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Sourced from https://www.medchemexpress.com/ulonivirine.html

Drug name

Ulonivirine (MK-8507)

Developer(s)

export_notes

Drug information

Drug's link(s)
Generic name

MK-8507

Brand names

Not provided

Compound type

Small molecule

Summary

MK-8507, also known as Ulonivirine, is a selective, potent and novel non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in clinical development for the treatment of HIV-1. MK-8507 inhibits HIV-1 allosterically through the classic NNTRI binding location adjacent to the polymerase active site. Preclinical research indicates that MK-8507 displays activity against the most common resistance mutations associated with NNRTIs (e.g. Y181C and K103N) and possesses strong antiviral effects. The pharmacokinetics of MK-8507 support once-weekly oral administration. In Nov 2021, Merck announced the pausing of MK-8507 development following reduced CD4+ T-cell and lymphocyte counts in participants enrolled in combination drug trials (MK-8507 + Islatravir).

Approval status

Ulonivirine (previously known as MK 8507) is an orally-administered investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) being developed by MSD for the treatment of HIV-1 infection.

Regulatory authorities

Unknown

Therapeutic area(s)

  • HIV
Use case(s)
  • Pre-Exposure Prophylaxis (PrEP)
  • Treatment
  • Prevention

Administration route

Oral

Associated long-acting platforms

Oral solid form

Use of drug

Ease of administration
  • Self-administered
User acceptance

Not provided

Dosage

Available dose and strength

Not provided

Frequency of administration

Not provided

Maximum dose

Not provided

Recommended dosing regimen

Not provided

Additional comments

Not provided

Dosage link(s)

Not provided

Associated technologies

Not provided

Comment & Information

Not provided

Developer(s)

MSD
Originator
United States

Merck & Co., Inc. is an American multinational pharmaceutical company known as Merck Sharp & Drone (MSD) in territories outside of the USA and Canada. Merck was originally established in 1891, and is currently headquartered in Rahway, New Jersey. The company is particularly well known for developing and manufacturing biologic therapies, vaccines, medicines and animal health products.

Drug structure

MK-8507 Chemical Structure

MK-8507 Chemical Structure

Sourced from https://www.medchemexpress.com/ulonivirine.html

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Scale-up and manufacturing prospects

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Not provided

Manufacturing

Not provided

Specific analytical instrument required for characterization of formulation

Not provided

Excipients

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredient Database (IID) for the specified route of administration

Not provided

Residual solvents used

Not provided

Delivery device(s)

No delivery device

Description

Ulonivirine (MK-8507) - 5-phenoxy-3H-pyrimidin-4-one derivates and their use as HIV reverse transcriptase inhibitors

Brief description

Ulonivirine compound and analogues and their use as HIV reverse transcriptase inhibitors

Representative patent

WO2014058747

Category

compound

Patent holder

Merck Sharp & Dohme Corp.

Exclusivity

Not provided

Expiration date

September 29, 2033

Status

Granted in: AR, ARIPO (BW, GH, KE, NA), BR, CL, CN, CO, CR, DZ, EAPO (AM, AZ, BY, KZ, RU) EP, GE, GT, ID, IN, IR, KR, MA, MN, MX, NG, PE, PH, UA, US, VN, ZA Pending in: DO, NI, PK, SV, TH, VE

Description

Prodrugs of HIV reverse transcriptase inhibitors

Brief description

Ulonivirine prodrugs

Representative patent

WO2015153304

Category

Compound (prodrug)

Patent holder

Merck Sharp & Dohme Corp.

Exclusivity

Not provided

Expiration date

March 27, 2035

Status

Granted in Brazil, China, India, US, Europe

Publications

Fluoride Pharmacokinetics in Urine and Plasma Following Multiple Doses of MK-8507, an Investigational, Oral, Once-Weekly Nonnucleoside Reverse Transcriptase Inhibitor. Gillespie G. et al., J Clin Pharmacol. 2022 Feb;62(2):199-205. doi: https://doi.org/10.1002%2Fjcph.1957. Epub 2021 Nov 12. PMID: 34435371; PMCID: PMC9298720.



MK‐8507 is an investigational HIV‐1 nonnucleoside reverse transcriptase inhibitor being developed for the treatment of HIV‐1 infection. MK‐8507 contains 2 trifluoromethyl groups that may result in fluoride release through metabolism, but the extent of MK‐8507–related fluoride release in humans has yet to be determined. This double‐blind, placebo‐controlled, 2‐period, parallel‐group, multiple‐dose trial in healthy participants without HIV‐1 who were administered a fluoride‐restricted diet and once‐weekly doses of MK‐8507 aimed to estimate the relationship between MK‐8507 dose and fluoride exposure. A total of 15 adult male and 3 adult female (of non‐childbearing potential) participants were randomized to receive MK‐8507 200 mg (n = 6), MK‐8507 800 mg (n = 6), or placebo (n = 6). Change from baseline in mean daily fluoride excretion averaged over 7 days following the administration of MK‐8507 200 mg resulted in a net mean increase of 19.8 μmol (90% confidence interval, 12.2‐27.4) relative to placebo and did not exceed 57 μmol, a threshold related to the mean difference between the daily reference dose set by the US Environmental Protection Agency and the average dietary fluoride intake in the United States. However, daily urinary fluoride excretion exceeded the threshold following administration of 800 mg MK‐8507 (75.1 μmol [90% confidence interval, 67.5‐82.7]). Assuming a linear relationship between MK‐8507 dose and estimated mean daily fluoride released at steady‐state, data interpolation suggests that the US Environmental Protection Agency reference dose for fluoride would not be exceeded in most patients when administering MK‐8507 at doses currently under clinical investigation (≤400 mg once weekly).

Pharmacokinetic and Safety Profile of the Novel HIV Nonnucleoside Reverse Transcriptase Inhibitor MK-8507 in Adults without HIV. Ankrom W et al., Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0093521. doi: https://doi.org/10.1128%2FAAC.00935-21. Epub 2021 Sep 13. PMID: 34516246; PMCID: PMC8597757.

MK-8507 is a novel HIV-1 nonnucleoside reverse transcriptase inhibitor in clinical development with potential for once-weekly oral administration for the treatment of HIV-1 infection. Two randomized, double-blind, placebo-controlled phase 1 studies in adults without HIV-1 evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of MK-8507; drug interaction with midazolam (a cytochrome P450 3A4 substrate) and food effect were also assessed. In study 1, 16 participants received oral ascending single doses of MK-8507 (2 to 400 mg) or placebo in an alternating fashion. In study 2, 24 participants received ascending single doses of MK-8507 (400 to 1,200 mg) or placebo and multiple doses (once weekly for 3 weeks) of MK-8507 (100 to 400 mg) or placebo. MK-8507 pharmacokinetics were approximately dose proportional at 2 to 1,200 mg. MK-8507 had a time to maximum concentration of 2 to 7 h and a mean terminal half-life of ∼58 to 84 h. MK-8507 doses of ≥100 mg achieved a plasma concentration at 168 h postdose (7 days) associated with antiviral efficacy. A high-fat meal had no clinically meaningful effect on MK-8507 pharmacokinetics, and MK-8507 400 mg once weekly had no clinically meaningful effect on midazolam pharmacokinetics. Single and multiple doses of MK-8507 were generally well tolerated. No trends with dose and no clinically meaningful changes were observed in vital signs, electrocardiograms, and laboratory safety tests. The pharmacokinetics and safety data are supportive of once-weekly oral administration and support further clinical investigation of MK-8507 for the treatment of HIV-1 infection.

Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week. Schürmann D. et al. J Acquir Immune Defic Syndr. 2022;89(2):191-198. doi:10.1097/QAI.0000000000002834

Background: MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor being developed for treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing.

Setting: A phase 1, open-label, proof-of-concept study was conducted in treatment-naive adults with HIV-1 infection to assess monotherapy antiviral activity.

Methods: In 3 sequential panels, participants aged 18-60 years with baseline plasma HIV-1 RNA ≥10,000 copies/mL and CD4+ T-cell count >200/mm3 received a single oral dose of 40, 80, or 600 mg MK-8507 in the fasted state. Participants were assessed for HIV-1 RNA for at least 7 days, PKs for 14 days, and safety and tolerability for 21 days postdose.

Results: A total of 18 participants were enrolled (6 per panel). The mean 7-day postdose HIV-1 RNA reduction ranged from ∼1.2 to ∼1.5 log10 copies/mL across the doses assessed. One patient had a viral rebound associated with emergence of an F227C reverse transcriptase variant (per chain-termination method sequencing) 14 days postdose; this variant was found in a second participant by ultra-deep sequencing as an emerging minority variant. MK-8507 PKs were generally dose-proportional and similar to observations in participants without HIV-1 infection in prior studies; mean MK-8507 half life was 56-69 hours in this study. MK-8507 was generally well tolerated at all doses.

Conclusions: The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants.

Li G, Wang Y, De Clercq E. Approved HIV reverse transcriptase inhibitors in the past decade [published correction appears in Acta Pharm Sin B. 2023 Aug;13(8):3581. doi: 10.1016/j.apsb.2023.06.004.]. Acta Pharm Sin B. 2022;12(4):1567-1590. doi:10.1016/j.apsb.2021.11.009

HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.

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Timeline

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Percentage of Trial Eligibility per Cohort

Age groups distribution for all clinical trials
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Territory by income level

Low Middle & Upper Middle Income
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Territory by approval status

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