Among treatment-naïve adults with HIV infection, once daily monotherapy with GSK3640254 (GSK’254), a next generation HIV-1 maturation inhibitor, was found to be safe, effective, and well-tolerated, according to results of a global phase IIa double-blind, randomized, placebo-controlled trial published in Clinical Infectious Diseases.
Findings from previous trials demonstrated that GSK’254 monotherapy was safe and effective in otherwise healthy adults with HIV infection, and the coadministration of GSK’254 with either dolutegravir or tenofovir alafenamide/emtricitabine elicited no drug-drug interactions. In this phase IIa proof-of-concept trial, researchers aimed to evaluate the antiviral efficacy, tolerability, and pharmacokinetics of GSK’254 among treatment-naïve adults with HIV infection.
In part 1 of the trial, patients received either a 10- or 200-mg dose of GSK’254 or placebo for 10 days. Eligible patients were aged 18 to 65 years with HIV infection, had a body weight of greater than or equal to 50 kg (men) or 45 kg (women), and a BMI between 18.5 and 31.0 kg/m2. In addition, all patients were naïve to antiretroviral therapy (ART), had a plasma HIV RNA viral load of greater than or equal to 5000 copies/mL, and a CD4+ T-cell count of greater than or equal to 350 cells/mm3. At day 11, the researchers performed an interim analysis and found treatment-emergent resistance among patients who received GSK’254 200 mg. Owing to this resistance, part 2 of the trial modified the duration of GSK’254 monotherapy from 10 to 7 days. Patients included in part 2 received either a 40-, 80-, or 140-mg dose of GSK’254 or placebo once daily for 7 days, followed by combination ART on day 8. The primary endpoints were the maximum change in plasma HIV RNA from baseline, change from baseline to day 11 (part 1), and change from baseline day 8 (part 2).
Among a total of 34 patients included in the final analysis, the mean age was 31.8 years and 94% were men; none were lost to follow-up. The greatest decrease in plasma HIV RNA from baseline occurred among patients in the 200- and 140-mg dose groups, with maximum mean declines of 2.0 and 1.5 log10, respectively. Of note, a 42.7-mg dose of GSK’254 was estimated to achieve 50% of the maximum decline in plasma HIV RNA from baseline (95% CI, 7.6-77.8).
The median time to HIV-1 RNA nadir was 11.5 and 8 days among patients included in part 1 and part 2 of the trial, respectively. In part 1, although a greater than 1.5 log10 decrease in plasma HIV RNA from baseline was observed among patients treated with GSK’254 200 mg, changes in plasma HIV RNA remained close to baseline among those treated with the 10-mg dose. Treatment resistance occurred among 4 patients treated with GSK’245 200 mg at day 11, with no resistance observed at days 8, 9, or 10.
In part 2, there was a greater than1.5 log10 decrease in plasma HIV RNA from baseline observed in 3 patients who received GSK’254 140 mg and 1 patient who received GSK’254 40 mg. No treatment resistance emerged after 7 days of monotherapy.
Overall, 22 (65%) patients treated with GSK’254 reported adverse events, of which headache and oropharyngeal pain were the most common. Although 1 patient reported 2 severe adverse events, including cardiomyopathy and anal abscess, the researchers noted that neither event was related to treatment with GSK’254. Of note, There were 14 abnormal laboratory results of potential clinical important were observed in 14 patients, including decreased neutrophil (n=6) and leukocyte counts (n=3), and increased leukocyte counts (n=2) and chloride concentrations (n=2). In addition, increases in both heart rate and blood pressure were observed in 4 patients.
This study was limited by its small sample size and the inclusion of only 2 women, thus results may not be generalizable to other patient populations.
“Overall, results from this study support the clinical development of GSK’254 and informed dose selection for the ongoing phase IIb study evaluating GSK’254 in combination with 2 nucleoside reverse transcriptase inhibitors,” the researchers concluded.
Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Spinner CD, Felizarta F, Rizzardini G, et al. Phase IIa proof-of-concept evaluation of the antiviral efficacy, safety, tolerability, and pharmacokinetics of the next-Generation maturation inhibitor GSK3640254. Clin Infect Dis. Published online Jan 6, 2022. doi:10.1093/cid/ciab1065