A Novel Integrase Inhibitor, GS 9137, Targets HIV’s Third Enzyme
by Chael Needle
[LifeGuide] Treatment Horizons
The four classes of anti-HIV medications currently approved for combination therapy all work to inhibit the various stages of the virus’s replication process. Entry inhibitors, for example, target the fusing of HIV to the outside of a cell. Reverse transcriptase inhibitors, both nucleoside and non-nucleoside, block the process by which HIV’s RNA within the host cell is converted into DNA. The viral assembly of HIV is arrested by protease inhibitors. Integrase inhibitors, like reverse transcriptase and protease inhibitors, also zero in on an enzyme; in this case, the enzyme integrase is needed for HIV to integrate its viral genetic material into the host’s DNA and begin making copies. Only a handful of these inhibitors are currently in development, and none have been, or are close to being, approved.
“Since integrase is a viral target, an integrase inhibitor in theory may be less likely to interfere with the function of human cells and could cause fewer side effects than compounds that target cellular functions,” says Andrew Cheng, MD, PhD, Vice President Clinical Research, Gilead Sciences, about why integrase inhibitors may be more efficacious than other drug classes. Gilead Sciences has licensed GS 9137, a novel oral integrase inhibitor candidate, from Japan Tobacco, which had previously tested it, as JTK-303, in Phase I trials.
Investigators have recently announced results of a Phase I/II dose-escalation randomized study of GS 9137 at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado. The forty HIV-positive study participants were both treatment-naive and treatment-experienced, though at study entry patients were not receiving antiretroviral therapy. Patients had a viral load between 10,000 and 300,000 copies/mL and CD4 cell counts greater than or equal to 200 cells/mm3.
Ten patients received placebo and forty received one of five doses of GS 9137—200 mg twice daily, 400 mg twice daily, 800 mg twice daily, 800 mg once daily, and 50 mg boosted with 100 mg ritonavir once daily—with food for ten days. At all doses, GS 9137 monotherapy demonstrated significant antiviral activity compared to placebo, with the ritonavir-boosted dosage showing the greatest decrease in viral load. The 800 mg twice-daily dose showed the next greatest activity against HIV. GS 9137 was well-tolerated, with some mild to moderate side effects reported but reported to be not associated with the candidate drug. No one discontinued the trial.
“Integrase inhibitors represent a promising new class for two important reasons. As patients live longer and stay on treatment for longer periods of time, they can develop resistance to certain medications, and in some cases, entire classes of anti-HIV medications,” says Dr. Cheng. “Integrase inhibitors hold the potential to be effective for patients who have developed resistance to other agents or even entire classes of antiretrovirals.”
The safety and efficacy of GS 9137 requires further study in larger, controlled clinical studies, says Dr. Cheng about the next steps in research. “In order to determine the compounds’ safety and efficacy as part of combination therapy, the company is initiating a larger, partially-blind, placebo-controlled 48-week Phase II study of GS 9137 in combination with optimized background regimen in approximately 200 treatment-experienced patients. Phase II studies of GS 9137 are scheduled to begin in the second quarter of this year. We’ll know more about its development course once the Phase II study is complete and we can review the data.”
Chael Needle wrote about the close of the SMART (Strategies for Management of Anti-Retroviral Therapy) trial for the February issue.
March 2006 |
