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New Once-Daily Integrase Inhibitor Looks Strong in Early Trial
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
S/GSK1349572, a GlaxoSmithKline integrase inhibitor, controlled HIV quickly in a monotherapy trial that enrolled people with no integrase inhibitor experience [1]. Seven of 10 people taking the highest dose studied reached an undetectable viral load while taking only S/GSK1349572 for 10 days. The highest dose being studied is 50 mg once daily, a relatively low amount of drug, as other studies reported here in posters indicate potency with low doses in vitro.
This double-blind dose-ranging trial enrolled 35 HIV-infected adults with a viral load above 4999 copies and a CD4 count above 99. No one had a tried another integrase inhibitor, and no one had taken other antiretrovirals in the 12 weeks before the study began. Regular alcohol users or substance abusers were excluded, as were people with hepatitis B or C infection. Researchers randomized study participants to 10 days of monotherapy with S/GSK1349572 or placebo. Nine people got 2 mg of S/GSK1349572, 9 got 10 mg, 10 got 50 mg, and 7 got placebo.
All study participants were men, 28 were white, and 7 were African American. Median starting viral load stood around 4.5 log in the S/GSK1349572 groups and 4.1 in the placebo group (about 30,000 and 12,000 copies). CD4 counts ranged from 123 to 797, with median values of 435, 398, and 502 in the 2-, 10-, and 50-mg groups and 472 in the placebo group.
All 35 study participants completed all study visits. No one died, had a severe side effect, or withdrew from the study because of side effects or other complications. Of the most common side effects--diarrhea, fatigue, and headache--only headache affected more people taking S/GSK1349572 than placebo. The only grade 3 side effects with S/GSK1349572 were migraine with 50 mg, an asymptomatic lipase elevation with 10 mg, and an asymptomatic triglyceride jump with 10 mg. The researchers saw no significant trends in laboratory abnormalities, vital signs, or electrocardiographic readings.
On day 11 viral load drops averaged 1.51 to 2.46 log copies/mL across the three S/GSK1349572 groups, while the average load remained essentially unchanged in the placebo group. Seven of 10 people randomized to 50 mg of S/GSK1349572 had a viral load below 50 copies on day 11, and 9 had fewer than 400 copies. In that group, viral suppression remained 2.5 log below the starting value from day 10 (the last day of dosing) to day 14.
GSK labeled the virologic response rate with 50 mg "unprecedented," and they offered a look at other monotherapy trials to make that point. Compared with the 2.46-log drop with S/GSK1349572, maximum declines were 1.7 log with raltegravir and 2.03 log with elvitegravir, two other integrase inhibitors. The best results in other classes were -1.99 log with the nonnucleoside etravirine, -1.96 log with the fusion inhibitor enfuvirtide, and -1.85 log with the protease inhibitors lopinavir/ritonavir. No one can say whether such differences in a cross-study comparison have any clinical meaning, but the GSK drug can clearly knock down viral loads fast.
Phenotypic testing uncovered no sign of declining viral susceptibility to S/GSK1349572 during the study. No mutations seen in people taking the integrase inhibitors raltegravir or elvitegravir (or seen in lab studies of S/GSK1349572) emerged during the trial. GSK's Sherene Min noted two other 5th IAS Conference reports on S/GSK1349572 that demonstrate a different resistance profile with this new agent and limited in vitro cross-resistance with raltegravir [2,3].
Phase 2b studies of S/GSK1349572, using the 50-mg dose, begin this month.
References
1. Lalezari J, Sloan L, Dejesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB105.
2. Sato A, Kobayashi M, Yoshinaga T, et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor . 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WEPEA097.
3. Underwood M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WEPEA098.
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