• A Picture of Progress
• Traditional Antiretroviral Classes
• Newer Antiretroviral Classes
• Commentary
• Selected Sources

The antiretroviral drug pipeline was last reviewed in BETA three years ago (see "The HIV/AIDS Drug Pipeline: A Status Report" in the Summer/Autumn 2002 issue). That report called on pharmaceutical companies to "ensure a steadier stream of innovative and affordable approaches to managing HIV infection." Is this goal being achieved?

A Picture of Progress

The most obvious sign of progress is the arrival of the entry inhibitor class of drugs into the clinic with the March 2003 approval of T-20 (enfuvirtide, Fuzeon). The entry inhibitor class includes several subclasses of agents -- attachment inhibitors, coreceptor antagonists, and fusion inhibitors such as T-20 -- that prevent HIV from gaining access to cells (see sidebar and "Newer Antiretroviral Classes," below). The approval of the first drug in a new class of antiretrovirals is a significant step forward in treatment and a hopeful sign of future advances.

Another way to see the changes in drug development over the past few years is to look at the current status of the drugs highlighted in the 2002 report. These included new drugs or reformulations of existing drugs that were considered to be closest to approval and two new agents that had just reached the advanced clinical development stage (Phase II/III studies). (For more information on clinical trials and phases of research, see "A Guide to Clinical Trials" in this issue.)

Somewhat surprisingly, all of these drugs are now approved and all but one are in clinical use (see below). Tipranavir (Aptivus) was granted accelerated approval by the Food and Drug Administration (FDA) this past June (see "News Briefs" in this issue). Extended release d4T (stavudine, Zerit XR) was approved in December 2004 but is not yet commercially available.

Often unnoticed in drug development are the compounds that never move out of preclinical research, or those that appear promising in preclinical studies but fade away in early human trials due to pharmacologic, efficacy, or safety concerns. Such was the case for many antiretroviral compounds that were alive in 2002 but are no longer being pursued. However, some candidates have survived and may progress to approval in the next few years, just as those shown above have done. In the meantime, this report provides an update on agents that have moved to the final preapproval stage of drug development (Phase III) and a list of new compounds in all stages of clinical development as of May 2005. (For recent reports on several agents further back in the development pipeline, see "News Briefs" in this issue.)

Traditional Antiretroviral Classes

Among the three traditional antiretroviral drug classes, there are 12 new compounds in more advanced clinical trials: six NRTIs, four NNRTIs, and two PIs (see table below). The furthest along are the NRTI Reverset (formerly D-d4FC), the NNRTI capravirine (formerly AG-1549), and the PI TMC-114, all of which are in Phase III studies.

Reverset is a cytidine analog like 3TC (lamivudine, Epivir) and FTC (emtricitabine, Emtriva). As with many other investigational drugs from the three traditional classes, Reverset is being developed for use against HIV strains that are resistant to currently approved therapies as well as wild-type (nonmutated) virus. In treatment-naive HIV positive people, once-daily Reverset alone has produced maximum reductions in HIV viral load of 1.2-2.3 logs after ten days. In another ten-day monotherapy trial, Reverset was studied in eight NRTI-experienced individuals whose current therapy was failing to suppress HIV. The mean viral load before Reverset treatment was 4.53 log copies/mL. At the end of the ten-day study, the mean viral load decrease was 0.8 logs, and four of the eight subjects achieved viral loads below 400 copies/mL.

Capravirine is an NNRTI with potent activity against HIV, including strains with the K103 mutation -- the genetic change that causes resistance to the entire NNRTI class. Previously, the FDA put a hold on capravirine due to concerns about vasculitis (blood vessel inflammation), but the drug was subsequently cleared for further clinical study. Phase II research has shown that capravirine can produce durable viral suppression in some people, although a recent trial evaluating the addition of capravirine to a standard PI-based regimen did not show any significant difference between subjects who received capravirine and those who did not after 48 weeks of treatment. There was some evidence that capravirine was more effective in people with 3TC and AZT resistance, but this needs to be confirmed. Several Phase II and III trials are ongoing.

TMC-114 is a protease inhibitor with activity against PI-resistant HIV. TMC-114 appears to be effective in HIV positive people on previously failing PI regimens when it is boosted with low-dose ritonavir (TMC-114/r) to increase its potency. An interim analysis of 24-week data from two ongoing dose-ranging trials in 497 treatment-experienced subjects showed that TMC-114/r produced significantly better virological response (greater than 1.8 log viral load decrease from baseline) compared with optimized regimens containing comparator PIs. After 24 weeks, 47% of subjects receiving 600/100 mg TMC-114/r twice daily achieved viral loads below 50 copies/mL; viral suppression rates in the 400/100 mg once daily, 800/100 mg once daily, and 400/100 mg twice daily arms were 30%, 31%, and 38% respectively. Two-thirds of the TMC-114/r-treated individuals whose regimens also included T-20 achieved viral loads below 400 copies/mL. Such a regimen may be highly valuable as salvage therapy, for which there are few current options. These trials will continue through 96 weeks, and a new Phase III trial is beginning (see "Open Clinical Trials" in this issue).

Newer Antiretroviral Classes

To date, only one drug (the fusion inhibitor T-20) has been approved outside of the three traditional antiretroviral classes. Although research is ongoing to develop drugs from novel classes, most compounds that have progressed beyond early Phase I trials act as entry inhibitors, including several attachment inhibitors and coreceptor antagonists in Phase II trials. The maturation inhibitor PA-457 is also in Phase II, and in late June Gilead announced a new Phase I/II study of their integrase inhibitor, GS-9137.

The only investigational drug from a newer antiretroviral class currently in Phase III clinical development is the entry inhibitor maraviroc (formerly UK-427,857). Specifically, maraviroc is a CCR5 coreceptor antagonist (see sidebar) and appears to be very potent. In HIV positive people beginning antiretroviral therapy, maraviroc treatment has been associated with a viral load drop of 1.42 logs after only ten days. Other preliminary data indicate that dose adjustments will be needed when maraviroc is combined with other antiretroviral agents due to pharmacokinetic drug-drug interactions (see "Drug Interactions and Anti-HIV Therapy" in this issue).

Laboratory research has shown that HIV resistant to maraviroc appears to be susceptible to other coreceptor antagonists. Phase II/III studies of maraviroc in treatment-naive and treatment-experienced individuals are in progress (see "Open Clinical Trials" in this issue for two currently enrolling studies).

Commentary

Antiretroviral drug development over the past few years has led to improvements in how HIV disease is managed, with lower pill burdens, useful reformulations of older drugs, fixed-dose combination pills, and more effective therapies, especially for people without extensive treatment history. But the movement forward seems slow. After the recent approval of tipranavir, no other experimental agent is under review for FDA approval. Only one -- Tibotec's TMC-114 -- will be available through an expanded access program (EAP) for people with few treatment options (see "News Briefs" in this issue).

And what of the innovative and affordable approaches that were called for in the 2002 drug progress report? Additional entry inhibitors may prove to be a breakthrough in the management of HIV/AIDS. Like T-20, however, they are likely to be expensive. Another answer has been increased pharmacokinetic enhancement, or boosting, of approved PIs (see "Drug Interactions and Anti-HIV Therapy" in this issue). This approach takes advantage of drugs that are already available and about which a great deal is already known, and renders them more potent, more convenient, or both. Yet the boosted PI strategy is hampered by the present need for ritonavir (Norvir) as the boosting agent -- a drug available through only one manufacturer (Abbott) that dramatically raised the price of this PI by 400% in December 2003. It had been hoped that research would have provided a cheaper and more accessible boosting alternative by now.

Although there has been progress in the pipeline since 2002, those who fund and carry out HIV research should be encouraged to "think out of the pipe," to move from better managing this infection to realizing a cure.

John Hawes (jhawes7@comcast.net) is a science writer and editor who frequently writes about HIV/AIDS.

Selected Sources

1. Hammond, J.L. and others. Long-term virologic response to capravirine in HIV-infected, NNRTI-experienced patients. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Chicago. September 14-17, 2003. Abstract H-871.

2. Hawley, P. and others. Absence of risk of vasculitis in a HIV population taking capravirine -- results of an active monitoring plan. 14th International AIDS Conference. Barcelona. July 7-12, 2002. Abstract TuPeB4549.

3. Katlama, C. and others. Efficacy of TMC114/r in 3-class experienced patients with limited treatment options: 24-week planned interim analysis of 2 96-week multinational dose-finding trials. 12th Conference of Retroviruses and Opportunistic Infections (CROI). Boston. February 22-25, 2005. Abstract 164LB.

4. Muirhead, G. and others. A novel probe drug interaction study to investigate the effect of selected ARV combinations on the pharmacokinetics of a single oral dose of UK-427,857 in HIV+ subjects. 12th CROI. Abstract 663.

5. Murphy, R.L. and others. Tolerance and potent anti-HIV-1 activity of Reverset following 10 days of monotherapy in treatment-naive individuals. 11th CROI. San Francisco. February 8-11, 2004. Abstract 137.

6. Murphy, R.L. and others. Tolerance and anti-HIV activity of Reverset following 10 days as add-on therapy to current regimens in treatment-experienced HIV-infected individuals. 44th ICAAC. Washington, DC. October 30 - November 2, 2004. Abstract H-1130.

7. Pesano, R. and others. 24 week safety, tolerability, and efficacy of capravirine as addon therapy to nelfinavir and 2 nucleoside reverse transcriptase inhibitors in patients failing a non-nucleoside reverse transcriptase inhibitor-based regimen. 12th CROI. Abstract 555.