Dupilumab sBLA Submission for COPD Accelerated Based on Second Positive Phase 3 Trial Findings

Sanofi and Regeneron Pharmaceuticals announced Monday their plan to submit a supplemental biologics license application (sBLA) to the US Food and Drug Administration (FDA) for approval of dupilumab (Dupixent) for treatment of chronic obstructive pulmonary disease (COPD) by the end of the year—an earlier target than originally planned, according to a company statement.

The decision to move ahead quickly follows the codevelopers' report of findings from the phase 3 NOTUS clinical trial of dupilumab in patients with COPD and evidence of type 2 (T2) inflammation. The NOTUS trial met its primary endpoint “with overwhelming efficacy,” the companies said, showing that dupilumab significantly reduced COPD exacerbations by 34% compared with placebo. The results were similar to those announced earlier this year from the replicate phase 3 BOREAS clinical trial in which exacerbations were reduced by 30%. Participants in both studies who received dupilumab experienced rapid and significant improvements in lung function by as early as 12 weeks, gains that were sustained at 52 weeks.

Sanofi and Regeneron also announced that the current results of what had been planned as an interim analysis of the NOTUS trial will be considered the primary analysis of the phase 3 study.

“This is the first and only time an investigational biologic in COPD has shown a significant and clinically meaningful reduction in exacerbations in two Phase 3 trials, Naimish Patel, MD, Sanofi head of global development, immunology, and inflammation said in the statement. He added that the accelerated timeline would benefit the 300 000 people in the US with COPD with evidence of T2 inflammation, a disease for which there have been no new treatments for more than a decade.

The 2 phase 3 trials: NOTUS, BOREAS

The NOTUS and BOREAS studies are replicate phase 3 double-blind placebo-controlled trials to evaluate the efficacy and safety of dupilumab in adults who were current or former smokers who have uncontrolled moderate to severe COPD. Participants in NOTUS (n=935) are aged 40 to 85 years and in BOREAS (n=939) were 40 to 80 years. All participants had evidence of type 2 inflammation (ie, blood eosinophils ≥300 cells/uL) and were receiving maximal standard-of-care inhaled therapy.

During the 52-week treatment period in both trials, participants were randomly assigned to receive dupilumab or placebo every 2 two weeks added to a maximal standard-of-care inhaled triple therapy of inhaled corticosteroids, long-acting beta agonists, and long-acting muscarinic antagonists.

Key findings from NOTUS for participants receiving dupilumab vs placebo:

• 34% reduction in moderate or severe acute COPD exacerbations over 52 weeks (P=.002), the primary endpoint.
• Improved lung function from baseline by 139 mL in FEV1 at 12 weeks vs 57 mL for placebo (P=.001), with the benefit versus placebo sustained at week 52 (115 mL in FEV1 for dupilumab vs 54 mL for placebo, P=.018), both of which were key secondary endpoints.

Key findings from NOTUS were consistent with those from BOREAS:

• 30% reduction in moderate or severe acute COPD exacerbations over 52 weeks (P=.005), the primary endpoint.
• Improved lung function from baseline by 160 mL in FEV1 at 12 weeks compared to 77 mL for placebo (P<.001), with the benefit versus placebo sustained through week 52 (P=.003).

The companies said that the safety of dupilumab in the NOTUS study was generally consistent with its known profile in its approved indications and consistent with safety findings in the BOREAS trial, although the rate of adverse events leading to deaths in NOTUS was 2.6% compared with 1.5% for placebo.

Further results from the NOTUS clinical trial are expected to be presented at an upcoming medical meeting, according to the statement.

The FDA earlier this year granted breakthrough therapy designation for dupilumab as add-on maintenance treatment in adult patients with uncontrolled COPD associated with a history of exacerbations and an eosinophilic phenotype based on the positive results from BOREAS.

Source: Dupixent significantly reduced COPD exacerbations in second positive Phase 3 trial, accelerating FDA submission and confirming potential to become first approved biologic for this serious disease. Sanofi. Press release. November 27, 2023. Accessed November 27, 2023. https://www.sanofi.com/en/media-room/press-releases/2023/2023-11-27-06-30-00-2785836