Drug Database: VH4524184

Pharmacology Pharmacology

Pharmacology

Mechanism of Action

Integrase strand transfer inhibitor (INSTI). VH4524184 is a third-generation INSTI with potent antiviral activity and an improved in vitro resistance profile compared to the second-generation INSTIs dolutegravir (DTG) and cabotegravir (CAB).^3,4 As an INSTI, VH4524184 inhibits HIV replication by blocking viral DNA integration into the host genome.⁴

VH4524184 is currently being developed for oral administration and as a long-acting injectable treatment for HIV.^2,5

Half-life (T_½)

In the first part of a Phase 1 study (NCT05631704) evaluating single ascending oral doses of VH4524184 in adults without HIV, the mean terminal half-life of VH4524184 was approximately 24 hours (range from 22.1 to 28.5 hours).⁶

A Phase 1 ascending-dose study (NCT06310551) is evaluating two long-acting formulations of VH4524184 administered by subcutaneous (SC) and intramuscular (IM) injection in adults without HIV. Interim results indicate that the median terminal half-life of formulation A ranged from 3.5 weeks (IM thigh) to 7.8 weeks (SC), and the median terminal half-life of formulation B (ultra-long-acting) ranged from 14.9 weeks (IM thigh) to 19.8 weeks (SC).^5,7

Resistance

In a Phase 2a trial (NCT06214052) evaluating VH4524184 monotherapy (10 mg, 50 mg, or 300 mg administered orally every 3 days) in treatment-naive adults, no VH4524184 resistance mutations were seen at the end of the 10-day monotherapy period.^3,8

Select Clinical Trials Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT06214052

Sponsor: ViiV Healthcare
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this proof-of-concept study was to evaluate the pharmacokinetics (PK), safety, tolerability, and antiviral effect of three different doses of oral VH4524184 monotherapy in treatment-naive adults.
Study Population:

• Participants were treatment-naive adults with HIV.
• Participants had HIV RNA ≥3,000 copies/mL and CD4 counts ≥200 cells/mm³ at screening.⁸

Selected Study Results: Results presented at CROI 2025 showed that VH4524184 monotherapy had comparable potency to DTG monotherapy. In the 50-mg and 300-mg dose groups, VH4524184 monotherapy led to a maximum reduction from baseline in plasma HIV RNA of greater than 2 log10 copies/mL.³

Study Identifiers: INNOVATE; NCT07202546

Sponsor: ViiV Healthcare
Phase: 2b
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of two different doses of oral VH4524184, each taken with emtricitabine/tenofovir alafenamide (Descovy), compared to dolutegravir/lamivudine (Dovato) in treatment-naive adults.
Study Population:

• Participants are treatment-naive adults with HIV.
• Participants have HIV RNA ≥1,000 copies/mL and CD4 counts >200 cell/mm³ at screening.
• Participants do not have known or suspected resistance mutations to INSTIs or NRTIs.²

Additional studies evaluating VH4524184 for HIV treatment have been completed or are being conducted, including the following Phase 1 trials:

• NCT05631704 was a single- and multiple-ascending dose study evaluating the safety, tolerability and PK of oral VH4524184, as well as the CYP3A interaction potential of VH4524184, in adults without HIV. This study has been completed, and results are available from Clin Infect Dis (2025).^6,9
• NCT06310551 is a single-ascending dose and multiple dose study evaluating the safety, tolerability, and PK of long-acting injectable formulations of VH4524184 in adults without HIV. Results thus far are available from CROI 2026. This study is currently recruiting participants.⁵

Adverse Events Adverse Events

Adverse Events

NCT06214052

In this Phase 2a trial, treatment-naive adults received either oral VH4524184 monotherapy 10 mg (n = 6), 50 mg (n = 6), or 300 mg (n = 7) administered every 3 days over 10 days or placebo (n = 3). Adverse events (AEs), all of which were Grade 1 or 2, occurred in 42% of participants receiving VH4524184 and 67% of participants receiving placebo. VH4524184-related AEs were reported in five participants and included diarrhea, dizziness, fatigue, increased amylase, increased lipase, nausea, and vomiting. All VH4524184-related AEs were Grade 1, and each occurred in one participant. There were no serious adverse events (SAEs) or AEs resulting in study discontinuation.^3,8

Drug Interactions Drug Interactions

Drug Interactions

A Phase 1 study (NCT05631704) evaluating the effects of oral VH4524184 on the PK of the CYP3A probe substrate midazolam indicates that VH4524184 does not inhibit or induce CYP3A4.⁶

In a Phase 1 trial (NCT06310616), the effect of oral VH4524184 on the PK of an oral contraceptive (ethinyl estradiol/norethindrone acetate [EE/NEA]) was assessed in female participants without HIV. Results demonstrated that VH4524184 did not alter the steady-state PK of EE and had no clinically significant effect on NEA concentrations. Furthermore, the steady-state PK of VH4524184 was not significantly altered by EE/NEA coadministration.^10,11

References References

References

1. ViiV Healthcare website. HIV medicines in development. Accessed May 11, 2026
2. ViiV Healthcare. A Phase 2b randomized, open-label active controlled study evaluating the safety and efficacy of oral VH4524184 coadministered with emtricitabine and tenofovir alafenamide in treatment naive viremic persons with HIV-1 (INNOVATE study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 30, 2025. NLM Identifier: NCT07202546. Accessed May 11, 2026
3. Rogg L, Núñez SA, Mingrone MV, et al. Proof-of-concept Phase 2a trial of VH4524184 (VH-184), a third-generation integrase strand transfer inhibitor. Conference on Retroviruses and Opportunistic Infections (CROI); March 9-12, 2025; San Francisco, CA. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2025. Accessed May 11, 2026
4. Seki T, Arita S, Ishida K, et al. In vitro characterization of VH4524184 (VH-184, S-365598), a new third-generation integrase strand transfer inhibitor (INSTI) with a unique resistance profile. International AIDS Conference; July 22-26, 2024; Munich, Germany. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2024. Accessed May 11, 2026
5. ViiV Healthcare. A Phase 1 double-blind (sponsor-unblinded), placebo-controlled randomized, single ascending dose and multiple dose study to investigate the safety, tolerability, and pharmacokinetics of parenterally administered VH4524184 in healthy adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 5, 2024. NLM Identifier: NCT06310551. Accessed May 11, 2026
6. Rogg L, Underwood M, Hanan N, et al. Phase 1 evaluation of VH4524184, a third-generation integrase strand transfer inhibitor with an enhanced resistance profile. Clin Infect Dis. 2025;81(3):510-520. doi:10.1093/cid/ciaf135. Accessed May 11, 2026
7. Back H, Rogg L, Halliday F, et al. Pharmacokinetics and evaluation of potential dosing regimens for long-acting VH4524184. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2026; Denver, CO. Accessed May 11, 2026
8. ViiV Healthcare. A Phase 2a, randomized, double-blind (sponsor unblinded), placebo-controlled, study to investigate the antiviral effect, safety, tolerability and pharmacokinetics of VH4524184 in HIV-1 infected treatment naïve adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 9, 2024. NLM Identifier: NCT06214052. Accessed May 11, 2026
9. ViiV Healthcare. A Phase 1 double-blind (sponsor-unblinded), placebo-controlled randomized, single and multiple ascending dose first-time-in-human study to investigate the safety, tolerability, and pharmacokinetics of VH4524184 and the potential for changes in cytochrome P450 3A (CYP3A) activity. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 18, 2022. NLM Identifier: NCT05631704. Accessed May 11, 2026
10. ViiV Healthcare. A Phase 1, single-center, open-label study to evaluate the pharmacokinetics of oral contraceptive containing norethindrone and ethinyl estradiol (Loestrin) when co-administered with VH4524184 in healthy adult female participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 1, 2024. NLM Identifier: NCT06310616. Accessed May 11, 2026
11. Doyle E, Kahl L, Goodchild J, et al. Lack of clinically significant drug–drug interactions between the third-generation integrase strand transfer inhibitor VH4524184 (VH-184) and combined oral contraceptives. Br J Clin Pharmacol. 2025;91(S1):15-16. doi:10.1002/bcp.70221. Accessed May 11, 2026