Regulatory Decision Summary for Favipiravir (*Reeqonus)

 

Decision issued

No decision was issued by Health Canada. The company chose to cancel its submission before a final decision was issued.

Date of cancellation

February 24, 2022

What was the purpose of this submission?

Reeqonus (favipiravir tablets) was originally submitted by Dr. Reddys Laboratories under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 on December 18, 2020 (Control No. 247556); this submission was then refiled on September 13, 2021 as a New Drug Submission – COVID (NDS-CV) Control No. 256417 due to expiry of the Interim Order. The purpose of this NDS-CV was to obtain a market authorization for the indication in the acute treatment of mild to moderate COVID-19 in hospitalized patients.

What did the company submit to support its submission?

The proposed indication for Reeqonus in the acute treatment of mild to moderate COVID-19 was based primarily on the efficacy and safety data from the pivotal Phase III adaptive, randomised, patient-blind, multicentre, standard of care-controlled study JP324. This study was conducted in 156 hospitalized Japanese patients with moderate COVID-19 who had non-severe pneumonia; 107 patients were in the favipiravir group and 49 patients were in the standard of care group (control group). Favipiravir was administered orally for up to 14 days as a 1,800 mg twice daily on day 1 (loading dose) followed by 800 mg twice daily; no clinical proof of concept study was conducted to support the dosing regimen used in study JP324. Additional efficacy and safety data for favpiravir were from six supportive clinical studies.

What was the status of the submission when it was cancelled? What was Health Canadas assessment of the submission at the time of cancellation?

The primary endpoint in study JP324 was the median time to recovery by Day 28 defined as SARS-CoV-2-negative RT-PCR result after alleviation of the following parameters: body temperature, oxygen saturation (SpO2), and findings from chest imaging. At Day 28, the median time to recovery was approximately 3 day shorter in the favipiravir group compared to the control group, i.e., 11.9 days vs. 14.7 days (p = 0.0136). Although statistically significant, the difference in the median time to recovery between the favipiravir group and control group was relatively modest. In addition, it was noted that the results for this endpoint could have been affected by the inconsistencies in qualitative RT-PCR measurement of SARS-CoV-2 as these measurements were done in a decentralized manner with different commercial kits that had different limits of detection (LOD). Furthermore, the efficacy results demonstrated no clear benefit of favipiravir compared to the control group with respect to the sensitivity analyses of the primary endpoint as well as with respect to secondary endpoints, including the results for individual components of the composite primary endpoint. Most notably, about 10% of patients in the favipiravir group progressed to more severe disease requiring supplemental oxygen or invasive mechanical ventilation by Day 28 whereas no patients progressed to more severe disease in the control group during this time.

The administration of favipiravir in study JP324 was associated with an increased incidence of adverse events of hyperuricemia, increased blood uric acid and increased liver function enzymes; most of these events were mild to moderate in severity. There was an increased incidence of discontinuation due to adverse events in the favipiravir group as compared to the control group (12% vs 0%).

Additional evidence related to efficacy and safety of favipiravir in COVID-19 provided by the sponsor was from six supportive clinical studies. No firm conclusion regarding favipiravir efficacy in COVID-19 could be drawn from this evidence due to limitations in the design of these studies (i.e., open-label or observational), small sample size, missing information, different dosing regimen, different patient population investigated and/or negative outcomes. No new safety issues compared to study JP324 have been identified based on the evidence from these six studies. Available evidence suggests that favipiravir may have adverse effects on the heart, fetus and male reproductive system. Indeed, based on available clinical data, the possibility of a delayed QTc prolongation effect of favipiravir cannot be excluded. In addition, the non-clinical studies with favipiravir revealed a risk of teratogenicity and testicular toxicity; there is either no or limited evidence concerning these risks from the clinical studies with favipiravir at this time.

In conclusion, based on the review of submitted evidence, Health Canada was not able to establish a positive benefit-harm profile for favipiravir in the acute treatment of mild to moderate COVID-19. The sponsor was given an opportunity to provide additional supporting clinical trial evidence. However, on February 24, 2022 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.

What consequences does the cancellation have for patients accessing the drug under the Special Access Programme (SAP), or via clinical trials?

There is no expected impact for patients using SAP or in clinical trials.

Additional information

*Proposed Brand Name:

Reeqonus