Accelerated first-in-human clinical trial of EIDD-2801/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2

Abstract

A recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK). Single and multiple ascending dose (SAD and MAD, respectively) cohorts were dosed in randomized, double-blind, and placebo-controlled fashion, with a 6:2 active-to-placebo ratio in each cohort. A food-effect (FE) cohort included 10 subjects who were randomized to receive drug in the fasted or fed state followed by the fed or fasted state to complete a fed and fasted sequence for each subject. Dose escalation decisions were accelerated and MAD cohorts were initiated prior to completion of all SAD cohorts with the provision that the total daily dose in a MAD cohort would not exceed a dose proven to be safe and well-tolerated in a SAD cohort. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the Research Ethics Committee (REC) and Medicines and Healthcare products Regulatory Agency (MHRA). Working to standard industry timelines, the FIH study would have taken approximately 46 weeks to complete and 33 weeks to enable phase 2 dosing. Data from this study supported submission of a phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within 8 weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.

The pill of recovery; Molnupiravir for treatment of COVID-19 patients; a systematic review

“…All AEs reported were mild (≤ grade 2 severity); diarrhea, nausea, cough, loss of smell or taste and flu like symptoms were reported and rapidly. Hence, A remarkable advantage of Molnupiravir over other injectable antiviral drugs is its oral availability, possibility of widespread global application as well as a favorable safety profile and high tolerability ( Holman et al, 2021 , Rosenke et al, 2021 ).…”

Oral anti-COVID-19 drugs that were recently evaluated by FDA or EMA: a review

“…Moreover, the studies show that molnupiravir has a high genetic barrier to viral resistance [6]. It was proved effective in animal models [23][24][25][26][27][28][29] and safe in phase 1, 2 and 3 of the clinical trials [30][31][32][33][34][35][36][37][38]. There are still four clinical trials ongoing, according to www.clinicaltrials.gov (as at December 12, 2021).…”

Molnupiravir: First Approval

“…Molnupiravir (Lagevrio ® ) is an orally-administered, small-molecule, antiviral prodrug that inhibits replication of RNA viruses through viral error induction [ 1 ]. The drug was invented by Drug Innovation Ventures at Emory (DRIVE; wholly owned by Emory University) and is being developed by Merck, in collaboration with Ridgeback Biotherapeutics, for the prevention and treatment of Coronavirus disease 2019 (COVID-19) [ 1 , 2 ]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, uses an RNA-dependent RNA polymerase (RdRp) complex for replication [ 3 ].…”

“…It should be administered as soon as possible after a COVID-19 diagnosis and within 5 days of symptom onset [ 7 ]. Molnupiravir underwent an accelerated first-in-human clinical trial programme through extraordinary collaboration between the drug developers, contract research organization and regulatory authorities [ 2 ].

Key milestones in the development of molnupiravir for COVID-19.

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