A Phase 1 Study to Evaluate the Potential Drug-Drug Interaction Between Islatravir and Lenacapavir

People with HIV-1 may find adhering to life-long daily oral antiretroviral therapy difficult, which can lead to treatment failure or drug resistance. Longer-acting treatments may improve adherence, treatment outcomes, and quality of life. Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, plus lenacapavir (LEN), the first-in-class HIV-1 capsid inhibitor, are being evaluated as a weekly oral regimen for HIV-1. We investigated drug-drug interactions (DDI) between ISL and LEN by evaluating the pharmacokinetics and safety of a single-dose oral co-administration of 20 mg of ISL and 600 mg of LEN relative to single-agent administration in 55 adults without HIV. Co-administration showed similar pharmacokinetic profiles compared with single-agent administration; no clinically meaningful pharmacokinetic DDI was identified. The percent geometric least-squares mean (%GLSM) ratios for ISL exposure parameters were 88%-105%, and corresponding 90% confidence intervals (CIs) were within prespecified bounds (60%-167%). While there were no clinically significant differences in LEN exposure between ISL+LEN and LEN administration, the %GLSM ratios for LEN exposures were 80%-90%, with 90% CIs within 60%-167% except for maximum LEN concentration. High percentage coefficient of variation was observed for LEN pharmacokinetic parameters, resulting in relatively wide 90% CIs. ISL and LEN were generally well tolerated, with no serious or Grade 3 or 4 adverse events, deaths, or discontinuations of the study due to an adverse event. These results and positive initial findings from an ongoing Phase 2 study (NCT05052996) support further clinical development of ISL and LEN as a weekly combination oral treatment for HIV-1.