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The Pipeline: Three to Watch

Summer 2004


Four antiretroviral drugs were approved in 2003: emtricitabine (FTC, Emtriva), a nucleoside reverse transcriptase inhibitor (NRTI); the protease inhibitors (PIs) atazanavir (Reyataz) and fosamprenavir (Lexiva); and T-20 (enfuvirtide, Fuzeon), the first of a new anti-HIV drug class, entry inhibitors.

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.

D-D4FC, a Potent New NRTI

D-D4FC (Reverset, formerly known as DPC-817) is a new drug from an old class of antiretrovirals -- the NRTIs, which include drugs such as AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir). Since drug resistance is an increasing problem, much of the current research into new drugs from the existing classes of antiretrovirals is directed at compounds that are effective against resistant virus. D-D4FC is no exception. In vitro (laboratory) studies have shown that D-D4FC has potent antiviral activity against HIV strains resistant to other NRTIs, including AZT, 3TC, and tenofovir DF (Viread). Of note, evidence of mitochondrial toxicity, which is associated with this class, has not been seen in studies of D-D4FC to date.

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.)

SCH-D, Another Attempt at Coreceptor Blocking

SCH-D (also known as SCH 417690) belongs to the same broad class of entry inhibitor drugs as T-20. However, while T-20 is a fusion inhibitor that blocks HIV from fusing with a host (human) cell after attaching to its membrane, SCH-D is a coreceptor antagonist that attempts to prevent HIV from initially binding to a host cell by blocking an essential coreceptor. In order to attach to a cell and gain entry, HIV requires two things: a CD4 receptor that resides on the surface of certain human cells, and a secondary receptor, or coreceptor. Depending on the type of HIV strain, the virus uses either the CCR5 or the CXCR4 coreceptor to complete its attachment to the cell's surface.

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.)

BMS-488043, a Novel Attachment Inhibitor

Another investigational agent that represents a new anti-HIV drug class is BMS-488043, a compound being developed by Bristol-Myers Squibb. Like Schering's compound, BMS-488043 is also an attachment inhibitor, but this agent blocks attachment by binding to the virus rather than a human cell. HIV uses a molecule on its surface called gp120 to attach to a cell's CD4 receptors. BMS-488043 blocks viral entry by selectively binding to gp120 and preventing HIV from attaching to a CD4 receptor. One benefit of attacking HIV in this manner is that attachment is blocked regardless of the type of cell coreceptor present. (In contrast, SCH-D will work only for cells that have CCR5, rather than CXCR4, coreceptors.) Results from studies in healthy, HIV-negative volunteers indicated that BMS-488043 could be given orally and had a good safety profile. The results of an early Phase I clinical study in HIV-positive individuals were presented at the Retrovirus conference by George Hanna of Bristol-Myers Squibb.

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.


An important reason to focus on these three new compounds, besides the potency and relative safety suggested by these early studies, is that each of them represents a different method of attacking HIV. The problem of drug resistance, and the role it plays in treatment failure, is growing -- not only among those who currently are on treatment, but also in people who have never been exposed to antiretroviral therapy. The latter situation can occur when a person is infected with a drug-resistant HIV strain. HIV is increasingly becoming resistant to the currently available drugs in the first three antiretroviral classes, as well as to T-20, the only currently approved member of the fourth (entry inhibitor) class. New drugs that can durably suppress viral load in people with resistant virus are urgently needed. By attacking the virus using drugs with different mechanisms of action, the problem of viral resistance may be overcome enough to ensure that people with HIV will always have adequate treatment options. The three investigational drugs described here represent promising first steps in that direction.


half-life: the time required for half the total amount of a drug to be eliminated from the body.

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 ( is a freelance science writer who frequently writes about HIV/AIDS.

Selected Sources

  1. Hanna, G. and others. Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043. 11th Conference on Retroviruses and Opportunistic Infections (CROI). San Francisco. February 8-11, 2004. Abstract 141.

  2. Hanna, G. and others. Safety, tolerability, and pharmacokinetics of a novel, small-molecule HIV-1 attachment inhibitor, BMS-488043, after single and multiple oral doses in healthy subjects. 11th CROI. Abstract 535.

  3. Lin, P.F. and others. Characteristics of a small molecule HIV-1 attachment inhibitor BMS-488043: Virology, resistance, and mechanisms of action. 11th CROI. Abstract 534.

  4. 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. Abstract 137.

  5. Schurmann, D. and others. SCH D: Antiviral activity of a CCR5 receptor antagonist. 11th CROI. Abstract 140LB.

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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.