GSK3640254 / ViiV Healthcare - LARVOL DELTA

Efficacy and safety of the HIV-1 maturation inhibitor GSK3640254 plus dolutegravir as a two-drug regimen in adults naive to antiretroviral therapy (DYNAMIC): 24-week results from a randomised phase 2b study. (PubMed, EClinicalMedicine) - P2 | "Participants were centrally randomised to receive once-daily oral GSK'254 100 (N = 22), 150 (N = 20), or 200 mg (N = 22) or lamivudine (3TC) 300 mg (double-blinded dose) (N = 21), all with open-label DTG 50 mg. GSK'254 plus DTG demonstrated generally comparable efficacy and safety to DTG plus 3TC, supporting potential further evaluation of maturation inhibitors for HIV-1 treatment. ViiV Healthcare."

Journal • P2b data • Human Immunodeficiency Virus • Infectious Disease • CD4

Efficacy and safety of the HIV-1 maturation inhibitor GSK3640254 plus two NRTIs in adults naive to antiretroviral therapy (DOMINO): 24-week results from a randomised phase 2b study. (PubMed, EClinicalMedicine) - P2 | "Participants were centrally randomised to receive once-daily oral GSK'254 100, 150, or 200 mg (double-blinded dose) or open-label dolutegravir (DTG) 50 mg, each with open-label NRTIs. GSK'254 plus two NRTIs demonstrated efficacy and safety with no treatment-emergent resistance, consistent with DTG plus two NRTIs, supporting potential further evaluation of maturation inhibitors. ViiV Healthcare."

Journal • P2b data • Human Immunodeficiency Virus • Infectious Disease • CD4

Invention of VH-937, a Potent HIV-1 Maturation Inhibitor with the Potential for Infrequent Oral Dosing in Humans. (PubMed, ACS Med Chem Lett) - "VH3739937, (VH-937, 24) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, 3). Structure-activity optimization led to the invention of VH-937, which combined the best overall antiviral profile with pharmacokinetic properties in animal models. These properties indicate the potential for infrequent dosing, a finding confirmed in initial clinical studies in humans that suggests its potential as a once-weekly dosing agent."

Journal • Human Immunodeficiency Virus • Infectious Disease

Next-Generation Maturation Inhibitor GSK3640254 Showed Broad Spectrum Potency Without MI Resistance (CROI 2024) - "In vitro analysis of GSK'254 predicted activity against a broad array of gag polymorphisms, including those hindering prior MI class compounds. Clinical data from the DOMINO study supported the efficacy of this novel MI, GSK'254, as no virus tested from the study demonstrated a decrease in potency to GSK'254 at baseline, through week 4 on treatment, or at any time of protocol defined virologic failure. The clinical durability observed for GSK'254 in this study suggests a sufficient genetic barrier without emergence of resistance."

Human Immunodeficiency Virus • Infectious Disease

DYNAMIC: A Clinical Trial of GSK3640254 + Dolutegravir (DTG) in Human Immunodeficiency Virus-1 Infected Treatment-naive Adults (clinicaltrials.gov) - P2 | N=85 | Terminated | Sponsor: ViiV Healthcare | Phase classification: P2b ➔ P2

Phase classification • Human Immunodeficiency Virus • Infectious Disease • CD4

DOMINO: A Dose-Range Finding Clinical Trial Study in Human Immunodeficiency Virus (HIV-1) Infected Treatment-Naive Adults (clinicaltrials.gov) - P2 | N=169 | Terminated | Sponsor: ViiV Healthcare | The decision is not based on any safety or efficacy concerns. It reflects the company strategy for portfolio progression.

Combination therapy • Phase classification • Trial completion date • Trial termination • Human Immunodeficiency Virus • Infectious Disease • CD4

Effects of the HIV-1 maturation inhibitor GSK3640254 on QT interval in healthy participants. (PubMed, Pharmacol Res Perspect) - "Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400-mg moxifloxacin dose on Day 7 (all with a moderate-fat meal). By concentration-QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL . No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100-mg dose."

Journal • Human Immunodeficiency Virus • Infectious Disease

Efficacy and Safety of the HIV-1 Maturation Inhibitor GSK3640254 + Dolutegravir as a 2-Drug Regimen in Treatment-Naive Adults: 24-Week Results From the Phase IIb DYNAMIC Study (EACS 2023) - "Method : In this double-blind, phase IIb trial, participants were randomized to once-daily GSK’254 100, 150, or 200 mg or lamivudine (3TC) 300 mg, all with open-label DTG 50 mg, stratified by HIV-1 RNA <100,000 versus ≥100,000 c/mL. Conclusions : The maturation inhibitor GSK’254 combined with DTG had efficacy and adverse event profiles similar to DTG + 3TC, with low discontinuation rates and no treatment-emergent resistance across all doses. These results support further development of maturation inhibitors for 2-drug combination therapy (including non–INSTI-based combinations)."

Clinical • P2b data • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • CD4

Efficacy and Safety of the HIV-1 Maturation Inhibitor GSK3640254 + 2 NRTIs in Treatment-Naive Adults: 24-Week Results From the Phase IIb, Dose-Range Finding DOMINO Study (EACS 2023) - "Method : In this partially blinded, phase IIb trial, participants with HIV-1 RNA ≥1000 c/mL were randomized to receive once-daily oral GSK’254 100, 150, or 200 mg (blinded dose) or open-label dolutegravir (DTG), all with 2 open-label NRTIs. Serum gastrin levels reflected normal acid secretion. Conclusions : GSK’254 + 2 NRTIs demonstrated comparable efficacy to DTG + 2 NRTIs with no treatment-emergent resistance across all doses and a comparable safety/tolerability profile, supporting evaluation of maturation inhibitors for HIV-1 treatment."

Clinical • P2b data • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • CD4 • GAST

DYNAMIC: A Clinical Trial of GSK3640254 + Dolutegravir (DTG) in Human Immunodeficiency Virus-1 Infected Treatment-naive Adults (clinicaltrials.gov) - P2b | N=85 | Terminated | Sponsor: ViiV Healthcare | The decision is not based on any safety or efficacy concerns. It reflects the company strategy for portfolio progression.

Combination therapy • Trial termination • Human Immunodeficiency Virus • Infectious Disease • CD4

DYNAMIC: A Clinical Trial of GSK3640254 + Dolutegravir (DTG) in Human Immunodeficiency Virus-1 Infected Treatment-naive Adults (clinicaltrials.gov) - P2b | N=85 | Completed | Sponsor: ViiV Healthcare | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

Pharmacokinetics and Tolerability of the Maturation Inhibitor GSK3640254 Co-Administered With Darunavir/Ritonavir and/or Etravirine in Healthy Adults. (PubMed, Br J Clin Pharmacol) - "GSK'254 pharmacokinetics were not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • Pain

Integrating In Vitro Biopharmaceutics into Physiologically Based Biopharmaceutic Model (PBBM) to Predict Food Effect of BCS IV Zwitterionic Drug (GSK3640254). (PubMed, Pharmaceutics) - "Thus, by using Simcyp v20 software, the PBBM model accurately predicted the results of the food effect and predicted data were within a two-fold error with 70% being within 1.25-fold. The developed model strategy can be effectively adopted to increase the confidence of using PBBM models to predict the food effect of BCS class IV drugs."

Journal • Preclinical

Open-Label, Drug-Drug Interaction Study Between the HIV-1 Maturation Inhibitor GSK3640254 and a Metabolic Probe Cocktail in Healthy Participants. (PubMed, Br J Clin Pharmacol) - "Co-administration of GSK'254 with a metabolic probe cocktail in healthy participants indicated very low risk of clinically relevant effect on PK of any substrates or associated metabolites. No new safety/tolerability concerns were identified. These results support ongoing phase IIb and planned phase III studies of GSK'254 in PLWH."

Journal • Human Immunodeficiency Virus • Infectious Disease

Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity. (PubMed, J Med Chem) - "Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Effects of the HIV-1 maturation inhibitor GSK3640254 on QT interval in healthy participants (HIV-Glasgow 2022) - "Four sequential treatment periods composed the main QTc study (part 2): GSK’254 100 mg, GSK’254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400-mg moxifloxacin dose on day 7 (all administered with a moderate-fat meal). No clinically relevant effects on QTc prolongation, heart rate, or cardiac conduction were seen in healthy participants at concentrations associated with projected therapeutic GSK’254 doses being evaluated in phase IIb studies. These results support continued clinical development of GSK’254."

Clinical • Human Immunodeficiency Virus • Infectious Disease

Investigation of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of the HIV-1 Maturation Inhibitor GSK3640254 Using an Intravenous Microtracer Combined With EnteroTracker for Biliary Sampling. (PubMed, Drug Metab Dispos) - "Significance Statement The combination of an intravenous C microtracer with duodenal bile sampling using EnteroTracker in a human absorption, distribution, metabolism, and excretion study enabled derivation of absorption and first-pass parameters, including fraction absorbed, proportion escaping first-pass extraction through the gut wall and liver, hepatic extraction, and other conventional clinical pharmacokinetic parameters. This approach identified hepatic metabolism and biliary excretion as a major elimination pathway for absorbed drug, which would be overlooked based solely on analyses of plasma, urine, and fecal matrices."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation. (PubMed, J Med Chem) - "GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects."

Journal • Human Immunodeficiency Virus • Infectious Disease

DYNAMIC: A Clinical Trial of GSK3640254 + Dolutegravir (DTG) in Human Immunodeficiency Virus-1 Infected Treatment-naive Adults (clinicaltrials.gov) - P2b | N=85 | Active, not recruiting | Sponsor: ViiV Healthcare | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4

DOMINO: A Dose-Range Finding Clinical Trial Study in Human Immunodeficiency Virus (HIV-1) Infected Treatment-Naive Adults (clinicaltrials.gov) - P2b | N=150 | Active, not recruiting | Sponsor: ViiV Healthcare | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4

Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254. (PubMed, Clin Infect Dis) - P2b | "This monotherapy study established a dose-antiviral response relationship for GSK'254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216)."

Clinical • Journal • P2a data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • Pain

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - P1 | "The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1."

Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease

Effect of Therapeutic and Supratherapeutic Oral Doses of GSK3640254 on Cardiac Conduction Compared to Placebo and a Single Oral Dose of Moxifloxacin (clinicaltrials.gov) - P1; N=46; Completed; Sponsor: ViiV Healthcare; Recruiting ➔ Completed

Clinical • Trial completion • Human Immunodeficiency Virus • Infectious Disease

GSK3640254 Is a Novel HIV-1 Maturation Inhibitor With an Optimized Virology Profile. (PubMed, Antimicrob Agents Chemother) - "Virus-like particles containing the A364V mutation exhibited a p25 cleavage rate 9.3 times faster than wild-type, providing a possible mechanism for MI resistance. The findings demonstrate that GSK'254 potently inhibits a broad range of HIV-1 strains expressing Gag polymorphisms."

Journal • Gastrointestinal Disorder • Human Immunodeficiency Virus • Infectious Disease

Drug-drug Interaction (DDI) Study of GSK3640254 With Darunavir/Ritonavir (DRV/RTV) and Etravirine (ETR) (clinicaltrials.gov) - P1; N=54; Completed; Sponsor: ViiV Healthcare; Active, not recruiting ➔ Completed

Clinical • Trial completion • Human Immunodeficiency Virus • Infectious Disease