(Compound details obtained from NIAID Therapeutics Database1 and ClinicalTrials.gov2)
Mechanism of Action: Maturation Inhibitor (MI). GSK3640254 is a next-generation HIV-1 MI that acts during the last step of the HIV lifecycle. GSK3640254 binds to HIV-1 Gag, inhibiting the final protease-mediated cleavage event between capsid (CA) protein p24 and spacer peptide 1 (SP1) within the Gag polyprotein. Prevention of Gag polyprotein separation to its component proteins p24/CA and SP1 results in the release of immature, noninfectious virions.3–5
Half-life (T½): In a Phase 1 pharmacokinetic (PK) study (NCT03231943) evaluating single and repeated daily oral administration of GSK3640254 (bis-hydrochloride salt formulation) in healthy adults, the mean half-life of GSK3640254 was approximately 24 hours for the 10- to 700-mg doses.6
In a relative bioavailability study (NCT03575962), two different formulations of GSK3640254 (bis-hydrochloride salt or mesylate salt formulations), administered as single oral 200-mg doses, were evaluated in healthy adults. The mean plasma half-life of the mesylate salt formulation was approximately 24 hours and was similar to that of the bis-hydrochloride salt formulation.6
Resistance: In a Phase 2a trial (NCT03784079), GSK3640254 monotherapy was evaluated in treatment-naive adults with HIV. In Part 1 of the study, six participants each received 10 mg or 200 mg of GSK3640254 for 10 days. At Day 11, four participants in the 200-mg group developed the A364A/V resistance-associated mutation (RAM); one of the four participants had virus showing phenotypic resistance to GSK3640254. No resistance emerged in the 10-mg group.7
In Part 2 of the study, six participants each received 40, 80, or 140 mg of GSK3640254 for 7 days. (The duration of Part 2 was modified from 10 days to 7 days to reduce the potential for treatment-emergent RAMs.) No treatment-emergent RAMs were seen.7
Select Clinical TrialsStudy Identifier: NCT03784079
Sponsor: ViiV Healthcare
Status: This study has been completed.
Study Purpose: The purpose of this proof-of-concept study was to evaluate the antiviral activity, safety, and pharmacokinetics of GSK3640254 monotherapy administered at various doses in treatment-naive adults.
- Participants were treatment-naive adults with HIV.
- Participants had HIV RNA ≥5,000 copies/mL at screening and CD4 counts ≥350 cells/mm3.7,8
Study Identifiers: DOMINO; NCT04493216
Sponsor: ViiV Healthcare
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety, efficacy, and dose-response of GSK3640254 (given at three different doses) compared to dolutegravir, each given in combination with abacavir/lamivudine or emtricitabine/tenofovir alafenamide in treatment-naive adults.
- Participants are treatment-naive adults with HIV.
- Participants have HIV RNA ≥1,000 copies/mL and CD4 counts ≥250 cells/mm3 at screening.2
Study Identifiers: DYNAMIC; NCT04900038
Sponsor: ViiV Healthcare
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety, efficacy, tolerability and resistance profile of GSK3640254 (given at three different doses) in combination with dolutegravir as compared to lamivudine in combination with dolutegravir in treatment-naive adults.
- Participants are treatment-naive adults with HIV.
- Participants have HIV RNA ≥1,000 copies/mL and CD4 counts ≥250 cells/mm3 at screening.9
In this Phase 2a trial, a total of 34 participants received GSK3640254 monotherapy across five dosing groups (n=6/dosing group) or placebo (n=4). Adverse events (AEs) occurred in 22 of 30 (65%) participants receiving GSK3640254 and in no participants receiving placebo. Except for two nondrug-related AEs, all AEs were mild to moderate in intensity. The most common AEs were headache (12%) and oropharyngeal pain (9%). Gastrointestinal AEs were reported in 21% of participants. A total of 14 cases of drug-related AEs occurred in nine participants (26%), with the most common being diarrhea, abdominal pain, and vomiting. There were no drug-related serious adverse events (SAEs) or treatment discontinuations due to an AE.7
Laboratory abnormalities of “potential clinical importance” occurred in 11 participants and included neutrophil count, leukocyte count, and chloride level abnormalities.7
GSK3640254 is an inhibitor of the drug transporter OATP1B3, and in vitro data has indicated that GSK3640254 may interact with substrates of OATP1B3, including tenofovir alafenamide. A Phase 1 PK drug interaction study (NCT03836729) was conducted to evaluate GSK3640254 coadministered with tenofovir alafenamide/emtricitabine (TAF/FTC) in healthy adults. Results showed that GSK3640254 did not have a clinically significant effect on the steady-state PK of TAF, tenofovir (the metabolite of TAF), or FTC.4
A Phase 1 drug interaction trial (NCT03816696) evaluating dolutegravir coadministered with GSK3640254 in healthy participants found no clinically significant interactions between both agents.10,11
The effect of GSK3640254 on the PK of the combination oral contraceptive ethinyl estradiol/levonorgestrel was assessed in a Phase I trial (NCT03984825); no significant PK interaction was seen.12,13
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed June 13, 2022
- ViiV Healthcare. A Phase IIb, randomized, partially blind, active controlled, dose-range finding study of GSK3640254 compared to a reference arm of dolutegravir, each in combination with nucleoside reverse transcriptase inhibitors, in HIV-1 infected antiretroviral treatment-naive adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 10, 2020. NLM Identifier: NCT04493216. https://clinicaltrials.gov/ct2/show/NCT04493216. Accessed June 13, 2022
- Rathi C, Johnson M, Joshi S, Ferron-Brady G. Model-informed selection of doses and sample size for a Phase 2a POC study of GSK3640254, a next generation HIV-1 maturation inhibitor. Abstract presented at: Population Approach Group Europe (PAGE) Meeting; June 11-14, 2019; Stockholm, Sweden. Abstract 8870. https://www.page-meeting.org/default.asp?abstract=8870. Accessed June 13, 2022
- Pene Dumitrescu T, Joshi SR, Xu J, et al. A Phase I evaluation of the pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and tenofovir alafenamide/emtricitabine in healthy participants. Antimicrob Agents Chemother. Published online March 22, 2021:AAC.02173-20, aac;AAC.02173-20v1. doi:10.1128/AAC.02173-20
- Spinner C, Felizarta F, Rizzardini G, et al. Phase IIA proof-of-concept trial of next-generation maturation inhibitor GSK3640254. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. http://www.croiwebcasts.org/console/player/48166?mediaType=slideVideo&. Accessed June 13, 2022
- Joshi SR, Fernando D, Igwe S, et al. Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next‐generation HIV‐1 maturation inhibitor. Pharmacol Res Perspect. 2020;8(6). doi:10.1002/prp2.671
- Spinner CD, Felizarta F, Rizzardini G, et al. Phase IIa proof-of-concept evaluation of the antiviral efficacy, safety, tolerability, and pharmacokinetics of the next-generation maturation inhibitor GSK3640254. Clin Infect Dis. doi:10.1093/cid/ciab1065
- ViiV Healthcare. A randomized, double-blind (sponsor-unblinded), placebo-controlled, adaptive trial to investigate the antiviral effect, safety, tolerability and pharmacokinetics of GSK3640254 in HIV-1 infected treatment-naïve adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 19, 2018. NLM Identifier: NCT03784079. https://clinicaltrials.gov/ct2/show/NCT03784079. Accessed June 13, 2022
- ViiV Healthcare. A Phase IIb, randomized, double-blind, parallel-group study to assess the efficacy, safety, tolerability, and resistance profile of GSK3640254 in combination with dolutegravir compared to dolutegravir plus lamivudine in HIV-1 infected, treatment-naïve adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 19, 2021. NLM Identifier: NCT04900038. https://clinicaltrials.gov/ct2/show/NCT04900038. Accessed June 13, 2022
- Pene Dumitrescu T, Joshi SR, Xu J, et al. Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults. Br J Clin Pharmacol. Published online February 3, 2021. doi:10.1111/bcp.14759
- ViiV Healthcare. An open-label two-way interaction clinical trial to evaluate the pharmacokinetic interactions between GSK3640254 and dolutegravir in healthy subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 22, 2019. NLM Identifier: NCT03816696. https://clinicaltrials.gov/ct2/show/NCT03816696. Accessed June 13, 2022
- Dumitrescu TP, Joshi S, Xu J, et al. Lack of a pharmacokinetic (PK) interaction between HIV-1 maturation inhibitor (MI) GSK3640254 (GSK’254) and oral contraceptive (OC) ethinyl estradiol (EE)/levonorgestrel (LNG). Abstract presented at: International Workshop of Clinical Pharmacology on HIV, Hepatitis, and Other Antiviral Drugs; September 28-30, 2020; Virtual. Abstract 13A. https://academicmedicaleducation.com/meeting/international-workshop-clinical-pharmacology-hiv-hepatitis-and-other-antiviral-drugs-167. Accessed June 13, 2022
- ViiV Healthcare. The effect of coadministration of GSK3640254 on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy female subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 10, 2019. NLM Identifier: NCT03984825. https://clinicaltrials.gov/ct2/show/NCT03984825. Accessed June 13, 2022
Last Reviewed: June 13, 2022