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Phase 1 results show safety and once-daily
potential of new HIV maturation inhibitor
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20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
Mark Mascolini
Two phase 1 trials of GSK3640254, an HIV maturation inhibitor, found the agent generally safe and tolerable in healthy adults without HIV infection [1]. Pharmacokinetic (PK) analysis yielded findings supporting once-daily dosing.
Being developed by ViiV Healthcare and GlaxoSmithKline, GSK3640254 inhibits HIV replication by disturbing the final step of HIV-1 Gag processing and thus produces immature, noninfectious virus. ViiV and GSK researchers described results of two phase 1 trials exploring the safety and PKs of GSK3640254 in healthy volunteers.
The first phase 1 trial randomized participants to GSK3640254 or placebo in a 3-to-1 ratio using a single ascending dose (SAD) design or a multiple ascending dose (MAD) design. The second trial evaluated the relative bioavailability of single doses of two salt forms of GSK3640254 in 14 volunteers. The first trial tested doses ranging from 1 to 700 mg daily, while the second trial tested 200 mg daily.
The SAD study involved 20 participants and the MAD study 58, all of them men. Across the SAD and MAD study groups, age averaged 33 to 42 years, body mass index 24.4 to 27.4 kg/m2, and proportions of whites 63% to 88%.
No deaths or serious adverse events occurred in either the SAD or MAD studies. In the combined studies 4 adverse events led to discontinuation and 9 adverse events were related to study drug. One adverse event leading to discontinuation, grade 1 maculopapular rash, was attributed to study drug. The most frequent adverse events in the combined SAD and MAD studies were headache, contact dermatitis due to ECG electrodes, diarrhea, dizziness, contusion, fatigue, and back pain.
GSK3640254 absorption was slow, with a median of about 4 hours to maximum concentration. A slow elimination half-life of about 24 hours suggested the viability of once-daily dosing.
Among the 14 men in the bioavailability study, age averaged 33.6 years and body mass index 25.4 kg/m2. Seven participants had 11 adverse events, all of them rated grade 1 and 2 of them related to GSK3640254 (both grade 1 headache). Relative bioavailability of the two GSK3640254 salt forms proved comparable. Neither of the two trials disclosed clinically significant changes in vital signs, ECG parameters, or lab values.
A phase 2 trial has begun to test the mesylate salt capsule formulation of GSK3640254 in antiretroviral-naive adults with HIV [2].
References
1. Joshi S, Fernando D, McKenzie L, et al. The initial phase 1 evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next generation HIV maturation inhibitor, as assessed in healthy subjects. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 4.
2. ClinicalTrials.gov. A proof of concept study of GSK3640254 in human immunodeficiency virus-1 (HIV-1) infected treatment-naive adults. ClinicalTrials.gov identifier NCT03784079. https://clinicaltrials.gov/ct2/show/NCT03784079
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