MK-2048 vaginal film / Merck (MSD) - LARVOL DELTA

Engineering vaginal film platform for mucoadhesion and sustained drug release for HIV-1 prevention. (PubMed, J Control Release) - "This study aims to develop a long-acting vaginal film to deliver an integrase inhibitor, MK-2048, for prevention of HIV-1 infection...The lead film evaluated in pigtail macaques showed drug concentrations above the IC95 (41 nM) in vaginal fluids and tissues for a period of at least 2 weeks, with no evidence of toxicity. Overall, these in vitro and in vivo studies demonstrate that this strategy can be applied to rationally develop polymeric film platforms that can sustain drug release in vivo, potentially improving user adherence."

Journal • Human Immunodeficiency Virus • Infectious Disease

Scaling a non-human primate physiologically-based pharmacokinetic model of extended-release MK-2048 and combination MK-2048/vicriviroc (MK-2048A) intravaginal rings into humans using phase 1 MTN-027 and MTN-028 studies (HIVR4P 2024) - "This work showcases the adaptation of a mechanistic NHP PBPK model for humans to predict vaginal fluid and plasma concentrations after IVR administration, leveraging data from the Phase 1 studies MTN-027 and MTN-028. The model's ability to predict most drug concentrations within a 90% prediction interval highlights its utility in guiding IVR design and dosing optimization for PrEP. Future work includes continued refinement of the PBPK model and extending the model to evaluate other vaginal formulations for PrEP interventions."

P1 data • PK/PD data

Structural basis for the enhanced antiviral activities of MK-2048, a second-generation HIV integrase strand transfer inhibitor (ACS-Fall 2024) - "This talk will go over the experimental and DFT calculated electron density of the active site (nucleotides CA & G, amino acids QPHY, catalytic engine DDE two Mg++ and associated water molecules) of Raltegravir and MK-2048, account for the how these subtle structural changes confer crucial non-covalent interactions (NCI) between MK-2048 with the highly conserved components of the binding pocket for improvements in both intrinsic potency and mutation profile, and bring your attention the importance of NCI analyses in MedChem discovery efforts. Integrase active site (CA & G, aa QPHY, DDE + two Mg++ + waters) with RAL & MK-2048 (PDB 3OYA & 3OYJ)"

Human Immunodeficiency Virus • Infectious Disease

FAME103: Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048 (clinicaltrials.gov) - P1 | N=37 | Completed | Sponsor: Hillier, Sharon, PhD | Active, not recruiting ➔ Completed

Trial completion

FAME103: Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048 (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Hillier, Sharon, PhD | Recruiting ➔ Active, not recruiting

Enrollment closed

Development and Evaluation of Nanoparticles-in-Film Technology to Achieve Extended In Vivo Exposure of MK-2048 for HIV Prevention. (PubMed, Polymers (Basel)) - "PNP films showed sustained drug levels for at least 3 weeks in the macaque vaginal fluid. This work demonstrates the synergy of integrating nanomedicine and polymeric film technology to achieve sustained vaginal drug delivery."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

FAME103: Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048 (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Hillier, Sharon, PhD | Trial completion date: Dec 2021 ➔ May 2022 | Trial primary completion date: Nov 2021 ➔ Mar 2022

Trial completion date • Trial primary completion date

FAME103: Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048 (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Hillier, Sharon, PhD; Trial primary completion date: Aug 2021 ➔ Nov 2021

Clinical • Trial primary completion date

FAME103: Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048 (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Hillier, Sharon, PhD; Trial primary completion date: May 2021 ➔ Aug 2021

Clinical • Trial primary completion date

FAME103: Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048 (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Hillier, Sharon, PhD; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048. (PubMed, Clin Infect Dis) - "In this first study evaluating 2 doses of a combination VCV/MK-2048 VR, both rings were found to be safe and well tolerated. VCV and MK-2048 were detectable in plasma, CVF, and cervical tissue samples, and drug release and plasma drug exposure were higher for the original-dose than for the low-dose ring."

Journal • P1 data • PK/PD data

Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings. (PubMed, Clin Infect Dis) - "Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships."

Clinical • Journal • P1 data • PK/PD data

Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells. (PubMed, Blood Adv) - "Our findings demonstrated that MK-2048 selectively induces HTLV-1-infected cell apoptosis via the activation of the UPR. This novel regulatory mechanism of the HIV IN inhibitor MK-2048 in HTLV-1-infected cells provides a promising prophylactic and therapeutic target for HTLV-1-related diseases including ATL."

Journal

Integrase Inhibitors: After 10 Years of Experience, Is the Best Yet to Come? (PubMed, Pharmacotherapy) - "The era of the integrase strand transfer inhibitors (INSTIs) for the treatment of human immunodeficiency virus (HIV) infection began with raltegravir in 2007. Since that time, several other INSTIs have been introduced including elvitegravir, dolutegravir, and, most recently, bictegravir, that have shown great utility as part of antiretroviral regimens in both treatment-naive and treatment-experienced patients...After 10 years of experience with INSTIs, newer agents are on the horizon such as cabotegravir and MK-2048 for potential use as either HIV pre-exposure prophylaxis or maintenance therapy. This review provides a brief overview of the INSTI class, including agents currently available and those still in development, reviews available data from both completed and ongoing clinical trials, and outlines simplification strategies using INSTIs."

Journal • Gene Therapies • Genetic Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease