Islatravir Subdermal Implant for HIV PrEP Has Promising Phase 1 Trial

Antiretroviral therapy (ART) has helped to substantially reduce mortality, morbidity, and transmission rates for HIV. However, according to the Joint United Nations Program on HIV/AIDS (UNAIDS), there are still 1.7 million new HIV infections each year.

Once-daily oral pre-exposure prophylaxis (PrEP) effectively reduces the risk of HIV transmission among at-risk persons, but this efficacy is dependent upon consistent usage. Thus, investigators sought to improve upon existing methods by creating a long-acting form of PrEP.

Islatravir (MK-8591), a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) with a long intracellular half-life, is currently in development to treat and prevent HIV-1.

Islatravir works by rapidly converting to its active triphosphate (TP) form, islatravir-TP, within targeted cells. Islatravir-TP inhibits reverse transcriptase to suppress HIV replication. In addition to its long intracellular half-life, islatravir has high antiviral potency against HIV and its drug-resistant variants.

Clinical studies show oral islatravir lasts for approximately 190 hours after oral administration in adults without HIV. For sustained concentration and medication adherence, investigators studied whether islatravir could by implanted subdermally.

Investigators conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV. The participants received either islatravir or placebo subdermal implants for the 12-week study period. They were monitored throughout the period and after implant removal.

Two doses were implemented: 54 mg (n=8 [two placebo]) and 62 mg (n=8 [two placebo]). The most reported side effects were mild to moderate implant-site reactions (induration, hematoma, pain). At both doses, islatravir was safe and produced average concentrations above the PK threshold throughout the 12-week study period.

Between June 4, 2018 and January 25, 2019, 16 participants took part in the trial. Six received the 54 mg implant and two received a placebo in Panel A (all male, average age 35.9 years, all white). In Panel B, six received the 62mg implant and two received a placebo (n=6 male, n=2 female, average age 36.8 years, all white).

The primary endpoints were safety and tolerability of islatravir implant and the pharmacokinetics (PK) of islatravir-triphosphate concentration at Day 85 (C85d) in peripheral blood mononuclear cells (PBMCs). Secondary endpoints were additional PK levels of for islatravir-TP in PBMCs and the plasma PK profile of islatravir.

Limited assessment of rectal and vaginal tissue pharmacokinetics demonstrated steady-state levels of active islatravir-TP at all examined dose levels, comparable to reported levels of tenofovir diphosphate in rectal tissue following single doses of emtricitabine/tenofovir28.

A key objective of the study was to determine whether there would be adequate release of islatravir to maintain the therapeutic intracellular concentrations of islatravir-TP of >0.05 pmol/106cells in PBMCs throughout implant placement. According to the study, “both the islatravir 54 mg and 62 mg implants resulted in mean concentrations above the PK threshold through 12 weeks, but only the 62 mg implant demonstrated islatravir-TP concentrations above the threshold for all participants for the entire 12 weeks. Concentrations rapidly rose to sufficient levels, with a Tmax of approximately 2 hours in plasma, and the threshold concentration for intracellular islatravir-TP exceeded 1 hour after placement.”

For future trials, they hope to address and remedy the implant-site reactions.