The Pipeline: Three to Watch
While this is certainly good news, the likelihood that an antiretroviral drug will be approved in 2004 seems slim. Currently only one compound -- Boehringer Ingelheim's PI, tipranavir -- is in Phase III clinical trials (see "Tipranavir: the First Nonpeptidic Protease Inhibitor," BETA, Winter 2004, and "Open Clinical Trials" in this issue). Yet no oral or poster presentations on tipranavir were presented at the 11th Conference on Retroviruses and Opportunistic Infections, the major annual venue for new basic and clinical research related to HIV infection, held February 8-11 in San Francisco.
In fact, this year's meeting did not have an entire oral session devoted solely to investigational compounds as in the past. There was one session on the pharmacology (composition and effects) of new agents, but most of the presentations were of research on already approved drugs. And while there were numerous posters on new compounds, most concerned either laboratory or early clinical studies.
While the relatively empty drug pipeline is discouraging, there were three isolated oral presentations at the Retrovirus conference that offered new data on the use of investigational anti-HIV agents in people with HIV. These presentations reported results from early Phase I/II clinical trials of D-D4FC, a new NRTI; SCH-D, a coreceptor antagonist; and the attachment inhibitor BMS-488043. This issue's Drug Watch will discuss these aspiring drug candidates and why they are three to watch.
The results of the first Phase II study of D-D4FC, and the first data on the use of this investigational agent in people with HIV, were presented at the Retrovirus conference by Robert Murphy, M.D., from Northwestern University in Chicago. These preliminary results showed that D-D4FC -- when given without any other anti-HIV medications to people who had never been treated -- caused dramatic reductions in viral load after only ten days of treatment.
Thirty HIV-positive, treatment-naive individuals (24 men, six women) with CD4 cell counts above 50 cells/mm3 and viral loads above 5,000 copies/mL were enrolled in this monotherapy dose-escalation study. Subjects were randomized to one of three once-daily doses of D-D4FC -- 50, 100, or 200 mg -- or placebo for ten days. The study was double-blinded, which means that neither the subjects nor the clinicians knew who was taking what dose of the study drug or who was taking the placebo. At the start of the trial, the mean (average) baseline viral load was 4.49 log copies/mL (roughly 30,000 copies/mL) and the mean CD4 cell count was 468 cells/mm3.
At the end of the ten-day treatment period, the mean viral load in the people receiving D-D4FC dropped by approximately 1.7 log copies/mL, about a 95% decrease from baseline levels. For the different dose groups, the mean reductions from baseline were 1.67, 1.74, and 1.77 log copies/mL for the 50, 100, and 200 mg doses, respectively. Safety evaluations revealed that all adverse events, including headache and fatigue, were mild or moderate and occurred at similar rates in the active drug and placebo groups.
D-D4FC's effect on viral load compared favorably with that of other potent NRTIs, such as emtricitabine, 3TC, and tenofovir. Importantly, no serious drug-related adverse events were reported; however, it should be kept in mind that this study's duration was less than two weeks. D-D4FC has a long half-life (13-17 hours) and is orally bioavailable, which means that it could potentially be used as a once-daily oral treatment.
Based on the results of this early clinical trial and the drug's effectiveness against drug-resistant HIV, D-D4FC is being evaluated further in longer studies in people who have previously been treated with other antiretrovirals. The drug was discovered by Pharmasset and is being developed by Incyte. (For more information, see "Open Clinical Trials" in this issue.)
In laboratory studies, SCH-D has been found to bind specifically to CCR5 coreceptors (which appear to be most commonly used by HIV) and to effectively block a wide range of HIV isolates from attaching to cells. Compared with SCH-C, an earlier Schering-Plough coreceptor candidate no longer in development, SCH-D is about ten-fold more potent and appears not to cause heart toxicity, the downfall of its sister compound. Unlike T-20, SCH-D can be taken orally. Results of the first use of this CCR5 coreceptor antagonist in people with HIV were reported at this year's Retrovirus conference.
Mark Laughlin from Schering-Plough presented results of a 14-day study that was similar in design to the D-D4FC study. For 14 days, 48 people chronically (i.e., not recently) infected with HIV received only SCH-D at twice-daily doses of 10, 25, or 50 mg, or were given a placebo. Those participating in the study had not taken antiretroviral drugs in the previous eight weeks and had CD4 cell counts greater than 200 cells/mm3. The mean baseline viral load for the treatment groups ranged from approximately 36,000 copies/mL for the 10 mg dose group to over 100,000 copies/mL for the 50 mg dose group. The mean CD4 cell count ranged from 369 to 486 cells/mm3.
SCH-D demonstrated increasing antiviral activity over this range of doses, with the highest dose resulting in a 1.62 log reduction in viral load by the end of the two-week treatment period. Notably, 81% of the subjects in the highest dose group achieved a greater than 1 log drop (greater than 90% decrease from baseline) in their viral load. Mean viral load reductions with the other doses were also greater than 1 log: 1.08 and 1.56 log copies/mL for the 10 and 25 mg doses, respectively. The drug appeared to be safe and well tolerated in all dose groups.
This study is further proof that compounds that inhibit binding of the virus to secondary attachment receptors can reduce viral replication when used in people infected with HIV. (A Phase II study of SCH-D is now enrolling; see "Open Clinical Trials" in this issue.)
The antiviral activity of BMS-488043 was evaluated in a placebo-controlled, multiple-dose study in 30 HIV-positive adults (26 men, four women). Participants were antiretroviral-naive or had not taken any antiretroviral medication for at least 16 weeks before study entry; 14 of the 30 had previously taken antiretroviral therapy. Subjects had CD4 cell counts above 250 cells/mm3 and viral loads between 5,000 and 500,000 copies/mL; at study entry the mean viral load was 4.61 log copies/mL (approximately 40,000 copies/mL) and the mean CD4 cell count was 399 cells/mm3. Participants received either 800 or 1,800 mg oral doses of BMS-488043 or placebo twice daily for seven days.
After seven days, BMS-488043 monotherapy produced an approximately ten-fold reduction in mean viral load, with the majority of participants in both dose groups experiencing a 1 log or greater decrease. However, the mean reduction in viral load eight days after the start of treatment (that is, one day after treatment ended) was just under 1 log: 0.72 and 0.96 log copies/mL in the 800 and 1,800 mg dose groups, respectively. Nevertheless, these reductions still represented nearly a 90% drop in the subjects' viral loads, including those who had received prior antiretroviral therapy. Mild to moderate side effects included fatigue, headache, insomnia, and diarrhea. No serious adverse events were noted. This study is the first demonstration (in other words, a "proof of concept") that a drug that binds to the virus rather than a host cell can reduce viral replication in humans and supports further evaluation of compounds belonging to this new antiretroviral class. Phase II research of BMS-488043 is expected to begin in late 2004.
mitochondrial toxicity: damage to the mitochondria as a side effect of drugs, which can lead to lactic acidosis, a potentially fatal buildup of lactic acid in the blood.
placebo: an inactive substance (e.g., a "sugar pill") or mock therapy.
John Hawes (firstname.lastname@example.org) is a freelance science writer who frequently writes about HIV/AIDS.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.