A second integrase inhibitor joined Merck's MK- 0518 in the rapid advance of a long-awaited new class of antiretrovirals towards the clinic on Wednesday at the Thirteenth Conference on Retroviruses and Opportunistic Infections, held this week in Denver. Edwin DeJesus presented data on the antiviral activity of an experimental integrase inhibitor, GS-9137 (also known as JTK-303), in treatment-naive and experienced patients. GS-9137 is being developed by Gilead Sciences.
Previous research has shown that GS-9137 is a potent in vitro inhibitor of HIV-1 integrase with favourable pharmacokinetics in humans. The drug is partly metabolised through the CYP3A enzyme, of which it is an inducer, so interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors are expected, but drug levels are boosted 20-fold when dosed with 100mg of ritonavir, allowing once-daily dosing.
This ten-day monotherapy study enrolled 40 HIV-positive participants, of whom half were treatment-experienced and half were treatment-naive. At baseline, patients were not currently receiving antiretroviral therapy and had HIV viral loads between 10,000 and 300,000 copies/ml and CD4 cell counts of at least 200 cells/mm3.
Thirty patients were randomly assigned to receive GS-9137 with food for ten days. There were six participants in each of five dosage arms: 200mg, 400mg, or 800mg GS-9137 twice daily; 800mg GS-9137 once daily; or 50mg GS-9137 boosted with 100mg ritonavir (Norvir) once daily. Ten subjects received placebo. Clinical and laboratory values were assessed throughout the study, and intensive pharmacokinetic sampling was performed on days 1 and 10.
After ten days on treatment viral load had declined by 1.44, 1.98, 1.78, 0.89, and 2.03 log copies/ml in the five dosage arms, respectively, compared with 0.26 in the placebo arm. The researchers reported that all GS-9137 dose arms “exhibited substantial antiviral activity” compared with placebo (p
An Emax dose-response model showed that antiviral activity was associated with steady state minimum plasma concentrations (Cmin) of GS-9137.
GS-9137 was well tolerated in all dosage arms, and there were no discontinuations or serious adverse events related to the study drug. All adverse side-effects related to GS-9137 were mild to moderate in severity (Grade 1 or 2) and resolved when the drug was discontinued.
DeJesus E et al. The HIV integrase inhibitor GS-9137 (JTK-303) exhibits potent antiviral activity in treatment-naive and experienced patients. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract LB160, 2006.