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New Oral Ribonucleoside Optimal at
800 mg Twice Daily vs SARS-CoV-2
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International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs, September 20-22, 2021
By Mark Mascolini for NATAP and Virology Education
Molnupiravir, an oral ribonucleoside analog active against SARS-CoV-2, appeared to be optimal at the highest of three doses studied, 800 mg twice daily, in an 18-person phase 1 dose-finding trial [1]. A just-reported unreviewed phase 2a trial found evidence that molnupiravir "is the first oral, direct-acting antiviral shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA" [2]. Altogether, molnupiravir studies to date have established the potential value of molnupiravir in SARS-CoV-2 treatment, prophylaxis, and transmission prevention [3].
This open-label phase 1b trial is part of AGILE, a randomized multiarm, multidose phase 1b/2a platform in the United Kingdom that uses a Bayesian adaptive design to accelerate testing of multiple anti-SARS-CoV-2 candidates [4]. Molnupiravir is a small-molecule prodrug that is rapidly and extensively hydrolyzed to N-hydroxycytidine (NHC), which is then phosphorylated to NHC-triphosphate, which induces lethal mutations in SARS-CoV-2.
The phase 1b trial aimed to assess the safety and optimal dose of molnupiravir. Researchers from the University of Liverpool and collaborators at other UK sites enrolled community-dwelling adults with SARS-CoV-2 infection confirmed by PCR within 5 days of COVID-19 symptoms. Participants had oxygen saturation of at least 95%. The trial excluded pregnant or breastfeeding women and people with major kidney or liver disease.
For each molnupiravir dose assessed, investigators randomized participants 2-to-1 to receive the antiviral or standard care alone. A review committee established dose-limiting toxicities by treatment day 7, the primary endpoint of this trial. They defined a dose as unsafe if it resulted in a 25% or greater dose-limiting toxicity risk more than 30% higher than standard care.
Among 18 people enrolled (median age 56, median body mass index 29.5 kg/m2), the researchers randomized 12 to receive molnupiravir and 6 to receive standard care. Twelve participants received at least one molnupiravir dose in three dosing cohorts-300, 600, and 800 mg twice daily in a fasted state. Three of 4 participants receiving 300 mg twice daily, 4 of 4 receiving 600 mg, and 3 of 4 receiving 800 mg completed treatment.
Participants generally tolerated molnupiravir well, and researchers reported no serious adverse events or dose-limiting toxicities. The adverse events were grade 1 or 2, and most were symptoms of COVID-19: gastrointestinal (diarrhea, nausea), respiratory (cough), central nervous system (loss of smell or taste), and flu-like symptoms. Proportions of participants with at least one adverse event were 100% (4 of 4) taking 300 mg of molnupiravir twice daily, 100% (4 of 4) taking 600 mg, 25% (1 of 4) taking 800 mg, and 83% (5 of 6) receiving standard care.
Concentrations of the prodrug molnupiravir generally remained undetectable or barely detectable with all three doses studied. On treatment day 5, geometric mean area under the concentration-time curve (and coefficient of variation) for NHC, the major metabolite of molnupiravir, over the first 4 hours of dosing was 3470 (42.4) ng.h/mL with 300 mg of molnupiravir twice daily, 3880 (56.3) ng.h/mL with 600 mg twice daily, and 7880 (39.0) ng.h/mL with 800 mg twice daily. Respective peak concentrations were 1620 (51.0) ng/mL, 1820 (84.6) ng/mL, and 4180 (28.1) ng/mL. These concentrations were similar to those recorded in healthy volunteers. Time to peak plasma concentration ranged from 0.5 to 2.0 hours.
Trial results indicated that 800 mg of molnupiravir twice daily for 5 days should proceed to a phase 2 placebo-controlled trial in AGILE. That dose had a 7.4% higher risk of dose-limiting toxicity than standard care. Two subsequent studies confirmed 800 mg twice daily as the optimal dose (MOVe-OUT and NCT04405570).
References
1. Khoo S, FitzGerald R, Fletcher T, et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase 1, open-label, dose-escalating, randomised controlled study. International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs 2021. September 20-22, 2021. Abstract 1.
2. Fischer W, Eron JJ, Holman W, et al. Molnupiravir, an oral antiviral treatment for COVID-19. Version 1. medRxiv. Preprint. 2021 Jun 17.doi: 10.1101/2021.06.17.21258639
3. Merck. Interim results from phase 2/3 studies of molnupiravir, an investigational oral antiviral therapeutic for mild to moderate COVID-19, presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). July 12, 2021.
https://www.merck.com/news/interim-results-from-phase-2-3-studies-of-molnupiravir-an-investigational-oral-antiviral-therapeutic-for-mild-to-moderate-covid-19-presented-at-the-european-congress-of-clinical-microbiology-i/
4. ClinicalTrials.gov. AGILE (Early Phase Platform Trial for COVID-19). ClinicalTrials.gov identifier NCT04746183.
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