Drug Database: Ulonivirine

Pharmacology

Pharmacology

Mechanism of Action

Non-nucleoside reverse transcriptase inhibitor (NNRTI). Ulonivirine (ULO) is a novel NNRTI with potent in vitro activity against multiple HIV-1 subtypes and common NNRTI-resistant mutant viruses.^3,4 NNRTIs are noncompetitive inhibitors of HIV-1 reverse transcriptase. They work by binding to a hydrophobic pocket in the HIV-1 p66 subunit of reverse transcriptase, located approximately 10 Å away from the polymerase active site. NNRTI binding causes inhibition of reverse transcription by inducing allosteric conformational changes.^3,5,6

Half-life (T_½)

In two Phase 1 studies (MK-8507-001 and MK-8507-002) evaluating the safety and pharmacokinetics of ulonivirine in adults without HIV, the mean terminal half-life of ulonivirine following single oral doses of a suspension (2 to 400 mg) or a tablet (400 to 1,200 mg) ranged from approximately 58 to 84 hours.³

Resistance

A Phase 1 trial (MK-8507-003; NCT02174159) assessed single oral doses (40, 80, and 600 mg) of ulonivirine monotherapy in 18 treatment-naive adults with HIV. One participant, who had initiated standard-of-care ART 14 days after dosing with ulonivirine 600 mg, experienced viral rebound. Resistance testing in this participant showed that the F227C NNRTI resistance-associated mutation was first detected at 10 days postdose. Investigators concluded that the emergence of the F227C mutation would be considered clinically irrelevant in the context of combination ART.^7,8

Select Clinical Trials

Select Clinical Trials

Study Identifiers: IMAGINE-DR; MK-8591-013; NCT04564547

Sponsor: Merck Sharp & Dohme LLC
Phase: 2b
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety and efficacy of a switch to once-weekly islatravir (20 mg) and ulonivirine (100, 200, or 400 mg) in adults with viral suppression on bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy).
Study Population:

• Participants were adults with HIV who had been virologically suppressed on Biktarvy for at least 6 months and had no history of treatment failure on any regimen.
• Participants had HIV RNA <50 copies/mL and CD4 counts ≥200 cells/mm³ at screening.
• Participants had no known resistance to NNRTIs.^9,10

Selected Study Results: The MK-8591-013 study was stopped early due to decreases in total lymphocyte and CD4 counts seen across islatravir trials. Available data was presented at IAS 2025 and showed that islatravir plus ulonivirine (given at three different dose levels) was effective in maintaining viral suppression through Week 24. The adverse event (AE) profile of islatravir plus ulonivirine was similar to that of Biktarvy. Decreases in total lymphocyte and CD4 counts were seen in all islatravir plus ulonivirine study arms. Long-term follow-up showed that the declines in total lymphocyte and CD4 counts were generally reversible after participants had discontinued both study drugs.¹⁰

Study Identifiers: MK-8591B-060; NCT06891066

Sponsor: Merck Sharp & Dohme LLC
Phase: 2b
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of a switch to once-weekly islatravir (2 mg) and ulonivirine (200 mg) in adults with viral suppression on Biktarvy.
Study Population:

• Participants are adults with HIV who have been virologically suppressed on Biktarvy for at least 6 months and have no history of treatment failure on any past or current regimen.
• Participants have HIV RNA <50 copies/mL and CD4 counts ≥200 cells/mm³.
• Participants have no prior exposure to islatravir or ulonivirine and no resistance mutations associated with ulonivirine.^11,12

Selected Study Results: Results presented at AIDS 2026 showed that once-weekly islatravir plus ulonivirine was effective in maintaining viral suppression through Week 24 and had similar efficacy to Biktarvy. No safety concerns were seen with islatravir plus ulonivirine, and the AE profile of islatravir plus ulonivirine was comparable to Biktarvy.¹²

Study Identifiers: MK-8591B-062; NCT07266831

Sponsor: Merck Sharp & Dohme LLC
Phase: 2/3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of the Phase 2 open-label portion of this study is to evaluate the safety and efficacy of once-weekly islatravir (2 mg) plus ulonivirine (200 mg) compared with Biktarvy in treatment-naive adults.

The purpose of the Phase 3 double-blind portion of this study is to evaluate the safety and efficacy of a once-weekly islatravir/ulonivirine (2/200 mg) fixed-dose combination tablet compared with Biktarvy in treatment-naive adults.
Study Population:

• Participants are treatment-naive adults with HIV.
• Phase 2: Participants have HIV RNA ≥500 and ≤ 100,000 copies/mL and have CD4 counts ≥200 cells/mm³.
• Phase 3: Participants have HIV RNA ≥500 copies/mL.
• Participants have no prior exposure to islatravir or ulonivirine.²

Additional studies evaluating ulonivirine have been completed or are planned. Some of these studies are described below.

• MK-8507-001 and MK-8507-002 were Phase 1 studies that evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of ulonivirine in adults without HIV. Investigators also assessed the potential for ulonivirine to induce CYP3A4 activity and the effect of food on ulonivirine pharmacokinetics. These studies have been completed, and results are available from Antimicrob Agents Chemother (2021).³
• MK-8507-015 was a Phase 1 trial that evaluated the safety of multiple once-weekly doses of ulonivirine in adults without HIV. This study has been completed, and results are available from IAS 2025.¹³
• MK-8507-003 (NCT02174159) was a Phase 1 open-label study that assessed the safety, tolerability, pharmacokinetics, and antiviral activity of a single dose of ulonivirine monotherapy in treatment-naive adults with HIV. This study has been completed, and results are available from HIV Glasgow 2020 and the J Acquir Immune Defic Syndr (2021).¹⁴

Adverse Events

Adverse Events

IMAGINE-DR (MK-8591-013; NCT04564547)

In this Phase 2b study, adults with viral suppression on Biktarvy received either weekly oral islatravir (20 mg) plus ulonivirine (100, 200, or 400 mg) (n = 121) or continued daily oral Biktarvy (n = 40). Dosing of islatravir plus ulonivirine was stopped early due to declines in total lymphocyte and CD4 counts seen across all islatravir trials, including this trial. Available safety data showed that islatravir plus ulonivirine had a comparable AE profile to that of Biktarvy. Three participants discontinued islatravir plus ulonivirine because of drug-related AEs—diarrhea in one participant receiving islatravir plus ulonivirine 200 mg; abdominal pain, diarrhea, headache, nausea, oral herpes, and pain in another participant receiving islatravir plus ulonivirine 200 mg; and decreased appetite in a third participant receiving islatravir plus ulonivirine 400 mg. Long-term follow-up showed that total lymphocyte and CD4 counts trended back to baseline after participants discontinued islatravir and ulonivirine.^9,10

MK-8591B-060 (NCT06891066)

In this Phase 2b study, adults with viral suppression on Biktarvy received either weekly oral islatravir (2 mg) plus ulonivirine (200 mg) (n = 78) or continued daily oral Biktarvy (n = 79). The AE profile of islatravir plus ulonivirine was comparable to the AE profile of Biktarvy. Drug-related AEs occurred in 10 participants (12.8%) receiving islatravir plus ulonivirine and none of the participants receiving Biktarvy. All drug-related AEs associated with islatravir plus ulonivirine were Grade 1 or 2 in severity, and the only islatravir plus ulonivirine drug-related AE occurring in more than one participant was dizziness (n = 2). There were no drug-related serious adverse events (SAEs) associated with islatravir plus ulonivirine. One participant receiving islatravir plus ulonivirine discontinued study treatment due to a Grade 2 drug-related skin reaction. Treatment with islatravir plus ulonivirine had no notable effect on total lymphocyte and CD4 counts.¹²

Drug Interactions

Drug Interactions

In a Phase 1 drug-drug interaction study (NCT06619678) evaluating coadministration of ulonivirine 200 mg and islatravir 2 mg in adults without HIV, no clinically meaningful interactions were observed.^15,16

A Phase 1 study (MK-8507-002) evaluating the interaction between ulonivirine and the CYP3A4 probe drug midazolam found that ulonivirine had no clinically significant impact on midazolam exposure and therefore is not a meaningful inducer of CYP3A4 activity.³

A Phase 1 study evaluated the effects of rifabutin (a moderate CYP3A4 inducer) on the pharmacokinetics of ulonivirine. Although rifabutin coadministration led to a modest reduction in ulonivirine exposure, this interaction was not considered clinically meaningful.¹⁷

References

References

1. National Center for Biotechnology Information. PubChem Compound Summary for CID 73505111, ulonivirine. Accessed September 30, 2026
2. Merck Sharp & Dohme LLC. A Phase 2/3, randomized, active-controlled, open-label (Phase 2) and double-blind (Phase 3) study to evaluate the antiretroviral activity, safety, and tolerability of islatravir (ISL) and ulonivirine (ULO) once weekly compared with bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once daily in treatment-naïve adult participants living with HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 1, 2025. NLM Identifier: NCT07266831. Accessed September 30, 2026
3. Ankrom W, Jackson Rudd D, Schaeffer A, et al. Pharmacokinetic and safety profile of the novel HIV nonnucleoside reverse transcriptase inhibitor MK-8507 in adults without HIV. Antimicrob Agents Chemother. 65(12):e00935-21. doi:10.1128/AAC.00935-21. Accessed September 30, 2026
4. Diamond TL, Lai M-T, Feng M, et al. Resistance profile of MK-8507, a novel NNRTI suitable for weekly oral HIV treatment. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-11, 2021; Virtual. Accessed September 30, 2026
5. Schauer GD, Huber KD, Leuba SH, Sluis-Cremer N. Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence. Nucleic Acids Res. 2014;42(18):11687-11696. doi:10.1093/nar/gku819. Accessed September 30, 2026
6. Seckler JM, Barkley MD, Wintrode PL. Allosteric suppression of HIV-1 reverse transcriptase structural dynamics upon inhibitor binding. Biophys J. 2011;100(1):144-153. doi:10.1016/j.bpj.2010.11.004. Accessed September 30, 2026
7. Schürmann D, Jackson Rudd D, Schaeffer A, et al. Single oral doses of MK-8507, a novel non-nucleoside reverse transcriptase inhibitor, suppress HIV-1 RNA for a week. J Acquir Immune Defic Syndr 1999. 2022;89(2):191-198. doi:10.1097/QAI.0000000000002834. Accessed September 30, 2026
8. Ankrom W, Schurmann D, Jackson Rudd D, et al. Single doses of MK-8507, a novel HIV-1 NNRTI, reduced HIV viral load for at least a week. Poster presented at: International Congress of Drug Therapy in HIV Infection (HIV Glasgow); October 5-8, 2020; Virtual. Poster O416. Accessed September 30, 2026
9. Merck Sharp & Dohme LLC. A Phase 2b, randomized, active-controlled, double-blind, dose-ranging clinical study to evaluate a switch to islatravir (ISL) and MK-8507 once-weekly in adults with HIV-1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once-daily. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 21, 2020. NLM Identifier: NCT04564547. Accessed September 30, 2026
10. Molina J-M, Ramgopal MN, Katlama C, et al. A double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ulonivirine in combination with islatravir in virologically suppressed adults living with HIV-1. International AIDS Society (IAS) Conference on HIV Science; July 13-17, 2025; Kigali, Rwanda. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2025. Accessed September 30, 2026
11. Merck Sharp & Dohme LLC. A Phase 2b, randomized, active-controlled, open-label clinical study to evaluate a switch to islatravir (ISL) and ulonivirine (ULO) once weekly in adults with HIV-1 virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once daily. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2025. NLM Identifier: NCT06891066. Accessed September 30, 2026
12. Luetkemeyer AF, Bloch M, Scribner A, et al. Randomized, active-controlled, phase 2b study evaluating efficacy and safety of switch to islatravir (ISL) 2 mg with ulonivirine (ULO) 200 mg once weekly in virologically suppressed adults living with HIV-1. International AIDS Conference; July 26-31, 2026; Rio, Brazil. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2026. Accessed September 30, 2026
13. Nussbaum J, Liu Y, Pham M, et al. A double-blind, placebo-controlled, Phase 1 study to evaluate extended multiple dosing of ulonivirine (MK-8507) in adults without HIV. International AIDS Society (IAS) Conference on HIV Science; July 13-17, 2025; Kigali, Rwanda. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2025. Accessed September 30, 2026
14. Merck Sharp & Dohme LLC. A study to evaluate the safety, tolerability, pharmacokinetics and antiretroviral activity of MK-8507 in HIV-1 infected patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 24, 2014. NLM Identifier: NCT02174159.Accessed September 30, 2026
15. Merck Sharp & Dohme LLC. An open-label study to assess the two-way interaction between multiple weekly doses of MK-8507 and single doses of islatravir (MK-8591) in healthy adult participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 27, 2024. NLM Identifier: NCT06619678. Accessed September 30, 2026
16. Nussbaum J, Pham M, Vargo R, et al. An open-label Phase 1 study to evaluate drug interactions between multiple weekly doses of ulonivirine (MK-8507) and single doses of islatravir in adults without HIV. Abstract presented at: International AIDS Society (IAS) Conference on HIV Science; July 13-17, 2025; Kigali, Rwanda. Accessed September 30, 2026
17. Robinson M, Matthews RP, Kandala B, et al. P-1245. An open-label Phase 1 study to evaluate the effect of multiple doses of rifabutin on the single-dose pharmacokinetics of ulonivirine in adults without HIV. Open Forum Infect Dis. 2026;13(Suppl 1):ofaf695.1437. doi:10.1093/ofid/ofaf695.1437. Accessed September 30, 2026

Last Reviewed: September 30, 2026