Summary of Cancellation for Molnupiravir (*Lagevrio)

The New Drug Submission (NDS) for molnupiravir was initially filed under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to Coronavirus Disease 2019 (COVID-19) (Control No. 255709) on August 13, 2021, and then refiled as an NDS with flexibilities for designated COVID-19 drug (NDS-CV; Control No. 255584) on August 20, 2021, due to expiry of the Interim Order. The purpose of this NDS-CV was to seek a market authorization for molnupiravir in the treatment of mild to moderate COVID-19 in adults (≥18 years) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic test who have at least one risk factor for disease progression.

The proposed indication for molnupiravir was based primarily on the efficacy and safety data from a single pivotal Phase 3 MOVe-OUT study. MOVe-OUT was a global, randomized, placebo-controlled, double-blind clinical trial in symptomatic adult patients who were not vaccinated against SARS-CoV-2, and who had laboratory confirmed SARS-CoV-2 infection and symptom onset within 5 days of randomization. In addition, the study patients had to have one or more pre-defined risk factors for disease progression: over 60 years of age, diabetes, obesity (body mass index [BMI] ≥30), chronic kidney disease, serious heart conditions, chronic obstructive pulmonary disease, or active cancer. In the interim analysis patient population, (n = 387 who received molnupiravir and n = 388 who received placebo), the most common risk factors for progressing to severe COVID-19 were obesity (77%), age (over 60 years; 14%), and diabetes (14%). In the population of all patients (n = 710 who received molnupiravir and n = 701 who received placebo), the most common risk factors for progressing to severe COVID-19 were obesity (74%), age (over 60 years; 17%), and diabetes (16%). The study patients were randomized 1:1 to receive 800 mg of molnupiravir or placebo orally twice daily for 5 days. The primary endpoint was the percentage of patients who were hospitalized or died through Day 29 due to any cause.

In addition, third-party evidence from 2 clinical trials conducted in India by Aurobindo Pharma and Hetero Labs was submitted in March 2022. Finally, several Real-World Evidence (RWE) studies, including the PANORAMIC study, were submitted in this NDS-CV in October 2022. The RWE studies (n = 19) were from published articles (9), pre-print manuscripts (5) which are not peer-reviewed or conference abstracts (5) which are also not peer-reviewed.

A Notice of Non-Compliance (NON) was issued for this NDS-CV on February 3, 2023, based on a negative outcome of the clinical review, as summarized below. This was an interim decision, and the sponsor had an opportunity to provide additional evidence to support their proposed indication for molnupiravir. However, on April 26, 2023, the sponsor opted to withdraw the submission from review. Voluntary withdrawal of a submission does not disqualify a sponsor from refiling the application at a later date based on new evidence.

Based on the overall clinical evidence submitted in this NDS-CV, a benefit of molnupiravir in the treatment of mild to moderate COVID-19 in adults who are at risk for progressing to severe disease could not be established.

 

In the pivotal MOVe-OUT study, at the interim analysis of data from 775 randomized patients (385 patients in the molnupiravir group and 377 in the placebo group; 50% of the planned enrolment), treatment with molnupiravir resulted in a 6.8% absolute risk reduction of hospitalization or death, i.e., 7.3% (n = 28) patients met the primary endpoint in the molnupiravir group compared to 14.1% (n = 53) patients in the placebo group (risk difference [95% CI]: -6.8% [-11.3,-2.4]; p-value = 0.0012]). All 8 patients who died through Day 29 were in the placebo group and were hospitalized prior to their death. In contrast to the interim analysis results, no efficacy of molnupiravir was observed in the post-interim analysis that included 658 patients for whom the data for the primary endpoint was not available at the time of the interim analysis (324 patients in the molnupiravir group and 322 in the placebo group). Specifically, in the post-interim analysis population, more patients were hospitalized in the molnupiravir group compared to the placebo group, i.e., 6.2% versus 4.7% (95% CI: -2.1, 5.2); there was 1 death in each study group. The reason for the discordant efficacy results between the interim and post-interim analysis populations was not determined but it cannot be excluded that some differences in patient demographics and/or baseline characteristics played a role. The discordant efficacy results in the MOVe-OUT trial raise significant concerns about the validity of this study and therefore, Health Canada considers that the benefit of molnupiravir in the proposed indication has not been established in this study.

 

The evidence from the Aurobindo Pharma and Hetero Labs studies was not considered adequate to support the proposed indication for molnupiravir due to serious study limitations. Limitations included the risk of bias due to the open label design of these studies, differences in patient characteristics compared to Canadian patients and differences in standard of care compared to Canadian standard of care.

 

The main RWE study, PANORAMIC, was conducted in the United Kingdom by Oxford University in 25,000 mostly vaccinated adults infected with SARS-CoV-2 and at risk of progression to severe disease. The main limitation of this study was a risk of bias due to open label design. The PANORAMIC study was negative as it did not meet its pre-specified primary outcome of hospitalization or mortality rate through Day 28. Some RWE studies had design limitations including, but not limited to, observational (mainly) retrospective design; patient population different than the one included in the proposed indication; imbalances in baseline patient characteristics between molnupiravir and control groups; and limited and/or missing information. Overall, these studies did not demonstrate consistent effects of molnupiravir on hospitalizations or death due to COVID-19.

 

Molnupiravir was generally well tolerated in the MOVe-OUT study. Discontinuation due to an adverse event occurred in 1% of subjects receiving molnupiravir and 3% of subjects receiving placebo. Serious adverse events occurred in 7% of patients receiving molnupiravir and 10% receiving placebo; most serious adverse events were COVID-19 related. The most common adverse reactions in the molnupiravir group were diarrhea (2%), nausea (1%) and dizziness (1%); all these adverse reactions were Grade 1 (mild) or Grade 2 (moderate). No new or significant safety findings were made in the Aurobindo Pharma or Hetero Labs trials, or RWE studies compared to the MOVe-OUT trial.

 

The main potential risks associated with molnupiravir are related to adverse effects on the growth and development of the fetus in pregnant women (based on animal data), mutagenicity (based on in vitro data) and development of new SARS-CoV-2 variants (based on the mechanism of action). There is currently no or limited evidence concerning these risks from the clinical trials or RWE studies with molnupiravir.

 

In summary, based on the data submitted in this NDS-CV, the efficacy of molnupiravir in the treatment of mild to moderate COVID-19 in adults who are at risk for progressing to severe disease has not been established and therefore, the benefit-harm-uncertainty profile of molnupiravir is negative.

There is no expected impact for patients in clinical trials. Molnupiravir is not being accessed under the SAP.