Regulatory Decision Summary for Olumiant

The original purpose of this Supplemental New Drug Submission (SNDS) was to seek market authorization for Olumiant in the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult and pediatric patients aged 10 years and older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). A Notice of Deficiency (NOD) was issued on December 7, 2021, as the efficacy of Olumiant in the proposed new indication could not be established. A response to NOD submitted on June 2, 2022, did not satisfactorily address the concerns included in the NOD and therefore, a Notice of Non-Compliance (NON) was issued on February 16, 2023. This was an interim decision, and the sponsor had an opportunity to provide additional evidence to support the proposed indication for Olumiant. However, on May 19, 2023, the sponsor informed Health Canada that they would not be submitting a response to NON. Therefore, a NON-Withdrawal (NON-W) was issued for this SNDS.

The proposed indication for Olumiant in the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult and pediatric patients aged 10 years and older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) was initially supported by the safety and efficacy data from two Phase 3 randomized, double-blind, placebo-controlled trials, ACTT-2 and KHAA (COV-BARRIER).

Study ACTT-2 evaluated the combination of baricitinib 4 mg + remdesivir compared to placebo + remdesivir. All patients received background remdesivir 200 mg on Day 1, followed by 100 mg once daily (via intravenous infusion) on subsequent days for a total treatment duration of 10 days or until hospital discharge. The primary endpoint for the intent-to-treat population was time to recovery within 29 days after randomization. Recovery was defined as being discharged from the hospital without limitations on activities (National Institute of Allergy and Infectious Disease (NIAID) ordinal scale category 1; OS 1), being discharged from the hospital with limitations on activities and/or requiring home oxygen (OS 2) or hospitalized but not requiring supplemental oxygen and no longer requiring medical care (OS 3). The key secondary endpoint was clinical status on Day 15 assessed on the NIAID OS. For the overall population, treatment with baricitinib resulted in a 1-day shorter median time to recovery compared to placebo and this difference was statistically significant. Specifically, the median time to recovery was 7 days for baricitinib + remdesivir compared to 8 days for placebo + remdesivir (hazard ratio: 1.15 [95% confidence interval (CI) 1.00, 1.32]; p-value = 0.043). The difference in Day 29 mortality between the baricitinib and placebo groups in the overall population was not statistically significant, i.e., 4.5% vs. 7.3%, respectively (hazard ratio = 0.63; [95% CI 0.37 to 1.05]; p-value = 0.075).

Study KHAA evaluated baricitinib 4 mg compared to placebo. Patients could remain on background standard of care as defined per local guidelines, including antimalarials, antivirals, corticosteroids, and/or azithromycin. The most frequently used therapies were corticosteroids (79% of patients; 91% of those patients received dexamethasone) and remdesivir (19% of patients). The composite primary endpoint was the proportion of patients who died or progressed within the first 28-days of the study. Progression was defined as requiring non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation (including ECMO) and did not necessarily reflect the Day 28 outcome. Patients who required non-invasive ventilation/high-flow oxygen (OS 6) at baseline needed to worsen by at least 1 point on the NIAID OS to progress. A key secondary endpoint was all-cause mortality by Day 28. The proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation was lower in patients treated with baricitinib (27.8%) compared to placebo (30.5%), but this effect was not statistically significant (odds ratio = 0.85; [95% CI 0.67, 1.08]; p-value = 0.180). The 28-day mortality in the overall population was 8.1% for the baricitinib group vs. 13.1% for the placebo group (38.2% relative reduction; hazard ratio = 0.57; [95% CI 0.41 to 0.78]; nominal p-value = 0.002).

Based on the evidence from the ACTT-2 and KHAA trials, Health Canada was not able to determine the benefit of Olumiant in the proposed indication and a Notice of Deficiency (NOD) was issued on December 7, 2021. Specifically, the clinical significance of a small benefit of baricitinib with respect to the primary efficacy endpoint of time to recovery by Day 29 in study ACTT-2 (i.e., 1-day shorter time to recovery compared to placebo) was unclear and study KHAA did not meet its pre-specified primary efficacy endpoint and therefore, the results obtained for the secondary endpoints, including all-cause mortality by Day 28, were considered exploratory. In addition, no statistically significant effect of baricitinib on all-cause mortality by Day 28 was observed in the ACTT-2 trial. The NOD stated that the potential clinical relevance of the results for all-cause mortality by Day 28 in the ACTT-2 and KHAA trials showing 38.4% and 38.2% relative risk reduction with baricitinib as compared to placebo, respectively, needed to be confirmed in additional clinical trial(s).

In response to NOD dated June 2, 2022, the sponsor provided additional clinical safety and efficacy data from the RECOVERY, ACTT-4 and KHAA trials.

Study RECOVERY is a randomised, open-label, adaptive platform trial conducted in the United Kingdom that evaluates multiple possible treatments in patients with COVID-19. The baricitinib arm of this trial enrolled 8156 patients who were randomised to standard of care (SOC) + baricitinib or SOC alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). About two-thirds of patients were receiving simple oxygen supplementation and a small number of patients were receiving invasive mechanical ventilation or no respiratory support at all at baseline. The primary outcome of the baricitinib + SOC arm versus the SOC arm in the RECOVERY trial was 28-day all-cause mortality, assessed in the intent-to-treat population. Secondary outcomes included time to discharge from hospital and, among patients not on invasive mechanical ventilation at randomisation, the composite outcome of invasive mechanical ventilation (including ECMO), or death. A statistically significant reduction in 28-day all-cause mortality was observed with 514 (12%) of the 4,148 patients randomised to baricitinib versus 546 (14%) of the 4,008 patients randomised to SOC who died within 28 days (age-adjusted rate ratio = 0.87; [95% CI 0.77-0.99]; p-value = 0.028). However, the reduction in all-cause mortality in baricitinib-treated patients only reached statistical significance after adjusting for baseline imbalance in age (0.8-year difference in mean age with overlapping standard deviations) or other covariates and it failed to demonstrate a statistically significant risk reduction in an unadjusted analysis (rate ratio = 0.90; [95% CI 0.80-1.02]; p-value = 0.10). As there were no clearly pre-specified conditions for an adjusted analysis of the primary outcome in the trial protocol, the unadjusted analysis is considered the main analysis. Additionally, in accordance with the statistical analysis plan, the sensitivity analyses conducted among patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) found that among those with polymerase chain reaction (PCR) results available, the unadjusted hazard ratio for 28-day all-cause mortality was not statistically significant (i.e., 0.92; [95% CI 0.82 to 1.05]). Overall, the RECOVERY trial did not meet its pre-specified primary efficacy endpoint and thus, it failed to demonstrate that treatment with baricitinib was efficacious in reducing 28-day all-cause mortality in hospitalized patients with COVID-19.

Study ACTT-4 was a randomized, double-blind, double-placebo controlled trial that evaluated the efficacy and safety of baricitinib + remdesivir versus dexamethasone + remdesivir in hospitalised adults with COVID-19. This trial was terminated early for futility as baricitinib + remdesivir was unlikely to be superior to dexamethasone + remdesivir. The trial protocol did not pre-specify the possibility for testing for equivalence (or non-inferiority). Therefore, study ACTT-4 did not provide confirmatory evidence for the benefit of baricitinib in COVID-19.

The Day 60 results from the KHAA trial showed that similarly to Day 28 results submitted initially, all-cause mortality by Day 60 (a pre-specified exploratory analysis) favoured baricitinib over placebo. In a KHAA sub-study in patients requiring invasive mechanical ventilation or ECMO at baseline (OS 7), a pre-specified exploratory analysis showed that the proportion who died by Day 28 was 39.2% (20/51) for baricitinib compared to 58.0% (29/50) for placebo (estimated difference in Day 28 risk of mortality = -18.8% [95% CI: -36.3%, 0.6%]; hazard ratio = 0.54 [95% CI: 0.31, 0.96]). Overall, as stated above, study KHAA did not meet its pre-specified primary efficacy endpoint and therefore, the results obtained for the secondary efficacy endpoint of all-cause mortality by Day 28 are considered exploratory as they are not controlled for multiplicity.

Taken together, the new clinical data submitted in a response to the NOD did not satisfactorily address the concerns included in the NOD and therefore, a Notice of Non-Compliance (NON) was issued on February 16, 2023. The sponsor opted to not file a response to NON and so a NON-Withdrawal (NON-W) was issued for this Supplemental New Drug Submission (SNDS).

Based on the overall evidence submitted in this SNDS, it is considered that the benefit of Olumiant in the proposed COVID-19 indication has not been established and therefore, the benefit-harm-uncertainty profile of Olumiant in this indication is negative.