Islatravir (ISL) is a nucleoside analog currently in development as treatment for HIV-1 and as PrEP in several dosing paradigms. Throughout clinical development, including single doses up to 400 mg, ISL has been well tolerated without related cardiac events. Preclinical work demonstrates that ISL does not interact with the hERG channel at clinically meaningful concentrations, and thus the likelihood of an effect on cardiac repolarization is low.
This Phase 1 double-blind placebo-controlled trial consisted of 4 sequences and 2 treatment periods, with a total enrollment of 63 healthy study participants. Moxifloxacin (400 mg) and placebo were tested in a crossover manner, and both a supratherapeutic dose (240 mg) and the daily therapeutic dose (0.75 mg) of islatravir were assessed after single dose oral administration. Participants were domiciled and placed on Holter monitoring to collect the pre-dose readings through 24 hours post dosing, and also had scheduled triplicate 12-lead ECG assessments. PK assessments were obtained at specified timepoints while participants were domiciled, and then concurrently with the 12-lead ECG assessments.
Islatravir was generally well tolerated at both the 0.75 mg and 240 mg dose. As shown in Figure 1, the placebo corrected change from baseline QTcP (??QTcP) associated with both 0.75 mg and 240 mg ISL was less than 10 ms at all timepoints. In addition, exposure-response analysis showed that the ??QTcP at the observed geometric mean Cmaxmax associated with both 0.75 mg and 240 mg ISL was less than 10 ms, while 400 mg moxifloxacin (positive control) led to a ??QTcP of >10 ms, as expected.
Islatravir, at the therapeutic dose of 0.75 mg and at a supratherapeutic dose of 240 mg, does not prolong QTc.