Current status of the Merck LA/ER pipeline
Speaker: Jay Grobler, Executive Director of Infectious Diseases and Vaccines at Merck & Co, Inc.
Provided an update on Islatravir (ISL), a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) as monotherapy for LA oral HIV prevention, and MK-8507, a novel nucleoside reverse transcriptase inhibitor (NRTI) for co-administration with ISL for LA oral HIV treatment.
ISL has high potency against HIV-1, a long half-life and physical properties that allow low-dose oral administration with flexible dosing intervals.
Anticipated dosing intervals include daily, weekly or monthly administration as well as the potential for yearly administration via a subdermal implant.
Pre-clinical studies in NHPs suggest efficacy of ISL for HIV PrEP and PEP at concentrations that extrapolate to low oral doses in humans and the potential for single-dose oral ISL for PEP.
Extrapolating to humans, a simulated single 60 mg oral ISL dose achieved PBMC drug concentrations 1-2 fold higher than the lowest concentration that was completely protective in the NHP PEP study (no evidence of viral RNA, pro-viral DNA or antibodies to SIV).
Phase 2 studies (P016) support the safety, tolerability and favorable PK of monthly oral ISL (60mg and 120 mg).
Plasma ISL concentrations remained above the target exposure threshold (determined via translational PK/PD modelling) throughout the dosing interval.
Simulated PK of MK-8507 supports weekly oral dosing as combination therapy for HIV treatment.
MK-8507 was well-tolerated at all doses tested, and single doses as low as 40 mg reduced viral load in treatment-naïve PLWH for up to 7 days.
Future directions for ISL and MK-8507.
Phase 3 PrEP studies of monthly oral ISL (60 mg) will initiate this year. Phase 2 HIV treatment studies of weekly oral MK-8507 in combination with oral ISL (20 mg) will initiate soon in 2021 (NCT04564547).