Pipeline Insight: HIV - Extending treatment options

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE
  • About the Infectious Diseases & Respiratory pharmaceutical analysis team
• CHAPTER 1 EXECUTIVE SUMMARY
  • Scope of the analysis
    • More people than ever living with HIV and AIDS in North America and Western and Central Europe
  • Contributing experts
  • Datamonitor insight into the HIV market
    • In the main line HIV treatments, Truvada-containing regimes have taken over from Combivir as the new gold standard for the NRTI class and patient simplicity will be greatly improved with the launch of Atripla.
    • Non-nucleoside analogs (NNRTIs) are dominated by Sustiva and physicians have few choices when drug resistance develops.
    • Despite a large number of available products, two Protease Inhibitors (PIs) have over half the class market share. The role of PIs in salvage therapy is being re-defined by Prezista and Aptivus, yet a gold standard here has not yet emerged.
    • Entry Inhibitors (EIs), integrase inhibitors and other new drug classes represent a major opportunity for new product development but are initially targeting the small salvage market
• CHAPTER 2 PATIENT POTENTIAL
  • Definition of HIV
  • Epidemiology of HIV
    • Growing epidemics are underway in Eastern Europe, Central Asia and India
    • More people than ever living with HIV and AIDS in North America and Western and Central Europe
    • Increased HIV diagnosis is driven by immigration, a rise in risky behavior, more convenient diagnostics and braoder testing guidelines
      • Immigration from areas of high prevalence means the need for antiretroviral therapy in the seven major markets will continue to grow
      • Improved HIV tests and changes in CDC HIV testing guidelines should increase the HIV diagnosis and treatment rates and might reduce HIV transmission
      • The perception that HIV is a manageable condition and not a 'death sentence' has led to a rise in risky behavior, particularly among the younger age groups
      • The increased number of women becoming infected is driven by heterosexual intercourse
      • Concentration of HIV infections among Africa Americans and Hispanic Americans
  • Increased occurrence of HIV drug resistance in treatment-na�Ee patients is affecting front line treatment strategies
  • Treatment efficacy remains the primary unmet medical need
  • Side effects and drug resistance are key unmet medical needs in individual drug classes
    • Drug resistance is a problem in most HIV drug classes - but for different reasons
    • Despite good efficacy, PIs are plagued by drug interactions, resistance and side effects
    • 'Pill burden' is no longer an unmet need across the ARV drug classes
    • No one issue stands out with NRTIs; new drugs must be good 'all round'
    • Entry Inhibitors have commanded a premium price; this has made physicians wary of this drug class
• CHAPTER 3 R&D APPROACH
  • Overview of HIV drug classes
    • Nucleoside analogs (NRTIs), the oldest HIV drug class, have a mature market dynamic and physicians may choose between many available products
    • Non-nucleoside analogs (NNRTIs) are dominated by Sustiva and physicians have few choices when drug resistance develops
    • Despite a large number of available products, two Protease Inhibitors (PIs) take over half the class market share
    • Entry Inhibitors (EIs) and other new drug classes represent a major opportunity for new product development but are targeted to the small salvage market when first launched
  • Clinical trial endpoints are shifting in response to the newer unmet needs in HIV
    • Early trial were based on 'hard' clinical endpoints, such as progression to AIDS or death
    • The availability of HIV viral load diagnostics enabled trials to measure the direct effect on the virus, use 'soft' clinical endpoints and reduced the length of trials
      • Reduction in viral load
      • CD4 Elevation
      • Efficacy Equivalence
  • With improved understanding of HIV and the advent of HAART therapy, endpoints have changed significantly
    • Activity against resistant virus - a must for most of the HIV pipeline
    • Quality of life considerations
• CHAPTER 4 HIV PIPELINE ANALYSIS
  • Pipeline overview
  • A collaboration between Gilead and BMS has produced Atripla, the first of its kind
  • Tibotec J&Js highly anticipated pipeline products set to generate significant revenues for J&J
  • GSK currently dominates HIV market but with only one pipeline product its market share will be drastically reduced by 2016
• CHAPTER 5 NRTI LATE-STAGE DRUG ANALYSIS & FORECASTS
  • Fixed dose combinations dominate the NRTI market
    • Truvada-containing regimes replace Combivir as the new gold standard
    • Once daily Atripla eliminates the issue of pill burden and is forecast to become the first HIV blockbuster
  • Pipeline products attempt to tackle drug resistance
    • Multi-nucleoside resistance
  • Development of new drugs has been slow
  • Elvucitabine
    • Clinical trial data
    • Datamonitor analysis
  • Racivir
    • Clinical trial data
    • Datamonitor analysis
  • AVX-754
    • Clinical trial data
    • Datamonitor analysis
  • MIV-210
    • Clinical trial data
    • Datamonitor analysis
  • Amdoxovir
    • Clinical trial data
    • Datamonitor analysis
  • Late-stage development compounds recently discontinued
    • Reverset
• CHAPTER 6 NNRTI LATE-STAGE DRUG ANALYSIS AND FORECASTS
  • The NNRTIs are recommended for first line therapy, but can only be used for a limited time before class resistance develops.
    • Sustiva maintains its grip on the market and its gold-standard status
  • Class wide resistance is the primary unmet need for the NNRTIs and its prevalence is growing in treatment na�Ee patients
  • Pipeline NNRTIs are addressing the greatest unmet need for this class
  • TMC125
    • Clinical trial data
    • Datamonitor analysis
  • TMC278
    • Clinical trial data
    • Datamonitor analysis
  • BILR355
    • Clinical trial data
    • Datamonitor analysis
  • Innovative Early-Stage Project
    • Calanolide A
  • Late-stage development compounds recently discontinued
    • Capravirine
    • GW-695634
    • MIV-150
• CHAPTER 7 PI LATE-STAGE DRUG ANALYSIS AND FORECASTS
  • Overview of current PI Market
    • Boosting with ritonavir improves pharmacokinetics, increases efficacy and is now standard practice; Abbott's ownership of ritonavir gives it a competitive advantage in the PI market
    • Kaletra the gold standard in the PI class is now available in once daily, temperature stable tablets without food restrictions
    • The competitive pressure from Reyataz is strong
  • Current developmental compounds tackle resistance but not side effects or drug-drug interactions
  • Aptivus (tipranavir)
    • Clinical trial data
    • Datamonitor analysis
  • Prezista (TMC114)
    • Clinical trial data
    • Datamonitor analysis
  • Brecanavir
    • Clinical trial data
    • Datamonitor analysis
  • Innovative early-stage projects
    • PPL-100
• CHAPTER 8 EI AND OTHER LATE-STAGE DRUG ANALYSIS AND FORECASTS
  • Overview of current EI Market
    • There is no gold standard treatment in the EI drug class; Fuzeon sales are limited to the salvage market
    • Roche and Trimeris aim for once weekly needle-free T-20 to increase patient tolerability
    • Fuzeon boosts efficacy of other products
  • The EI and others pipeline encompasses a wide range of products, with a variety of targets and mechanisms of action being investigated
    • CCR5 and CXCR4 receptors have become important antiretroviral targets as the two main co-receptors essential for HIV entry into uninfected cells
  • CCR5 Inhibitors- poor results from most pipeline compounds have tarnished the reputation of this class
    • Vicriviroc
      • Clinical trial data
      • Datamonitor analysis
  • Maraviroc
    • Clinical trial data
    • Datamonitor analysis
  • CXCR4 inhibitors
    • AMD070
      • Clinical trial data
      • Datamonitor analysis
  • Attachment inhibitors
    • TNX-355
      • Clinical trial data
      • Datamonitor analysis
  • Integrase Inhibitors
    • MK-0518
      • Clinical trial data
      • Datamonitor analysis
    • GS-9137
      • Clinical trial data
      • Datamonitor analysis
  • Maturation Inhibitors
    • Bevirimat (PA-457)
      • Clinical trial data
      • Datamonitor analysis
  • Innovative Early-Stage Projects
    • PRO-140
    • TRI-999 and TRI-1144
• APPENDIX A
  • Methodology
    • Datamonitor forecast methodology.
      • Epidemiology forecasts
      • Product forecasts
      • Definition of a standard unit
      • Estimation of launch dates
  • Datamonitor drug assessment summary
  • Contributing experts
  • Bibliography and Press Releases
  • Frequently Used Websites
  • Company websites
• APPENDIX B
  • About Datamonitor
    • About Datamonitor Healthcare
  • Datamonitor Healthcare's therapy area capabilities
    • About the Infectious disease analysis team
    • Key therapy team members
      • Mansi Shah, Analyst, Infectious Diseases
      • Morris Paterson, Senior Analyst, Infectious Diseases
  • Disclaimer
  • List of Tables
    • Table 1: Regional HIV and AIDS overview, 2005
    • Table 2: DHHS and BHIVA HIV treatment guidelines
    • Table 3: DHHS and BHIVA HIV recommended treatment combinations
    • Table 4: Overview of the HIV pipeline by company
    • Table 5: Overview of number of marketed drugs and developmental drugs for key HIV companies
    • Table 6: Overview of Currently Marketed NRTIs
    • Table 7: Overview of NRTI drug pipeline
    • Table 8: Key clinical trials of Elvucitabine
    • Table 9: Overview of Phase II trial of Elvucitabine
    • Table 10: Key clinical trials of AVX-754
    • Table 11: Overview of current Phase IIb trial of of AVX-754
    • Table 12: Key clinical trials of MIV-210
    • Table 13: Key clinical trials of Amdoxovir
    • Table 14: Overview of current Phase II trial of Amdoxovir
    • Table 15: Overview of currently marketed NNRTIs
    • Table 16: Overview of NNRTI drug pipeline
    • Table 17: Key clinical trials of TMC125
    • Table 18: Key clinical trials of TMC278
    • Table 19: Overview of current Phase IIb trial of TMC278
    • Table 20: Key clinical trials of BILR355
    • Table 21: Overview of currently marketed PIs
    • Table 22: Overview of PI drug pipeline and recently launched PIs
    • Table 23: RESIST 1 & 2 trial summary
    • Table 24: Key ongoing clinical trials for Prezista
    • Table 25: Previous trials of Prezista
    • Table 26: Key clinical trials of Brecanavir
    • Table 27: Key clinical trials of Maraviroc
    • Table 28: Key clinical trials of AMD070
    • Table 29: Overview of the XACT trial
    • Table 30: Key clinical trials of TNX-355
    • Table 31: Overview of Phase II trial of TNX-355
    • Table 32: Results from MK-0518 head-to-head trial with Sustiva
    • Table 33: Key clinical trials of MK-0518
    • Table 34: Overview of Phase II trial of MK-0518
    • Table 35: Overview of Phase II trial of MK-0518
    • Table 36: Key clinical trials of GS-9137
    • Table 37: Overview of the Phase I/II study
    • Table 38: Key clinical trials of PA-457
    • Table 39: Overview of Phase IIa study of Bevirimat
    • Table 40: Average development timeline of HIV NMEs
    • Table 41: Estimated launch dates for the US and EU
  • List of Figures
    • Figure 1: Global HIV epidemic, 1990-2005
    • Figure 2: HIV prevalence in the 7 major markets
    • Figure 3: Annual HIV incidence, US, Germany and UK, 1995-2003
    • Figure 4: HIV-infected individuals accessing treatment in the UK
    • Figure 5: HIV incidence by transmission group in Western Europe
    • Figure 6: HIV acquired through heterosexual contact in the UK
    • Figure 7: Increased ratio of women infected in the 7 major markets
    • Figure 8: Drug Resistance in Newly Diagnosed HIV +ve U.S. Individuals
    • Figure 9: Drug Resistance in Newly Diagnosed HIV +ve UK Individuals
    • Figure 10: A comparison of clinical trials evaluating 3 drug combinations
    • Figure 11: Drivers of switching from first- to second-line ARV therapy
    • Figure 12: Unmet medical needs in individual HIV drug classes, 2006
    • Figure 13: Underlying causes of HIV drug resistance
    • Figure 14: Improving Outcomes With Evolving Antiretroviral Regimens
    • Figure 15: HIV virus lifecycle
    • Figure 16: US quarterly sales of HIV drug classes, 2002-2005
    • Figure 17: Market share within each ARV drug class, major markets 2005
    • Figure 18: Overview of HIV drug development pipeline, 2006
    • Figure 19: HIV market share 2005 and 2016
    • Figure 20: 2016 antiretroviral sales by company
    • Figure 21: Quarterly sales of currently marketed NRTIs
    • Figure 22: Atripla sales forecast 2006-2016
    • Figure 23: Mutations in the reverse transcriptase gene associated with resistance to NRTIs
    • Figure 24: Prevalence of major drug resistance mutations (IAS-USA definitions) in patients failing HAART
    • Figure 25: Levels of unmet needs in the NRTI class
    • Figure 26: Elvucitabine sales forecast 2006-2016
    • Figure 27: Racivir sales forecast 2006-2016
    • Figure 28: AVX-754 sales forecast 2006-2016
    • Figure 29: MIV-210 sales forecast 2006-2016
    • Figure 30: Amdoxovir sales forecast 2006-2016
    • Figure 31: Mutations in the reverse transcriptase gene associated with resistance to NNRTIs
    • Figure 32: Level of unmet needs in the NNRTI class
    • Figure 33: Activity of NNRTIs against resistance causing mutations
    • Figure 34: SWOT analysis for TMC125
    • Figure 35: TMC125 sales forecast 2006-2016
    • Figure 36: SWOT analysis for TMC278
    • Figure 37: TMC278 sales forecast 2006-2016
    • Figure 38: SWOT analysis for BILR355
    • Figure 39: BILR355 sales forecast 2006-2016
    • Figure 40: Unmet needs in the PI class
    • Figure 41: Mutations in the protease gene associated with resistance to PIs
    • Figure 42: SWOT Analysis for Aptivus
    • Figure 43: Aptivus sales forecast 2006-2016
    • Figure 44: SWOT Analysis for Prezista
    • Figure 45: Prezista sales forecast 2006-2016
    • Figure 46: SWOT analysis for Brecanavir
    • Figure 47: Brecanavir sales forecast 2006-2016
    • Figure 48: HIV host cell entry mechanism
    • Figure 49: Molecular structure of Fuzeon
    • Figure 50: Unmet needs across the EIs and others class
    • Figure 51: HIV infection of target cells takes place via chemokine receptors
    • Figure 52: Prevalence of CCR5, CXCR4 and dual tropic strains
    • Figure 53: SWOT analysis for vicriviroc
    • Figure 54: Vicriviroc sales forecast 2006-2016
    • Figure 55: SWOT analysis for Maraviroc
    • Figure 56: Maraviroc sales forecast 2006-2016
    • Figure 57: SWOT analysis for AMD070
    • Figure 58: AMD070 sales forecast 2006-2016
    • Figure 59: SWOT analysis for TNX355
    • Figure 60: TNX355 sales forecast 2006-2016
    • Figure 61: SWOT analysis for MK-0518
    • Figure 62: MK-0518 sales forecast 2006-2016
    • Figure 63: SWOT analysis for GS-9137
    • Figure 64: GS-9137 sales forecast 2006-2016
    • Figure 65: SWOT analysis for Bevirimat
    • Figure 66: Bevirimat (PA-457) sales forecast 2006-2016