Gilead Sciences’ experimental “Quad” tablet and boosting agent cobicistat continue to show promise in two ongoing clinical trials reported Wednesday, February 17, at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco. The first study suggests Gilead’s four-in-one pill performs as well as the fixed-dose combination tablet Atripla, and the second study indicates that cobicistat is comparable with the mainstay booster Norvir (ritonavir) in terms of efficacy and safety.

Cobicistat, previously identified as GS 9350, generated excitement when it was debuted at last year’s CROI. At that time, Gilead announced it would combine cobicistat into a single once-daily pill with its experimental integrase inhibitor elvitegravir and Truvada (tenofovir plus emtricitabine). The company also reported it would develop cobicistat as a stand-alone agent for use with non-Gilead antiretrovirals (ARVs) requiring boosting.

The Quad

Twenty-four week data from the Phase II study of the Quad pill (Study 236-0104), reported at this year’s CROI by Calvin Cohen, MD, of the Community Research Initiative of New England in Boston, randomized 71 people who’d never taken ARV therapy before to take the experimental four-in-one tablet or Atripla.

Cohen reported the Quad pill was similar to Atripla in terms of efficacy. After six months of treatment, the proportion of patients with viral loads below 50 copies was 90 percent in the Quad group, compared with 83 percent in the Atripla group. These data allowed Cohen’s group to conclude that the Quad tablet is comparable, or non-inferior, to Atripla.   

CD4 counts increased by 123 cells in the Quad group 24 weeks after treatment, compared with a 124 CD4 cell gain in the Atripla group.

The Quad tablet was generally associated with fewer drug-related adverse events, particularly fewer central nervous system (CNS) adverse events. More people did, however, experience diarrhea while taking the Quad tablet compared with Atripla (8 percent versus 4 percent). There were no moderate-to-severe (Grade 3 or 4) adverse events among Quad patients, whereas there were two Grade 3 or 4 adverse events among those receiving Atripla patients.

One patient who received Atripla discontinued treatment after experiencing suicidal thoughts—a rare but possible side effect of efavirenz treatment. No patient in the Quad group discontinued treatment because of a drug-related adverse event.

Laboratory abnormalities—including increases in the pancreatic enzyme amylase, a decrease in neutrophils (a type of white blood cell), increases in cholesterol levels and elevated urine levels of protein—were similar in both groups.

Cobicistat Booster

The second study (Study 216-0105), also reported by Cohen, compared Reyataz and Truvada combined with either cobicistat or low-dose Norvir in treatment first-timers. Fifty people received the combination with cobicistat, and 29 received the combination with Norvir.

At 24 weeks, 84 percent of patients in the cobicistat group and 86 percent of those in the Norvir group had viral loads below 50 copies. CD4 counts increased by 206 cells in the cobicistat group, compared with 190 cells in the Norvir group.

Two cobicistat patients discontinued treatment because of adverse events, notably vomiting and rash, as did one Norvir patient because of yellowing of the eyes (scleral icterus). The most common treatment-related side effects were nausea, diarrhea and fatigue, along with evidence of potentially more cases of nausea among those receiving cobicistat compared with Norvir. There were two Grade 3 or 4 side effects—anemia and rash—among those receiving cobicstat, compared with no moderate-to-severe side effects among those in the Norvir group.

The most common laboratory side effects in both groups were increases in bilirubin, amylase and total cholesterol.

Of note, small increases in serum creatinine—commonly used to measure renal function, notably in estimates of glomerular filtration rates (GFR), which measures the ability of the kidneys to filter blood for waste products—were observed in some patients receiving cobicistat, notably in the clinical trial comparing cobicistat with Norvir (12 percent versus zero percent of patients, respectively).

Cohen briefly discussed the results of a separate study evaluating kidney function in healthy volunteers receiving cobicstat, which found that while cobicistat can lower the estimated GFR, it does not lower the actual GFR. In turn, Dr. Cohen said, it is not likely that cobicistant is associated with the same degree of kidney impairment typically seen with other renal-toxic medications. Further exploration of the effects of cobicistat on kidney function will likely be needed, however.

Forty-eight week data from both studies are pending, and Phase III studies of the Quad tablet and cobicistat are planned.