The Body Covers: The 11th Conference on Retroviruses and Opportunistic Infections
A Look at Antiretroviral Agents in Development -- An Attachment Inhibitor and Two CCR5 Receptor Antagonists
February 11, 2004
Every year at CROI there is a session on new antiretroviral agents. This year, that session included exciting data on novel agents targeting the various steps HIV requires to attach to a CD4 cell. Because these new agents act extracellularly, they potentially avoid interactions with intracellular components that may result in toxicity or adverse events. This makes them important potential weapons in the fight against HIV.
Earlier presentations in this session covered the role of several CCR5 receptor antagonists. CCR5 are receptor molecules in the surface of some lymphocytes. Blocking these receptors with a drug will prevent HIV from successfully entering inside the host cells. Several compounds are currently under investigation, but in this session we heard about two new CCR5 receptor antagonists.
GlaxoSmithKline presented information on the compound GW873140. In a double-blind, randomized study in healthy volunteers, this drug was fairly well tolerated with the exception of mild abdominal symptoms. We also heard information on Schering-Ploug's compound, called SCH-D. This molecule will be replacing the previous compound, SCH-C, which they initially had under investigation. SCH-D appears to have very good in vitro activity and a high barrier for the selection of resistant viruses.
Dr. G. Hanna from Bristol-Myers Squibb gave one of the most exciting presentations of this session. He introduced us to BMS-488043. This molecule interferes with an earlier step during viral entry into the host cell. It blocks entry by preventing the attachment of gp120 on the virus surface to the CD4 receptor on the cell surface. In initial in-vitro and animal study data, this compound appears to be fairly non-toxic with essentially no cross-resistance to currently available agents.
Dr. Hanna presented the results of the proof-of-concept study, involving HIV-infected subjects with a CD4 count >250 cells/mm3 and a viral load between 5 and 500,000 copies/mL. Some of the patients were treatment naive, while others were experienced but not currently receiving antiretroviral therapy. The subjects were randomized to receive active drug (monotherapy) versus placebo. The patients who received the active drug were randomized into two cohorts of 15 subjects who were given 800 mg or 1,800 mg twice daily with a high-fat meal. The rationale for the high-fat meal is that earlier studies showed a better absorption of this compound with meals. The baseline median viral load of these patients was 4.7 and the median CD4 count was ~350 cells.
After a week of therapy, the viral load decline was 0.72 and 0.96 log10 copies/mL for the two dosage groups. There were no serious adverse events or discontinuations in this study. This compound was generally safe and well tolerated.
This type of data usually results in a lot of initial excitement about the possibility that one of these compounds will eventually materialize into a drug with clinical usefulness in practice. Unfortunately, we must remember that as fast as these drugs reach the early stages of development, they can be abandoned just as quickly when unsatisfactory results from pharmacokinetic or pharmacodynamic studies start to emerge. It is unlikely that all of the compounds presented in this session will make it to full development. Some will never even make it to the next phase II trials. Yet the notion that our pipeline is becoming inundated with promising agents that target different viral replication steps is encouraging and certainly paints a prettier picture for the next couple of years.
Abstract: Single and Multiple Dose Escalation Study to Investigate the Safety, Pharmacokinetics and Receptor Binding of GW873140, a Novel CCR5 Receptor Antagonist, in Healthy Subjects (Oral 139)
Abstract: Antiviral Activity, Safety, and Tolerability of a Novel, Oral Small-Molecule HIV-1 Attachment Inhibitor, BMS-488043, in HIV-1-Infected Subjects (Oral 141)
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