Introduction
 
In the current antiretroviral landscape, resistance in all three of the established classes is proving to be problematic. Accordingly, current clinical trials are recruiting treatment-resistant patients, and many companies are actively positioning their drugs in later therapy. The emergence of the Entry Inhibitor class is also expected to change the market place.
 

 
Scope
 
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
 
Highlights
 
The majority of pipeline products are being developed for the treatment of resistant virus and are expected to be used in second and later lines of therapy. However, disappointing data and uncertain positioning has created a lack of clarity among physicians as to where some late-stage drugs should be used.
 

 
Datamonitor expects the NRTIs to remain the dominant class, contributing 38% of total sales by 2015, although the EIs will experience the most rapid growth. However, should the CCR5 inhibitors be used first-line, in 2015 over a quarter of sales will be accounted for by the EI class, compared to 14% if they are used in salvage therapy.
 

 
Several drugs, such as tipranavir and capravirine, are viewed as 'holding drugs' where physicians are likely to use them only until improved alternatives are available. To ensure maximum sales during this limited lifespan, companies should undertake an intensive initial marketing campaign before switching leads to premature sales decrease.
 

 
Reasons to Purchase
 
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

TABLE OF CONTENTS
 
CHAPTER 1 EXECUTIVE SUMMARY 3
 
Scope of the analysis 3
 
Datamonitor insight into the HIV market 3
 
Forecasts and assumptions 4
 
CHAPTER 2 PIPELINE DYNAMICS 16
 
An overview of the pipeline reveals few Phase III candidates 16
 
The CCR5 inhibitors could, potentially change the treatment paradigm, redistributing sales share from established products 17
 
New HIV players are expected to account for the majority of sales by 2015 19
 
GSK will see its share drastically reduced, but will still be the leading HIV company 20
 
Should all three pipeline compounds reach the market, Tibotec/J&J is expected to experience the strongest growth in antiretroviral sales 22
 
CHAPTER 3 PATIENT POTENTIAL 24
 
As HIV moves towards a chronic manageable disease, the epidemiology is changing 24
 
Disease definition 24
 
Despite awareness campaigns and measures to prevent transmission, HIV incidence in some countries continues to rise 25
 
Immigration from areas of high prevalence means the need for antiretroviral therapy in the seven major markets will continue to grow 26
 
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 28
 
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 28
 
Historically affecting men who have sex with men (MSM) and intravenous drug users (IVDU), HIV incidence is rapidly growing in women 30
 
The HIV-infected population is growing older 31
 
Recently, the number of HIV diagnoses in older age groups has increased 31
 
The widespread use of HAART has led to a life expectancy equivalent to that of the uninfected population 33
 
A greater number and range of therapies has resulted in a variety of treatment-experienced patients 35
 
Treatment-naïve patients make up a limited percentage of the overall HIV-treated population 35
 
In accordance with the US DHHS guidelines, intermediate treatment-experienced patients have been recognized as a rapidly growing group 35
 
Salvage therapy is becoming further downstream as third, fourth and even fifth lines of therapy become feasible due to new drug launches 36
 
The two main unmet needs in HIV therapy are resistance to currently available drugs and improved patient quality of life 39
 
Resistance, both acquired and developed, is becoming the main concern for HIV physicians 39
 
As HIV patients are living longer, quality of life considerations play a key role in prescription decisions 40
 
CHAPTER 4 R&D APPROACH 42
 
Clinical trial endpoints are shifting in response to the newer unmet needs in HIV 42
 
Early clinical trial endpoints were primarily based upon efficacy 42
 
With improved understanding of HIV and the advent of HAART therapy, endpoints have changed significantly 43
 
Activity against resistant virus – a must for most of the HIV pipeline 43
 
Quality of life considerations 44
 
Gilead’s 903 trial has set new standards in HIV clinical trial design 45
 
Gilead’s 903 trial is the first three-year, international, randomized, double-blind, clinical trial of an HIV drug regimen in treatment-naïve patients 45
 
Frequently cited as a landmark study, the standard set by the 903 trial is likely to be emulated in future clinical trial design 46
 
Several backbones are available for use in clinical trials, which is likely to affect future uptake of pipeline drugs 48
 
CHAPTER 5 NRTI LATE-STAGE DRUG ANALYSIS & FORECASTS 50
 
The NRTIs, being the oldest class with the most marketed drugs, is expected to undergo significant changes in dynamics in the next decade 50
 
The definition of a gold-standard NRTI is no longer clear cut 52
 
Traditionally, Combivir was widely regarded as the gold-standard NRTI 52
 
Viread, with its potent activity, favorable resistance profile and once-daily dosing, is perceived by some as the new gold standard 53
 
Truvada and Epzicom, launched in 2004, can also be viewed as candidates for the label of gold-standard NRTI 55
 
Drug resistance is the predominant therapeutic issue in the NRTI class and an unmet need of growing importance 57
 
Several pipeline NRTIs are expected to reach the market within the next five to 10 years 58
 
Within the NRTI class, most pipeline drugs have demonstrated activity against common resistant mutations 59
 
Several drugs with activity against problematic NRTI resistance mutations are being developed 59
 
Elvucitabine – demonstrable improvement in M184V patients 59
 
More frequently, patients with resistant virus are being recruited for NRTI clinical trials 64
 
Racivir – patients with M184V sought for study RCV-201 64
 
The treatment-experienced patient pool is likely to offer the greatest opportunities for pipeline NRTIs 68
 
With Epivir, Viread and the fixed-dose combinations firmly established as early-line therapy, companies are looking to the treatment-experienced patient pool 68
 
Reverset is being developed primarily for salvage therapy 68
 
The limited patient pool for new NRTIs has led to some companies out-licensing or ceasing developmental products 73
 
SPD-754 recently out-licensed to Avexa Ltd (and given fast-track status by the FDA) 73
 
GlaxoSmithKline terminates research agreement MIV-210 but development still ongoing 78
 
Several early-stage NRTIs have been discontinued in development 82
 
GS 7340 profile does not support continued development 82
 
Gilead terminated its licensing agreement for amdoxivir for strategic reasons 82
 
Boehringer Ingelheim opted to discontinue development of MIV-310 82
 
CHAPTER 6 PI LATE-STAGE DRUG ANALYSIS AND FORECASTS 84
 
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 84
 
Despite being challenged by Reyataz, Kaletra is still the PI gold standard 85
 
Based on recent sales, Reyataz poses a serious challenge as contender for the PI gold standard 87
 
Key unmet needs in PI therapy are being addressed by the pipeline 90
 
Despite being not being seen as the main unmet need, PI resistance is the major issue driving new product development 91
 
Despite PK problems, physicians believe tipranavir will have a valuable role to play in later stage PI therapy 93
 
Profile 93
 
Datamonitor analysis 98
 
TMC-114 – promising clinical data raises possibility of favorable positioning 102
 
Recent clinical trials show that the presence of I54L/M mutations does not reduce susceptibility to GW-640385 108
 
Profile 108
 
CHAPTER 7 NNRTI LATE-STAGE DRUG ANALYSIS AND FORECASTS 113
 
Usually the preferred first-line therapy, the NNRTIs can only be used for a limited time before class resistance reduces efficacy 113
 
One pill, once-daily Sustiva is the NNRTI gold standard 114
 
Class resistance is the major unmet need for the NNRTIs 116
 
The development of certain resistance mutations results in patients no longer being susceptible to the entire NNRTI class 116
 
Pipeline NNRTI compounds, with activity against these resistance mutations, may enable patients to use this class in second- and even third-line therapy 117
 
TMC-125’s activity against NNRTI-resistant virus is generating clinical and market interest in the compound’s potential 118
 
Profile 118
 
Key clinical trial overview 120
 
Trial results 120
 
Datamonitor analysis 121
 
TMC-278 – efficacy in naïve patients could mean potential for first-line positioning 122
 
Profile 122
 
Key clinical trial overviews 123
 
Trial results 124
 
Datamonitor analysis 125
 
GW-695634 – positive preliminary data but will it be enough to challenge the Tibotec compounds? 126
 
Profile 126
 
Key clinical trial overview 127
 
Trial results 128
 
Datamonitor analysis 128
 
Pharmacokinetic issues have had to be overcome to ensure the continued development of some NNRTIs 129
 
Surprising rates of failure on capravirine clouds future potential 129
 
Profile 129
 
Key clinical trial overview 132
 
Trial results 132
 
Datamonitor analysis 134
 
Phase II/III trials planned but no apparent progress for calanolide A 136
 
Profile 136
 
Key clinical trial overview 138
 
Trial results 138
 
Datamonitor analysis 138
 
CHAPTER 8 EI AND OTHERS LATE-STAGE DRUG ANALYSIS AND FORECASTS 140
 
The emergence of a new class of antiretrovirals could lead to changes in accepted treatment paradigms 140
 
The launch of Fuzeon made the effective treatment and increased survival of patients with advanced stage disease a realistic option 141
 
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 143
 
The EI and others pipeline encompasses a wide range of products, with a variety of targets and mechanisms of action being investigated 144
 
As the two main co-receptors essential for HIV entry into uninfected cells, CCR5 and CXCR4 receptors have become important antiretroviral targets 145
 
UK-427, 857 – resistance profile looks promising but concerns abound regarding viral tropism 147
 
Combination therapy with GW873140 – data proves promising 151
 
SCH-417690 (SCH-D) – CCR5 antagonist with potent antiviral effect 156
 
AMD070 – will the CXCR4 tropic virus be a large enough niche? 159
 
Monoclonal antibodies, being investigated in heavily treatment-experienced patients, could increase salvage therapy options 162
 
TNX-355 – a last resort for triple-class experienced patients? 163
 
PRO-542 – being positioned in highly treatment-experienced patients, but limited advances in clinical trials 167
 
PRO-140 – a second approach by Progenics 170
 
Other potential targets being investigated include attachment, maturation and integrase inhibition 171
 
PA-457’s totally novel mechanism of action warrants FDA fast-track status 171
 
BMS-488043 – proof of concept for first in class likely to lead to development of follow-up compounds 174
 
Integrase inhibitors represent a key hope for the future, but toxicity issues are clouding their immediate development 178
 
Discontinued drugs 178
 
Viraldon – Phase II/III trials discontinued due to failure to complete recruitment 178
 
Profile 178
 
APPENDIX A – PIPELINE PRODUCT PROFILES 179
 
NRTI profiles 179
 
Elvucitabine 179
 
Clinical trial overview 179
 
Racivir 180
 
Clinical trial overview 180
 
Reverset 181
 
Clinical trial overview 181
 
SPD-754 183
 
Trial reference 2 183
 
PI profiles 184
 
TMC-114 184
 
Clinical trial overview 184
 
NNRTI profiles 186
 
TMC-125 186
 
Clinical trial overview 186
 
Calanolide A 188
 
Clinical trial overview 188
 
Capravirine 190
 
Clinical trial overview 190
 
EI profiles 192
 
TNX-355 192
 
Clinical trial overview 192
 
UK-427, 857 193
 
Clinical trial overview 193
 
GW873140 194
 
Clinical trial overview 194
 
PRO-542 195
 
Clinical trial overview 195
 
APPENDIX B 197
 
Bibliography 197
 
Press releases 209
 
Websites 210
 
Conferences 211
 
Miscellaneous sources 212
 
Report methodology 212
 
APPENDIX B 214
 
About Datamonitor 214
 
About Datamonitor Healthcare 214
 
Datamonitor Healthcare’s therapy area capabilities 215
 
Disclaimer 216