Merck evaluating novel HIV drug as implant for long-lasting PrEP
Merck announced positive findings from early-phase clinical trials evaluating MK-8591, an investigational nucleoside reverse transcriptase translocation inhibitor, or NRTTI, for the prevention and treatment of HIV.
The results, presented at the International AIDS Society Conference on HIV Science in Mexico City, included findings from a phase 1 trial exploring the drug’s potential use as an implant for long-term HIV pre-exposure prophylaxis (PrEP).
The drug, which is being called Islatravir, also showed promise in phase 2b trials for treatment in combination with doravirine (DOR) and lamivudine (3TC) in ART-naive adults.
“This is a novel drug with potent antiviral activity and a good safety profile that might be used in the future for both the treatment and prevention of HIV,” Jean-Michel Molina, MD, professor at the University of Paris Diderot and physician in the department of infectious diseases at Saint-Louis Hospital in Paris, told Infectious Disease News. “These data are encouraging and justify large phase 3 trials.”
Implant could protect for 1 year
In the double-blind, placebo-controlled phase 1 trial, Randolph P. Matthews, MD, PhD, senior principal scientist in the department of translational pharmacology at Merck, and colleagues placed either a single prototype MK-8591 implant (54 mg or 62 mg) or placebo implant in subjects for 12 weeks. They assessed safety and tolerability throughout the trial and collected pharmacokinetics (PK) for MK-8591 parent and the active MK-8591-triphosphate until 4 weeks after implant removal.
The implants — which are cylindrical, resemble a matchstick and measure 4 cm by 2 mm — were generally well tolerated, and PK showed concentrations above target for both implants throughout the study, the researchers found.
“Modeling of the PK data suggested that the 62-mg implant has the potential to lead to concentrations above this target threshold for at least a year,” Matthews told Infectious Disease News. “We see these implants as an option for PrEP in both men and women, with the potential to be used in a variety of populations at risk of HIV-1 throughout the world.”
It is unclear when the implant would be available for patients, but future research “will examine implants with different doses and different makeup, with plans to conduct evaluations in larger populations,” Matthews said.
Phase 2b trials
Molina noted that NRTTIs differ from nucleoside reverse transcriptase inhibitors in that they have a “dual mechanism of action which makes them bind better to the reverse transcriptase with a higher antiviral activity and lower risk of resistance.”
In the first of two phase 2b trials, Molina and colleagues randomly assigned 121 patients in a 1:1:1:1 ratio to one of four once-daily treatments groups. In three groups, participants received one of three doses for MK-8591 (0.25/0.75/2.25 mg) plus doravirine (DOR, 100 mg) with lamivudine (3TC, 300 mg) added for at least the first 24 weeks. The fourth group received DOR and 3TC plus tenofovir disoproxil fumarate (TDF) — Delstrigo (DOR/3TC/TDF, Merck) — with placebo.
At 24 weeks, 89.7%, 100% and 87.1% of participants in the 0.25-mg, 0.75-mg and 2.25-mg groups, respectively, achieved viral suppression (HIV-1 RNA levels less than 50 copies/mL) compared with 87.1% who received DOR/3TC/TDF. The researchers reported no virologic failure at 24 weeks, and efficacy was consistent regardless of baseline HIV-1 RNA level.
In the second trial, Molina and colleagues evaluated at 48 weeks the same cohort of patients from the first trial. They reported that 89.7%, 90% and 77.4% of patients in the 0.25-mg, 0.75-mg and 2.25-mg groups, respectively, achieved viral suppression compared with 83.9% of patients in the DOR/3TC/TDF arm. Notably, six patients met the definition of protocol-defined virologic failure at 48 weeks, five in the MK-8591 group and one in the DOR/3TC/TDF group. However, none had HIV-1 RNA levels greater than 200 copies/mL or documented resistance to study drugs.
“MK-8591 has a very long half-life, which makes it suitable for intermittent administration,” Molina said. “It also has very high antiviral activity, so patients would need only to take approximately 1 mg per day instead of hundreds of [milligrams] with other related drugs.” – by Joe Gramigna
Matthews RP, et al. First-in-human trial of MK-8591-eluting implants demonstrates concentrations suitable for HIV prophylaxis for at least one year. Presented at: IAS Conference on HIV Science; July 21-25, 2019; Mexico City.
Molina J-M, et al. MK-8591 at doses of 0.25 to 2.25 mg QD, in combination with doravirine establishes and maintains viral suppression through 48 weeks in treatment-naive adults with HIV-1 infection. Presented at: IAS Conference on HIV Science; July 21-25, 2019; Mexico City.
Molina J-M, et al. Tolerability, safety and efficacy of MK-8591 at doses of 0.25 to 2.25 mg QD, in combination with doravirine and lamivudine through 24 weeks in treatment-naive adults with HIV-1 infection Presented at: IAS Conference on HIV Science; July 21-25, 2019; Mexico City.
Disclosures: Matthews is employed by Merck. Molina reports being a consultant for Gilead Sciences, Merck and ViiV Healthcare; and being on the speaker’s bureau and receiving research grant support from Gilead.