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Randomized Controlled Trial
. 2021 Aug 23;22(1):561.
doi: 10.1186/s13063-021-05538-5.

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

Wendy Holman  1 , Wayne Holman  1 , Stacy McIntosh  1 , Wendy Painter  2 , George Painter  2 , Jim Bush  3 , Oren Cohen  4
Affiliations
Randomized Controlled Trial

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

Wendy Holman et al. Trials. .

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.

Keywords: Accelerated start-up; Antiviral therapy; COVID-19; Phase I; Ribonucleoside analog; SARS-CoV-2.

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Conflict of interest statement

Wendy Holman, Wayne Homan, Stacy McIntosh, and Wendy Painter are employees of Ridgeback Biotherapeutics, which funded the study. George Painter holds a number of patents that are relevant to EIDD-2801 (molnupiravir)—see separately submitted ICMJE form. Jim Bush and Oren Cohen are employees of Covance, the CRO chosen by Ridgeback to assist in the execution of the study described.

Figures

Fig. 1
Fig. 1
Time from submission of the protocol to the ethics committee and regulatory authority to completion of dosing of 8 SAD, 7 MAD, and 1 FE cohorts under standard industry timelines compared with what was achieved under accelerated conditions. SAD, single ascending dose; MAD, multiple ascending dose; FE, food effect; FIH, first in human
See this image and copyright information in PMC

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