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The Antiretroviral Pipeline

September 2011

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Table of Contents


This year the antiretroviral pipeline report is produced against the background of global economic problems that have steadily worsened, with few indications of imminent recovery, the impact of which threatens the goal of universal treatment in both rich and poor countries.

In the United States, the waiting list for State AIDS Drug Assistance Programs (ADAPs) has increased by 900% in a year to over 8,000 by June 2011. In addition, ADAPs have implemented cost-containment strategies, including reducing formularies, increasing the threshold for financial eligibility, instituting a CD4 threshold of <350 cells/mm3, initiating waiting lists, and capping enrollment and access to the most expensive drugs. This bleak situation for uninsured or underinsured individuals who are otherwise ineligible for government assistance with antiretroviral therapy has so far been managed by patient assistance programs from drug manufacturers as a response to pressure from US activists in the Fair Pricing Coalition.1,2

In the UK, the public health care purchasers of HIV services in London (responsible for approximately 50% of HIV-positive people nationally) are seeking to contain national restrictions on National Health Service budgets by cost-saving from the drug budget. From April 2011, two-year contracts have been issued based on each manufacturer tendering bids for bulk volume purchasing. This aims to reduce use of antiretrovirals (ARVs) that have similar efficacy but are significantly more expensive, although treatment remains individualized and all licensed drugs can still be used based on clinical need. This policy was driven by the withdrawal of inflation linked funding and the need to find savings of £8-10 million.3


And last year a challenge to global access, in what was an otherwise hopeful and encouraging pipeline report, came with the first news that donors were restricting access to treatment for new patients in several countries.4 Partly as a result of activist pressure enrollment caps were later removed from PEPFAR programs in Uganda.5 Constricted health budgets in richer countries now politicize the choice between funding altruistic policies on global heath over those of providing health care for citizens at home.

Of course, in real terms, people in poorer countries are threatened most; they make up a broadly more marginalized demographic that is rarely prioritized for medical services. Despite this, right-wing health economists chose to propose that HIV funding has had a negative impact by dominating sponsor funding.6,7 In reality, the mobilization to focus on HIV, tuberculosis, and malaria has not only improved health investment in poor countries but has developed and strengthened the health infrastructure that was initially used as an excuse not to provide HIV treatment. Fortunately, each reactionary publication is vigorously rebutted with other articles and letters arguing the importance of the Global Fund to Fight AIDS, Tuberculosis and Malaria as a model for global health interventions.8

Consequently, new strategies are being formulated to try to prevent the potential health disaster that threatens to reverse the achievements of decades of prevention programs. In May 2011, the results from the HPTN 052 study added to accumulating data that quantify the significant impact of HIV treatment on reducing transmission -- by 96% in people starting treatment with CD4 counts >250 cells/mm3.9,10 If the incentive of access to antiretroviral treatment is removed this will reduce the primary incentive for people to test and will drive HIV back underground.

Six million people now on treatment are returned to health, often starting from advanced HIV infection (CD4 counts <100 cells/mm3)11 However, less than 50% of people in need of treatment globally based on criteria of a CD4 count of <200 cells/mm3 and 35% based on 350 cells/mm3 currently access treatment. Additionally, at least half of the people on treatment are using drugs whose greater toxicity increases the risk of serious health complications. The World Health Organization no longer recommends stavudine (d4T) and the European Medicines Agency reassessed the use of stavudine in Europe to circumstances where its use was driven as a lifesaving emergency (specifically based on economic rather than health advantages),12 yet d4T remains one of the most widely used nucleosides in antiretroviral combinations in poor countries. When data on side effects are collected, rates as high as 30-50% for irreversible peripheral neuropathy or lipoatrophy are commonly reported.

The demand for newer and more effective, efficient, safe, and affordable global treatment has never been greater. Western countries will remain a financially profitable market, but this is increasingly dependent on competitive rather than premium pricing.

This report summarizes results on pipeline compounds with promising future potential that have been presented in posters and presentations at key conferences. It is dependent on data that has passed some level of peer review, tempering the forward-looking statements of company press releases. It is limited to compounds that have cleared preclinical development and that have in vivo data in HIV-positive people.

Update From the 2010 Pipeline Report

Since last year's report, the only new chemical entity to be approved is the NNRTI rilpivirine (Edurant) in May 2011,13 with a fixed-dose combination of rilpivine/tenofovir/FTC (Complera) from Gilead and Tibotec approved in August 2011,14 for a U.S. Food and Drug Administration (FDA) indication for treatment-naive patients. An extended release formulation of nevirapine was also approved in March 2011.15

Gilead has completed and released 48-week data from ongoing phase III studies of a four-drug fixed dose combination (elvitegravir, cobicistat, tenofovir, and FTC), as it has with studies of the integrase inhibitor elvitegravir and the pharmacokinetic booster cobicistat. Additional pharmacokinetic and drug interaction studies have been reported for both compounds.17,19

Results from phase II studies of the integrase inhibitor dolutegravir (formerly S/GSK-572) in treatment-experienced patients were presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in February 2011, and planned phase III studies in treatment-experienced patients are now open.20

Phase II results for the NNRTI lersivirine in treatment-naive patients were presented at the International AIDS Society's (IAS) Conference in Rome, see below.

Phase II studies continue or are expected for an attachment inhibitor (BMS-663068), and a CCR5 inhibitor (cenicriviroc, formerly TBR-652).

Five compounds listed in last year's report as being in phase I studies have not visibly progressed, while three compounds had their development put on hold or discontinued: vicriviroc (a CCR5 inhibitor), GSK-761 (an NNRTI), and bevirimat (a maturation inhibitor).

Table 1 summarizes developments for the most important compounds highlighted in the 2010 pipeline report.

Table 1: Update on Pipeline Compounds in 2010 Report
rilpivirineTibotecNNRTIApprovedFiling submitted to FDA in July 2010 and approved for naive patients in May 2011.13
rilpivirine/tenofovir/FTC (Complera)Gilead/TibotecFixed-dose combination (NNRTI plus Truvada)ApprovedFiling submitted to FDA in November 2010 and approved for treatment-naive patients in August 2011.14
elvitegravirGileadIntegrase inhibitorPhase IIIPh3 48 week reached.16
cobicistatGileadPK enhancerPhase III48-week Ph2 results comparing to ritonavir were presented at ICAAC 2010 and published in the 27 March 2011 edition of AIDS.17,19
QuadGileadFixed dose combination (boosted integrase plus Truvada)Phase III48-week Ph2 results comparing to Atripla were presented at ICAAC 2010 and published in the 27 March 2011 edition of AIDS.17-19
dolutegravir (GSK1349572)ViiV/ShionogiIntegrasePhase IIbPh2b data in 24 people with raltegravir-resistance reported at CROI 2011 using twice-daily dosing.20
GSK 2248761 (IDX-12899)ViiVNNRTIPhase IIGSK announce that FDA put current development on hold due to toxicity concerns (four cases or seizure). No update since.21
UK-453061 (lersivirine)ViiVNNRTIPhase IINo clinical update. Ongoing studies continue.22,23
CTP-518GSKProtease inhibitorPhase INo update available.
BMS-663068BMSAttachment inhibitor (gp120)Phase IITwo studies at CROI 2011.24,25
VicrivirocMSDCCR-5 inhibitorPhase II/3All development halted permanent in July 2010.26
Bevirimat (MPC-4326; was PA-457)MyriadMaturation inhibitorPhase IIbDevelopment halted in June 2010.27
ibalizumab (TMB-355, was TNX-355)TaiMed BiologicsCD4-specific humanised IgG4 monoclonal antibodyPhase IIbNo updated information based on listed trials.28
cenicriviroc (TBR-652)TobiraCCR5Phase IISingle one-dose PK study reported at CROI 2011. No new data. Ph2 study in naive launched April 2011 (CVC +/- EFV vs efavirenz + Truvada).29,30
CMX-157Chimeri NRTI similar to tenofovirPhase IIMinor update on Ph1 by press release.31
SPI-251SequoiaPK enhancerPhase IINo further study results presented or trials listed.
PF-3716539Pfizer/ViiVPK enhancerPhase INo further data or new studies since acquired by ViiV but still listed in their pipeline.32
TMC558445TibotecPK enhancerPhase INo further study results presented or trials listed.
TMC-310911TibotecProteasePhase INo further reports. One 14-day Ph2 study listed as ongoing (from 2009).33

New Compounds First Reported in the Last Year

Several compounds first reported in vivo results this year and are summarized in Table 2.

GS-7340: A Prodrug of Tenofovir

GS-7340 is a formulation of tenofovir in development by Gilead that achieves higher levels of the active metabolite in lymph tissue and target cells including peripheral blood mononuclear cells (PBMCs) and has higher potency compared to equivalent tenofovir doses while maintaining reduced plasma concentrations (approximately 100-fold lower). The EC50 of GS 7340 against HIV-1 in MT-2 cells is 0.005 uM compared to 5 uM for tenofovir. This has the potential to require less active pharmaceutical ingredient (API), increase antiviral activity compared to tenofovir, and reduce systemic-related toxicity.

Results from the first dose-ranging study were presented at CROI 2011.34 The double-blind study randomized 30 treatment-naive patients (CD4 >200; viral load >15,000) to either 50 mg or 150 mg of GS-7340 or to tenofovir 300mg (ratio 1:1:1). After 14 days these three groups produced time weighted viral load reductions of -0.95 (+0.32), -1.07 (+0.14) and -0.54 (+0.32) log10 copies/mL, respectively. Mean viral load levels dropped by -0.95, -1.57, and -1.74 log in the tenofovir, 50 mg, and 150 mg arms, respectively. Blood levels were lower (Cmax/AUC by 94%/88% with 50 mg and by 80%/58% with 150 mg) than the tenofovir group with PBMC levels approximately 30-fold higher.

There were no study discontinuations and no grade 3 or 4 events. Side effects reported were generally mild (nausea, headache).

The potential of this compound looks promising. It is unfortunate that it was not prioritized for faster development. In vivo data were presented on GS-7340 nine years ago at CROI 2002.35

Festinavir: An NRTI (Previously OBP-601)

Festinavir is an NRTI with a chemical structure similar to stavudine (d4T), but which initial studies indicate should not have the same side effect concerns as it is a weak inhibitor of DNA synthesis in cell studies. BMS acquired development and marketing rights to Festinavir from Oncolys BioPharma in December 2010.36

Results from a phase Ib-IIa dose escalation study were presented as a poster at the 50th ICAAC in September 2010.37

Festinavir monotherapy was given for ten days to four groups of eight treatment-experienced patients currently not on treatment (each 6 active: 2 placebo) using oncedaily doses of 100, 200, 300, and 600 mg.

Mean reductions in viral load at day 10 were 0.87, 0.98, 1.36 and 1.22 log10/copies/mL in the 100, 200, 300, and 400mg groups, respectively (vs -0.07 in the placebo group) from baseline levels that ranged from 4.2 - 4.6 log10 copies/mL.

No pattern of side effects appeared over 10 days with all grade 2-3 (n = 13) and grade 4 (n = 2) side effects judged unrelated to the study drug. No new reverse transcriptase mutations emerged at day 10 and 17.

In vitro data on the drug susceptibility of festinavir, including to the Q151M NRTI multidrug resistant mutation were presented in a poster at CROI in 2008.38

Although antiviral activity was reduced in presence of in most viruses carrying nucleoside-associated mutations (5- to 10-fold), including M41L (0.3 to 4.3-fold), and D67N (1.6- to 7.8-fold) resistance mutations, together with K103N +/- M184V. Viruses carrying the Q151M mutation were hypersusceptible to OBP-601 (0.1- to 0.2-fold), even in the presence of K65R (0.3- to 1.3-fold).

Table 2: Compounds With First Data Presented During the Previous Year
GS-7340GileadNtRTIPhase IINew formulation of tenofovir suggesting improved PK.Abstract at CROI 2011.33
festinavir (OBP-601)BMSRTIPhase IIStructurally close to d4T but hopefully without associated toxicity.Abstract at ICAAC 2010.36

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
See Also
More on HIV Medications
HIV Drugs in Development

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