Regulatory Decision Summary for Paxlovid

Paxlovid (nirmatrelvir and ritonavir) is an oral antiviral drug. Nirmatrelvir (PF-07321332; a new active substance (NAS)) is a selective inhibitor of the SARS-CoV-2 3CL protease, which is a virally encoded enzyme that plays a critical role in the SARS-CoV-2 replication cycle. Nirmatrelvir must be co-administered with ritonavir, which serves as a pharmacoenhancer.

The efficacy and safety of Paxlovid in the treatment of mild-to-moderate COVID-19 in adult patients with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19 was supported by the results from the Phase 2/3, randomized, double-blind, placebo-controlled EPIC-HR (C4671005) study. This clinical trial involved non-hospitalized symptomatic adults (18 years of age and older) with a laboratory confirmed diagnosis of SARS-CoV-2 infection and at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Patients with COVID-19 symptom onset of ≤5 days were included in the study. Patients were randomized (1:1) to receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of prior COVID-19 infection or vaccination. The primary efficacy endpoint was the proportion of patients with COVID-19 related hospitalization or death from any cause through Day 28. The primary efficacy analysis was conducted in the modified intent-to treat (mITT) analysis set (all treated patients with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment), the mITT1 analysis set (all treated patients with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated patients with onset of symptoms ≤5 days).

A total of 1,361 participants were randomised to receive either Paxlovid or placebo. The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups. At time of the interim analysis, when 389 participants in the Paxlovid group and 385 participants in the placebo group were included in the mITT analysis set, Paxlovid reduced the proportion of participants with COVID-19 related hospitalisation or death through Day 28 by 89.1%, compared with placebo (0.8% of patients in the Paxlovid group were hospitalized or died compared to 7% of patients in the placebo group; absolute risk reduction: -6.32, 95% CI: -9.04, -3.59). This reduction was statistically significant (p<0.0001). Furthermore, no deaths were reported in the Paxlovid group compared with 7 deaths in the placebo group. Similar trends were observed for the primary efficacy analysis across subgroups of participants. Efficacy results were consistent in the mITT1 and mITT2 analysis sets. The final topline results from the EPIC-HR study have confirmed the positive results of the interim analysis.

The safety assessment of Paxlovid is based on the final topline data from the EPIC-HR study. A total of 2,224 patients received at least one dose of either Paxlovid (n=1,109) or placebo (n=1,115). Adverse events were those reported while subjects were on study medication and through Day 34 after initiating study treatment. The incidence of adverse events was 22.6% in the Paxlovid group compared to 23.9% for the placebo group. Adverse events (all grades regardless of causality) in the Paxlovid group (≥1%) that occurred at a greater frequency (≥5 subject difference) than in the placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), hypertension (1% and <1%), and myalgia (1% and <1%). The proportions of subjects who discontinued treatment due to an adverse event were 2% in the Paxlovid group and 4% in the placebo group.

The main risk associated with Paxlovid is related to potential for drug-drug interactions that may result in clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, or loss of therapeutic effect of Paxlovid and possible development of viral resistance. The risk of drug-drug interactions is mitigated through the Paxlovid Product Monograph.

The main uncertainty associated with Paxlovid is related to limited available clinical efficacy and safety evidence at this time. However, additional safety, efficacy and quality evidence, as well as post-market safety monitoring evidence, will be submitted to Health Canada post-authorization through Terms and Conditions that have been imposed on the authorization for Paxlovid.

In conclusion, based on the data provided, Health Canada considers that the benefit-harm-uncertainty profile of Paxlovid in the treatment of mild-to-moderate COVID-19 in adult patients with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19 is favourable under conditions of use described in the Paxlovid Product Monograph at this time; no safety and efficacy data were submitted for pediatric patients (12 years of age and older weighing at least 40 kg) and therefore, Paxlovid is not authorized for use in these patients. Paxlovid is also not authorized for:

• initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19;
• pre-exposure or post-exposure prophylaxis for prevention of COVID-19;
• use for longer than 5 consecutive days.

A Risk Management Plan for Paxlovid has been submitted and it is considered acceptable with revisions. Clinical outcomes in different populations will be monitored post-market.

For more information on Health Canada’s decision, please view the Summary Basis of Decision.