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CROI 2004; San Francisco, Calif.; Feb. 8-11, 2004

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The Body Covers: The 11th Conference on Retroviruses and Opportunistic Infections
GW873140, a Promising CCR5 Inhibitor Candidate

February 11, 2004

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The search for new categories of HIV medications continues. The need for new HIV medications is obvious, given the increasing rates of HIV resistant to current medications and the need to improve the convenience and potency of HIV treatments. Last year, we welcomed the arrival of drugs called entry inhibitors which target viral entry. This class of medications prevents HIV from gaining access to the human CD4 cell.

There are multiple steps to viral entry which involve the binding of the virus to specific human cell receptor molecules (called co-receptors, either "CXCR4" or "CCR5"), followed by the virus fusing to a human cell. Enfuvirtide (T-20, Fuzeon) is the first FDA-approved drug to block the entry process; it works by preventing fusion.

Another way to stop HIV should be by using drugs that block the attachment of HIV to any of the cell receptors. These drugs are called CCR5 receptor inhibitors and several candidates are currently the subjects of intense investigation. As opposed to the subcutaneous injection of enfuvirtide, all CCR5 inhibitors under development can be taken orally. An interesting feature of this class of compounds is that they appear to stick to the receptor for a very long time, suggesting once-daily, or perhaps even less frequent dosing. Two CCR5 inhibitors under investigation are Schering-Plough's SCH-C and SCH-D (Oral 140LB). The SCH compounds appear to work best when taken without food.

GlaxoSmithKline (GSK) has been working on a different CCR5 inhibitor called GW873140 (or "140"). Dr. Michelle Berrey, Director of GSK's Viral Disease-Discovery Medicine, characterized preliminary studies, saying that GW140 has an "unprecedented interaction with CCR5."

In this report, Dr. Steve Piscitelli, also from GSK, shared the preliminary experience of GW140 in 70 HIV-negative persons. The objective of these studies was to evaluate the safety and pharmacokinetics of GW140. Another objective was to see just how GW140 interacted with the CCR5 receptor on CD4 cells in the study subjects. GW140 appears to be well tolerated, with no serious side effects or laboratory toxicities. The drug levels are improved about two-fold when taken with food and there are no apparent differences in drug levels between men and women. The chemical caused mild cramps, nausea and diarrhea in a limited number of study subjects. After the dosing of GW140, the CCR5 receptor was completely blocked -- even when the blood level of the drug was undetectable. This means that GW140 should be able to be administered once-daily.

So overall, GW140 looks like an enormously promising candidate CCR5 inhibitor. Dr. Berrey stated that the compound "appears to be very safe in short-term studies." The next critical steps are to evaluate how well the compound works in blocking HIV in infected persons -- a key step in the development of any investigational agent for treating HIV. These studies should commence this year. Stay tuned.


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)
Authored by: J. Demarest, K. Adkison, S. Sparks, A. Shachoy-Clark, K. Schell, S. Reddy, L. Fang, K. O'Mara, S. Shibayama, S. Piscitelli
Affiliations: GlaxoSmithKline, Research Triangle Park, NC; Univ. of Wisconsin, Madison, WI; ONO Pharm. Ltd., Osaka, Japan

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

See Also
More on HIV Medications
More on Entry Inhibitors in Development

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