The Body Covers: The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment
GW695634 Demonstrates Potent Activity in 7-Day Monotherapy Study in an NNRTI Treatment-Experienced Population
July 27, 2005
There is a clear need to develop novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) that will maintain activity against HIV variants containing mutations associated with resistance against currently approved members of this family of drugs. In this context, the next-generation NNRTI GW695634 is a novel drug candidate.
GW695634 is a pro-drug of a previously tested compound called GW678248 that had been demonstrated in tissue culture to display potent antiviral activity against both wild-type HIV-1 as well as viruses containing a variety of NNRTI-associated mutations, including both K103N and Y181C.
This small study was performed to assess the antiviral activity and safety of GW695634 in HIV-infected individuals in a multicentered, double-blind, randomized, placebo-controlled, dose-ranging study. Accordingly, 46 patients received either a placebo or GW695634 at doses of 100 mg, 200 mg, 300 mg or 400 mg twice daily for 7 days.
At the time of screening, all 46 patients in the study had:
The results of this "proof-of-concept" study demonstrate that GW695634 displayed potent antiviral activity, resulting in declines in viral load ranging between 1.1 and 1.6 logs during the 7 days of monotherapy across all doses studied.
In terms of resistance, the 46 patients enrolled possessed a median of 2 NNRTI-associated primary mutations that included: L100I, K103N, V108I, Y181C/I, Y188C/L/H, G190S/A and P225H. Twenty-seven (61%) of the study patients had at least 1 NNRTI mutation at baseline: 9 patients (20%) had single mutations, 10 (23%) had 2 mutations and 8 (18%) had 3 mutations. Seventeen of the study patients had evidence of prior NNRTI resistance mutations, although when they entered the study, they had wild-type virus.
The highest reductions in viral load were obtained with the 300-mg twice-daily schedule of treatment. GW695634 was generally well tolerated during the 7 days of therapy. The most frequent adverse events reported were rash, nausea and diarrhea, and these were generally mild to moderate in intensity.
Thus, this study provides important evidence regarding the potent antiviral activity of GW695634 against viruses resistant to all currently approved members of the NNRTI family of drugs. Further evaluation of GW695634 is eagerly awaited in additional clinical trials that will take place during the next several years.
In view of the fact that several companies have withdrawn their novel NNRTI candidate molecules from consideration for future development, the current evaluation of GW695634 assumes considerable importance. GW695634 joins 2 novel, second generation NNRTIs (i.e., Tibotec's TMC-125 and TMC-278) that also show important promise for clinical development, but are currently further along in clinical development than GW695634.
Authored by: S Becker, J Lalezari, C Walworth, P Kumar, J Cade, J Ng-Cashin, Y Kim, J Scott, M St. Clair, L Jones, W Symonds
Affiliations: Pacific Horizon Medical Group, San Francisco, United States of America; Quest Clinical Research, San Francisco, United States of America; Orange County Center for Special Immunology, Fountain Valley, United States of America; Georgetown University Hospital, Washington, United States of America; HIV Wellness Center, Las Vegas, United States of America; GlaxoSmithKline, Research Triangle Park, United States of America
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