Comparative Effectiveness of Sotrovimab and Molnupiravir for Prevention of Severe COVID-19 Outcomes in Non-hospitalised Patients: An Observational Cohort Study Using the OpenSAFELY Platform

Background: Among the neutralising monoclonal antibodies (nMAbs) and antivirals approved in the UK for use in non-hospitalised high-risk COVID-19 patients, sotrovimab and molnupiravir have initially been the two most frequently prescribed drugs. The approval and early clinical use of them was based on two phase 3 RCTs in unvaccinated COVID-19 patients, prior to the emergence of the Omicron variant, and evaluations of their effectiveness in routine care with diverse populations are limited.

Objectives: To compare the effectiveness of sotrovimab vs. molnupiravir in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients.

Methods: Setting: With the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform. The primary care data from 24 million people in England were securely linked with data on COVID-19 infection and therapeutics, hospital admission, and death within the OpenSAFELY-TPP platform, covering a period where both medications were frequently prescribed in community settings. We included non-hospitalised adult COVID-19 patients at high risk of severe outcomes treated with sotrovimab or molnupiravir between December 16, 2021 and February 10, 2022.
Interventions: Sotrovimab or molnupiravir administered in the community by COVID-19 Medicine Delivery Units.
Main outcome measure: COVID-19 related hospitalisation or COVID-19 related death within 28 days after treatment initiation.
Statistical analysis: Cox proportional hazards model stratified by area was used, supplemented by propensity score weighting analysis.

Results: Patients treated with sotrovimab (n=3288) and molnupiravir (n=2663) were similar with respect to most baseline characteristics. Within 28 days after treatment initiation, 84 (1.4%) COVID-19 related hospitalisations/deaths were observed (31 treated with sotrovimab and 53 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio, HR=0.53, 95% CI: 0.32 to 0.88; P=0.014). Consistent results were obtained from propensity score weighted Cox models (HR=0.51, 95% CI: 0.31 to 0.83; P=0.007) and when restricted to fully vaccinated people.

Conclusions: In routine care of non-hospitalised high-risk adult patients with COVID-19 in England, those who received sotrovimab were at lower risk of severe COVID-19 outcomes than those receiving molnupiravir.