2015
    • Table 4: Geographical distribution of HCV genotypes
    • Table 5: Adjusted prevalence of HCV RNA positive individuals in the seven major markets, 2006
    • Table 6: HIV/HCV co-infection in the seven major markets
    • Table 7: The efficacy of the current standard of care is genotype-dependent, being lowest for HCV genotypes 1 and 4
    • Table 8: Dosing schedule for Peg-Intron and Rebetol combination therapy
    • Table 9: Dosing schedule for Pegasys and Copegus combination therapy
    • Table 10: Patients who achieve RVR and EVR are more likely to achieve SVR
    • Table 11: Key late-stage interferons
    • Table 12: The median half-life of Albuferon is significantly higher than that of both Pegasys and PEG-Intron
    • Table 13: Albuferon: key facts
    • Table 14: 48-week and 24-week results for US Albuferon combination trial in nonresponders show dose-dependent antiviral activity
    • Table 15: 12-week results for the Phase II Albuferon combination trial in HCV genotype 1 treatment-naïve patients
    • Table 16: Global sales forecast for Albuferon, 2010-2015
    • Table 17: Omega DUROS: key facts, 2006
    • Table 18: EVR data for Phase II trial of Omega IFN in combination with RBV, November 2005
    • Table 19: Key late-stage small molecule antivirals, 2006
    • Table 20: Viramidine: key facts,2006
    • Table 21: Efficacy results for VISER 1
    • Table 22: Stratification of patients supports weight-based viramidine dosing
    • Table 23: The accumulation of viramidine in plasma and red blood cells (RBCs) is lower than that of RBV
    • Table 24: Global sales forecast for viramidine, 2009-2015
    • Table 25: Valopicitabine (NM283): key facts, 2006
    • Table 26: Partial 24-week data for the NM283 Phase IIb trial in HCV genotype 1 nonresponders
    • 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
    • Table 28: Partial 4-week results for the Phase IIb NM283 trial in treatment-naïve HCV genotype 1 infected patients
    • Table 29: Global sales forecast for NM283, 2009-2015
    • Table 30: VX-950: key facts, 2006
    • Table 31: Preliminary 4-week results of VX-950's triple combination Phase II study in treatment-naïve, genotype-1 infected HCV patients
    • Table 32: Results of the US Phase Ib trial in HCV nonresponders
    • Table 33: Global sales forecast for VX-950, 2009-2015
    • Table 34: SCH-503034: key facts, 2006
    • Table 35: Phase I open-label combination study results
    • Table 36: Global sales forecast for SCH-503034, 2009-2015
    • Table 37: Celgosivir: key facts, 2006
    • Table 38: Global sales forecast for celgosivir, 2009-2015
    • Table 39: Comparative global sales forecasts for small molecule antivirals, 2009-2015
    • Table 40: Recently discontinued small molecule HCV antivirals
    • Table 41: UT-231B Phase II clinical trial design
    • Table 42: Key late-stage immunomodulators, 2006
    • Table 43: CpG 10101: key facts
    • 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
    • Table 45: Global sales forecast for CpG 10101, 2009-2015
    • Table 46: Recently discontinued small molecule HCV antivirals
    • Table 47: Developmental HCV drugs in Phase I, June 2006
    • Table 48: Therapeutic vaccines in development for the treatment of chronic HCV, 2006
    • Table 49: Drugs in development for the prevention of HCV re-infection post-transplant and HCV-related liver disease, 2006
    • Table 50: Developmental HCV drugs with uncertain commercial potential, 2006
    • Table 51: Zadaxin: key facts
    • Table 52: Virostat: key facts
    • Table 53: AVI-4065: key facts
    • Table 54: Treatment rates in the seven major markets
    • Table 55: Estimations of price premiums
    • Table 56: Forecast for viramidine in the US, 2009-2015
    • Table 57: Average clinical development times for developmental HCV drugs
    • Table 58: US patent expiry dates for HCV pipeline drugs
  • List of Figures
    • Figure 1: The global HCV market, 2002-2015
    • Figure 2: HCV market share by company, 2005, 2010 and 2015
    • Figure 3: Key unmet needs in HCV
    • Figure 4: Performance of key late-stage developmental drugs against key unmet needs
    • Figure 5: The number of possible combinations for commercially attractive developmental drug classes are numerous
    • Figure 6: Small molecule antivirals dominate the HCV pipeline
    • Figure 7: HCV pipeline: number of compounds per class and phase of clinical development, 2006
    • Figure 8: Estimated US launches of forecast HCV pipeline drugs, 2006-11
    • Figure 9: Performance of key late-stage developmental drugs against the three most important unmet needs
    • Figure 10: The global HCV market 2005, 2010 and 2015
    • Figure 11: HCV market share by company, 2005, 2010 and 2015
    • Figure 12: Roche has rapidly established itself in the chronic HCV market in 2002-05
    • Figure 13: Pegasys has been approved for six viral hepatitis indications
    • Figure 14: Pegasys is being used in most late-stage combination trials
    • Figure 15: Peg-Intron sales, US, M5EU and Japan, 2002-05
    • Figure 16: Vertex product pipeline, June 2006
    • Figure 17: Genotypes 1a and 1b combined account for over 70% of HCV infections in the US, 2006
    • Figure 18: The HCV genotype distribution in France has changed, mainly due to an increase in intravenous drug use
    • Figure 19: Injection drug use accounts for the majority of recent HCV infections
    • Figure 20: Over decades, HCV silently progresses to liver cirrhosis and cancer
    • Figure 21: Most chronic HCV patients present with significant fibrosis at first diagnosis
    • Figure 22: In the US, demand for liver transplantation far outstrips supply, 1993-2004
    • Figure 23: Estimated HCV prevalence by WHO region, 1999
    • Figure 24: Geographic differences and temporal trends of HCV epidemiology
    • Figure 25: Chronic HCV is more common in males and individuals of African origin
    • Figure 26: Chronic HCV patients can be segmented by treatment status, HCV genotype, viral co-infection and the stage of the underlying liver disease
    • Figure 27: Factors favoring and complicating HCV therapy in HIV/HCV co-infected patients
    • Figure 28: Higher efficacy clearly remains the most important unmet need, followed by better tolerability
    • Figure 29: New drug development needs to focus on patient subgroups other than white patients infected with HCV genotypes 2 or 3
    • Figure 30: Evolution of chronic HCV therapy in the US since the launch of Intron A in 1991
    • Figure 31: Strategies for tailoring HCV therapy to the individual patient
    • Figure 32: HCV genome organization
    • Figure 33: Key factors increasing the complexity of HCV trial design
    • Figure 34: Stratification of patients for clinical trial enrollment
    • Figure 35: Nonresponders and relapsers, predominantly those infected with HCV genotype 1, are now commonly enrolled in early-stage clinical trials
    • Figure 36: The number of possible combinations for commercially attractive developmental drug classes are numerous
    • Figure 37: Virological response: timepoints and definitions
    • Figure 38: Global sales forecast for Albuferon, 2010-2015
    • Figure 39: US Phase II trial design
    • Figure 40: Viramidine Phase II trial results
    • Figure 41: Global sales forecast for viramidine, 2009-2015
    • Figure 42: Global sales forecast for NM283, 2009-2015
    • 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
    • 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
    • Figure 45: Global sales forecast for VX-950, 2009-2015
    • Figure 46: Global sales forecast for SCH-503034, 2009-2015
    • Figure 47: Global sales forecast for celgosivir, 2009-2015
    • Figure 48: Comparative global sales forecasts for small molecule antivirals, 2009-2015
    • Figure 49: Global sales forecast for CpG 10101, 2009-2015