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Weekly Oral Prophylaxis With MK-8527 Protects Rhesus Macaques From Intrarectal Challenge With Simian-Human
Tracy L Diamond1, Yash Kapoor1, Fangbiao Li1
1MRL, Merck & Co., Inc., Rahway, New Jersey, USA.
Background:
MK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor being evaluated for prevention of HIV-1 acquisition. MK-8527 is phosphorylated intracellularly to its active form, MK-8527-triphosphate, which inhibits HIV-1 replication. This study evaluated the efficacy of oral MK-8527 as pre-exposure prophylaxis in rhesus macaques challenged intrarectally with simian-human immunodeficiency virus (SHIV).
Methods:
Two groups of male macaques (n = 8 per group) received weekly oral doses of MK-8527 for 12 weeks. Starting 1 week after treatment initiation, the macaques received weekly intrarectal challenge with SHIV162P3 for 10 weeks. Each group was treated in 3 dosing panels: Group 1 received MK-8527 6, 1, and 0 mg/kg (vehicle only), whereas Group 2 received MK-8527 2, 0.3, and 0.1 mg/kg. A washout period of ≥4 weeks followed each dosing panel. A control group (n = 8) was challenged without receiving MK-8527. Plasma viral loads were monitored weekly, with infection confirmed by 2 consecutive measurements of SHIV RNA >100 copies/mL. Concentrations of MK-8527 phosphorylated forms were quantified using liquid chromatography-tandem mass spectrometry.
Results:
Once-weekly doses of MK-8527 ≥ 0.1 mg/kg for 12 weeks conferred complete protection against intrarectal SHIV acquisition, and 7/8 untreated control macaques and 5/8 vehicle-only macaques became infected. The rate of infection for macaques receiving MK-8527 was at least 11.1-fold (P = .009) lower compared with the control or vehicle group. MK-8527-triphosphate trough concentrations at 0.1 mg/kg resulted in a mean inhibitory quotient of 2.2.
Conclusions:
Prophylaxis with MK-8527 completely protected macaques from SHIV infection, supporting its further clinical development for prevention of HIV-1 acquisition.
Insights
MK-8527, a novel HIV-1 pre-exposure prophylaxis, completely protected macaques from simian-human immunodeficiency virus (SHIV) infection. This nucleoside reverse transcriptase inhibitor shows promise for preventing HIV-1 acquisition in further clinical development.
Area of Science:
- Virology
- Pharmacology
- Infectious Diseases
Background:
- MK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor.
- It is phosphorylated to its active form, MK-8527-triphosphate, inhibiting HIV-1 replication.
- The study evaluated MK-8527 efficacy for HIV-1 prevention.
Purpose of the Study:
- To assess the efficacy of oral MK-8527 as pre-exposure prophylaxis (PrEP).
- To evaluate protection against intrarectal simian-human immunodeficiency virus (SHIV) challenge in rhesus macaques.
Main Methods:
- Rhesus macaques received weekly oral doses of MK-8527 for 12 weeks.
- Animals were challenged intrarectally with SHIV162P3 weekly for 10 weeks.
- Viral loads and drug concentrations were monitored; infection was confirmed by SHIV RNA levels.
Main Results:
- Once-weekly MK-8527 at ≥0.1 mg/kg provided complete protection against SHIV acquisition.
- Infection rates were significantly lower (≥11.1-fold) in treated macaques compared to controls.
- MK-8527-triphosphate trough concentrations at 0.1 mg/kg achieved a mean inhibitory quotient of 2.2.
Conclusions:
- MK-8527 prophylaxis demonstrated complete protection against SHIV infection in macaques.
- These findings support the further clinical development of MK-8527 for HIV-1 prevention.
- MK-8527 is a promising candidate for pre-exposure prophylaxis to prevent HIV-1 acquisition.
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