Pipeline Insight: HIV - Hold Your Horses

Published by: Datamonitor

Published: Apr. 21, 2005 - 216 Pages

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

About the Infectious Disease pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

Scope of the analysis

Datamonitor insight into the HIV market

Forecasts and assumptions

CHAPTER 2 PIPELINE DYNAMICS

An overview of the pipeline reveals few Phase III candidates

The CCR5 inhibitors could, potentially change the treatment paradigm, redistributing sales share from established products

New HIV players are expected to account for the majority of sales by 2015

GSK will see its share drastically reduced, but will still be the leading HIV company

Should all three pipeline compounds reach the market, Tibotec/J&J is expected to experience the strongest growth in antiretroviral sales

CHAPTER 3 PATIENT POTENTIAL

As HIV moves towards a chronic manageable disease, the epidemiology is changing

Disease definition

Despite awareness campaigns and measures to prevent transmission, HIV incidence in some countries continues to rise

Immigration from areas of high prevalence means the need for antiretroviral therapy in the seven major markets will continue to grow

Roughly 40% of the HIV/AIDS population in the seven major markets is currently undiagnosed. However, better access to diagnostics has resulted in increased diagnosis and, therefore, treatment rates

The perception that HIV is a manageable condition and not a 'death sentence' has led to a rise in risk behavior, particularly among the younger age groups

Historically affecting men who have sex with men (MSM) and intravenous drug users (IVDU), HIV incidence is rapidly growing in women

The HIV-infected population is growing older

Recently, the number of HIV diagnoses in older age groups has increased

The widespread use of HAART has led to a life expectancy equivalent to that of the uninfected population

A greater number and range of therapies has resulted in a variety of treatment-experienced patients

Treatment-naïve patients make up a limited percentage of the overall HIV-treated population

In accordance with the US DHHS guidelines, intermediate treatment-experienced patients have been recognized as a rapidly growing group

Salvage therapy is becoming further downstream as third, fourth and even fifth lines of therapy become feasible due to new drug launches

The two main unmet needs in HIV therapy are resistance to currently available drugs and improved patient quality of life

Resistance, both acquired and developed, is becoming the main concern for HIV physicians

As HIV patients are living longer, quality of life considerations play a key role in prescription decisions

CHAPTER 4 R&D APPROACH

Clinical trial endpoints are shifting in response to the newer unmet needs in HIV

Early clinical trial endpoints were primarily based upon efficacy

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

Gilead's 903 trial has set new standards in HIV clinical trial design

Gilead's 903 trial is the first three-year, international, randomized, double-blind, clinical trial of an HIV drug regimen in treatment-naïve patients

Frequently cited as a landmark study, the standard set by the 903 trial is likely to be emulated in future clinical trial design

Several backbones are available for use in clinical trials, which is likely to affect future uptake of pipeline drugs

CHAPTER 5 NRTI LATE-STAGE DRUG ANALYSIS & FORECASTS

The NRTIs, being the oldest class with the most marketed drugs, is expected to undergo significant changes in dynamics in the next decade

The definition of a gold-standard NRTI is no longer clear cut

Traditionally, Combivir was widely regarded as the gold-standard NRTI

Viread, with its potent activity, favorable resistance profile and once-daily dosing, is perceived by some as the new gold standard

Truvada and Epzicom, launched in 2004, can also be viewed as candidates for the label of gold-standard NRTI

Drug resistance is the predominant therapeutic issue in the NRTI class and an unmet need of growing importance

Several pipeline NRTIs are expected to reach the market within the next five to 10 years

Within the NRTI class, most pipeline drugs have demonstrated activity against common resistant mutations

Several drugs with activity against problematic NRTI resistance mutations are being developed

Elvucitabine - demonstrable improvement in M184V patients

More frequently, patients with resistant virus are being recruited for NRTI clinical trials

Racivir - patients with M184V sought for study RCV-201

The treatment-experienced patient pool is likely to offer the greatest opportunities for pipeline NRTIs

With Epivir, Viread and the fixed-dose combinations firmly established as early-line therapy, companies are looking to the treatment-experienced patient pool

Reverset is being developed primarily for salvage therapy

The limited patient pool for new NRTIs has led to some companies out-licensing or ceasing developmental products

SPD-754 recently out-licensed to Avexa Ltd (and given fast-track status by the FDA)

GlaxoSmithKline terminates research agreement MIV-210 but development still ongoing

Several early-stage NRTIs have been discontinued in development

GS 7340 profile does not support continued development

Gilead terminated its licensing agreement for amdoxivir for strategic reasons

Boehringer Ingelheim opted to discontinue development of MIV-310

CHAPTER 6 PI LATE-STAGE DRUG ANALYSIS AND FORECASTS

The PIs have traditionally been associated with a high pill burden and a poor side-effect profile, but new drugs in the class have addressed this problem

Despite being challenged by Reyataz, Kaletra is still the PI gold standard

Based on recent sales, Reyataz poses a serious challenge as contender for the PI gold standard

Key unmet needs in PI therapy are being addressed by the pipeline

Despite being not being seen as the main unmet need, PI resistance is the major issue driving new product development

Despite PK problems, physicians believe tipranavir will have a valuable role to play in later stage PI therapy

Profile

Datamonitor analysis

TMC-114 - promising clinical data raises possibility of favorable positioning

Recent clinical trials show that the presence of I54L/M mutations does not reduce susceptibility to GW-640385

Profile

CHAPTER 7 NNRTI LATE-STAGE DRUG ANALYSIS AND FORECASTS

Usually the preferred first-line therapy, the NNRTIs can only be used for a limited time before class resistance reduces efficacy

One pill, once-daily Sustiva is the NNRTI gold standard

Class resistance is the major unmet need for the NNRTIs

The development of certain resistance mutations results in patients no longer being susceptible to the entire NNRTI class

Pipeline NNRTI compounds, with activity against these resistance mutations, may enable patients to use this class in second- and even third-line therapy

TMC-125's activity against NNRTI-resistant virus is generating clinical and market interest in the compound's potential

Profile

Key clinical trial overview

Trial results

Datamonitor analysis

TMC-278 - efficacy in naïve patients could mean potential for first-line positioning

Profile

Key clinical trial overviews

Trial results

Datamonitor analysis

GW-695634 - positive preliminary data but will it be enough to challenge the Tibotec compounds?

Profile

Key clinical trial overview

Trial results

Datamonitor analysis

Pharmacokinetic issues have had to be overcome to ensure the continued development of some NNRTIs

Surprising rates of failure on capravirine clouds future potential

Profile

Key clinical trial overview

Trial results

Datamonitor analysis

Phase II/III trials planned but no apparent progress for calanolide A

Profile

Key clinical trial overview

Trial results

Datamonitor analysis

CHAPTER 8 EI AND OTHERS LATE-STAGE DRUG ANALYSIS AND FORECASTS

The emergence of a new class of antiretrovirals could lead to changes in accepted treatment paradigms

The launch of Fuzeon made the effective treatment and increased survival of patients with advanced stage disease a realistic option

Although Fuzeon has provided 'proof of concept', it cannot be considered a true comparator with all stages of therapy being targeted by the EI pipeline drugs

The EI and others pipeline encompasses a wide range of products, with a variety of targets and mechanisms of action being investigated

As the two main co-receptors essential for HIV entry into uninfected cells, CCR5 and CXCR4 receptors have become important antiretroviral targets

UK-427, 857 - resistance profile looks promising but concerns abound regarding viral tropism

Combination therapy with GW873140 - data proves promising

SCH-417690 (SCH-D) - CCR5 antagonist with potent antiviral effect

AMD070 - will the CXCR4 tropic virus be a large enough niche?

Monoclonal antibodies, being investigated in heavily treatment-experienced patients, could increase salvage therapy options

TNX-355 - a last resort for triple-class experienced patients?

PRO-542 - being positioned in highly treatment-experienced patients, but limited advances in clinical trials

PRO-140 - a second approach by Progenics

Other potential targets being investigated include attachment, maturation and integrase inhibition

PA-457's totally novel mechanism of action warrants FDA fast-track status

BMS-488043 - proof of concept for first in class likely to lead to development of follow-up compounds

Integrase inhibitors represent a key hope for the future, but toxicity issues are clouding their immediate development

Discontinued drugs

Viraldon - Phase II/III trials discontinued due to failure to complete recruitment

Profile

APPENDIX A - PIPELINE PRODUCT PROFILES

NRTI profiles

Elvucitabine

Clinical trial overview

Racivir

Clinical trial overview

Reverset

Clinical trial overview

SPD-754

Trial reference 2

PI profiles

TMC-114

Clinical trial overview

NNRTI profiles

TMC-125

Clinical trial overview

Calanolide A

Clinical trial overview

Capravirine

Clinical trial overview

EI profiles

TNX-355

Clinical trial overview

UK-427, 857

Clinical trial overview

GW873140

Clinical trial overview

PRO-542

Clinical trial overview

APPENDIX B

Bibliography

Press releases

Websites

Conferences

Miscellaneous sources

Report methodology

APPENDIX C

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

Disclaimer

List of Tables

Table 1: HIV pipeline by company, 2005

Table 2: Age at diagnosis in Western Europe, 1999-2003

Table 3: US guidelines recommended first-line (treatment-naïve) therapy, 2004

Table 4: Efficacy of a tenofovir containing regime compared to one containing stavudine in treatment-naïve patients

Table 5: Overview of the currently marketed NRTIs

Table 6: Key products in late-stage R&D pipeline for NRTIs

Table 7: Elvucitabine clinical trial summary

Table 8: Elvucitabine: Phase II trial summary

Table 9: Racivir clinical trial summary

Table 10: Racivir: Phase II trial summary

Table 11: Racivir: Phase II trial summary

Table 12: Reverset clinical trial summary

Table 13: Reverset: Phase IIb trial summary

Table 14: SPD-754 clinical trial summary

Table 15: SPD-754: Phase II trial summary

Table 16: SPD-754: Phase II trial summary

Table 17: MIV-210 clinical trial summary

Table 18: MIV-210: Phase I trial summary

Table 19: Overview of the PIs

Table 20: Kaletra: key facts

Table 21: Reyataz: key facts

Table 22: Key PIs in late-stage development

Table 23: Tipranavir: clinical trial summary

Table 24: Tipranavir: RESIST-1 trial summary

Table 25: Tipranavir: RESIST-2 trial summary

Table 26: Percentage of patients achieving a treatment response*

Table 27: TMC-114 clinical trial summary

Table 28: TMC-114: Phase IIb trial summary

Table 29: TMC-114: Phase IIa trial summary

Table 30: GW-640385: clinical trial summary

Table 31: GW-640385: Phase I trial summary

Table 32: Overview of the NNRTIs

Table 33: Key products in late-stage R&D pipeline for NRTIs, 2005

Table 34: TMC-125: clinical trial summary

Table 35: TMC-125: resistance testing data

Table 36: TMC-278: clinical trial summary

Table 37: TMC-278: Phase IIa trial summary

Table 38: TMC-278: Phase IIa trial summary

Table 39: GW-695634: clinical trial summary

Table 40: GW-695634: Phase I trial summary

Table 41: Capravirine: clinical trial summary

Table 42: Capravirine: Phase II trial summary

Table 43: Capravirine: Phase IIb trial summary

Table 44: Calanolide A: clinical trial summary

Table 45: Calanolide A: Phase II trial summary

Table 46: Key products in late-stage R&D pipeline for EIs & others

Table 47: UK-427, 857: clinical trial summary

Table 48: UK-427, 857: Phase II trial summary

Table 49: GW873140: clinical trial summary

Table 50: GW873140: Phase II trial summary

Table 51: GW873140: Phase II trial summary

Table 52: SCH-417690: clinical trial summary

Table 53: SCH-417690: Phase I trial summary

Table 54: AMD070: clinical trial summary

Table 55: AMD070: Phase Ia trial summary

Table 56: TNX-355: clinical trial summary

Table 57: TNX-355: Phase II trial summary

Table 58: PRO-542: clinical trial summary

Table 59: PRO-542: Phase I/II trial summary

Table 60: PRO-140: clinical trial summary

Table 61: PA-457: clinical trial summary

Table 62: PA-457: Phase I/II trial summary

Table 63: BMS-488043: clinical trial summary

Table 64: BMS-488403: Phase IIa trial summary

Table 65: BMS-488403: Phase I trial summary

Table 66: Elvucitabine: Phase I trial summary

Table 67: Racivir: Phase I trial summary

Table 68: Reverset: Phase IIa trial summary

Table 69: Reverset: Phase I trial summary

Table 70: TMC-114: Phase IIb trial summary

Table 71: TMC-125: Phase IIa trial summary

Table 72: TMC-125: Phase IIa trial summary

Table 73: Calanolide A: Phase I/II trial summary

Table 74: Capravirine: Phase II trial summary

Table 75: Capravirine: Phase II trial summary

Table 76: TNX-355: Phase Ib trial summary

Table 77: UK-427, 857: Phase I trial summary

Table 78: GW873140: Phase I trial summary

Table 79: PRO-542: Phase I trial summary

List of Figures

Figure 1: The HIV pipeline, 2005

Figure 2: CCR5 forecasted sales 2010-15

Figure 3: 2004 antiretroviral sales by company

Figure 4: HIV market share*, 2004 and 2015

Figure 5: 2015 antiretroviral sales by company

Figure 6: Estimated number of people living with HIV worldwide, 2000-04

Figure 7: Annual HIV incidence, US, Germany and UK, 1995-2004*

Figure 8: UK overseas population by ethnic group, 2001

Figure 9: Newly diagnosed HIV infections in Western Europe by route of transmission, 1999-2003

Figure 10: Age and year of diagnosis of new HIV infection in the UK, 1994--2004

Figure 11: Total AIDS cases per year, seven major markets, 1991-2001

Figure 12: The increased life expectancy due to HAART has led to third and later lines of therapy becoming usual

Figure 13: Timeline of the development of the HIV market

Figure 14: Viread quarterly uptake since launch

Figure 15: Elvucitabine sales forecast, 2005-15

Figure 16: Racivir sales forecast, 2005-15

Figure 17: Where Reverset may be used

Figure 18: Reverset sales forecast, 2005-15

Figure 19: SPD-754 sales forecast, 2005-2015

Figure 20: MIV-210 sales forecast, 2005-15

Figure 21: Tipranavir sales forecasts, 2005-15

Figure 22: TMC-114 sales forecasts, 2005-15

Figure 23: GW-640385 sales forecasts, 2005-15

Figure 24: TMC-125 sales forecasts, 2005-15

Figure 25: TMC-278 sales forecasts, 2005-15

Figure 26: GW-695634 sales forecasts, 2005-15

Figure 27: Capravirine sales forecasts, 2005-15

Figure 28: Calanolide A sales forecasts, 2005-15

Figure 29: HIV infection of target cells takes place via chemokine receptors

Figure 30: UK-427,857 sales forecasts, 2005-15

Figure 31: GW873140 sales forecasts, 2005-15

Figure 32: SCH-417690 sales forecasts, 2005-15

Figure 33: AMD070 sales forecasts, 2005-15

Figure 34: TNX-355 sales forecasts, 2005-15

Figure 35: PRO-542 sales forecasts, 2005-15

Figure 36: PA-457 sales forecasts, 2005-15

Abstract

• The changing epidemiology of HIV is discussed, as well as the changing unmet needs that are currently presenting themselves
• Late-phase clinical trials are examined, with comparators assessed and opinion leader comments on trial design included
• Forecasted sales of the antiretroviral market in the next 10 years with two possible scenarios relating to a changing treatment paradigm
• An assessment of the novel Entry Inhibitor class, its implications for future therapy, and its impact upon the seven major markets

• Understand key drivers in the antiretroviral market and predict the future performance of key compounds
• Understand the changing unmet needs of patients and clinical endpoints used in current trial design
• Evaluate scenario-based forecasts of the antiretroviral market in the next 10 years, taking into account patent expiry and generic incursion.

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