Updated: September 27, 2024 at 12:28AM.
The FDA has approved dupilumab (Dupixent; Regeneron, Sanofi) as an add-on maintenance therapy for adult patients who have inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. The approval came after 2 phase 3 trials—BOREAS (NCT03930732) and NOTUS (NCT04456673)—in which dupilumab achieved significant reduction in exacerbations while improving lung function and health-related quality of life compared with placebo.1
Dupilumab is a fully human monoclonal antibody that inhibits the signaling of the interleukin (IL)-4 and IL-13 pathways. It is not an immunosuppressant. Additionally, dupilumab has also received approval by the FDA in January 2024 for pediatric patients with eosinophilic esophagitis aged 1 to 11 who weigh at least 15 kg. This approval is an extension of a previous indication, which includes adults and children who are 12 years and older weighing at least 40 kg. Dupilumab has other indications in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, prurigo nodularis, and chronic spontaneous urticaria.1,2
“People living with inadequately controlled COPD have long awaited new medicines to help manage the daily suffering they experience from breathlessness, coughing, wheezing, exhaustion and unpredictable hospitalization. These patients often struggle with everyday activities many people take for granted such as taking a walk or running errands outside the home,” Jean Wright, MD, CEO of the COPD Foundation, said in a news release. “We welcome the approval of this new therapeutic option to offer patients a new way to help gain better control of their disease.”1
About the Trials
BOREAS Trial:
- Trial Name: Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate-to-severe COPD With Type 2 Inflammation (BOREAS)
- ClinicalTrials.gov ID: NCT03930732
- Sponsor: Sanofi
- Completion Date: May 2, 2023
NOTUS Trial:
- Trial Name: Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate to Severe COPD With Type 2 Inflammation (NOTUS)
- ClinicalTrials.gov ID: NCT04456673
- Sponsor: Sanofi
- Completion Date (Estimated): May 22, 2024
BOREAS (NCT03930732) and NOTUS (NCT04456673) are replicate, randomized, double-blind, placebo-controlled phase 3 clinical trials that evaluated the efficacy and safety of dupilumab in adults who were current or former smokers with moderate-to-severe COPD with an eosinophilic phenotype as defined by blood eosinophils of 300 cells or higher per µL. Additionally, the trials included adults with COPD across a broad range of clinical presentations, including chronic bronchitis and emphysema. A total of 1874 patients were enrolled across both studies, with those aged 40 to 80 years in BOREAS and 40 to 85 years in NOTUS.1
During the 52-week treatment period, patients in BOREAS and NOTUS received either 300 mg of dupilumab or placebo every 2 weeks added to a maximal standard of care inhaled triple therapy of inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). Double maintenance therapy, which included LABA and LAMA, was allowed if ICS was not appropriate.1,3,4
The primary end point for both BOREAS and NOTUS evaluated the annualized rate of acute moderate to severe COPD exacerbations. Key secondary end points included change from baseline in lung function—which was assessed by pre-bronchodilator forced expiratory volume (FEV1)—at weeks 12 and 52, change from baseline at 52 weeks in St George's Respiratory Questionnaire (SGRQ) total score compared to placebo, and safety.1,3,4
In the BOREAS trial, 939 patients were randomly assigned to receive either dupilumab (n = 468) or placebo (n = 471). The annualized rate of moderate or severe exacerbations was about 0.78 (95% CI, 0.64 to 0.93) in the dupilumab group and 1.10 (95% CI, 0.93 to 1.30) in the placebo group (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P < .001). Additionally, the prebronchodilator FEV1 increased from baseline to week 12 by a mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P < .001), and this difference was sustained through the 52-week point. Further, at week 52, the SGRQ score had improved by a mean of -9.7 (95% CI, −11.3 to −8.1) with dupilumab and -6.4 (95% CI, −8.0 to −4.8) with placebo (LS mean difference, −3.4; 95% CI, −5.5 to −1.3; P = .002).3
In the NOTUS trial, 935 patients were randomly assigned to receive either dupilumab (n = 470) or placebo (n = 465), and at the time of week 52, 721 patients were included in the analysis. Consistent with the positive findings of BOREAS, the annualized rate of moderate or severe exacerbations was also in favor of dupilumab (0.86 [95% CI, 0.70 to 1.06]) rather than placebo (1.30 [95% CI, 1.05 to 1.60]; rate ratio, 0.66 [95% CI, 0.54 to 0.82;]; P < .001). The prebronchodilator FEV1 increased from baseline to week 12 with dupilumab (139 ml [95% CI, 105 to 173]) compared with the placebo (57 ml [95% CI, 23 to 91]), with significant mean difference at weeks 12 (82 ml; P < .001) and 52 (62 ml; P = .02). Further, there were no significant differences in the change in SGRQ scores observed between groups from baseline to week 52.4
Overall, safety results were consistent with the known safety profile of dupilumab in its approved indications. The most common adverse events (AEs) across both trials and more commonly observed in those receiving dupilumab were viral infection, headache, nasopharyngitis, back pain, diarrhea, arthralgia, urinary tract infection, local administration reaction, rhinitis, eosinophilia, toothache, and gastritis. The investigators also observed cholecystitis, which was reported in approximately 0.6% of patients in the dupilumab group compared with 0.1% of the placebo group.1,3,4
“This latest FDA approval for [dupilumab] represents new hope for the hundreds of thousands of [patients with COPD] in the US who can sometimes struggle just to breathe during their everyday lives,” George D Yancopoulos, MD, PhD, board co-chair, president, and chief scientific officer at Regeneron, said in the news release. “[Dupilumab] has a proven track record as a first-in-class medicine, providing benefit to the many patients suffering from type 2 inflammatory related diseases such as asthma and atopic dermatitis. This latest approval represents an important next chapter for [dupilumab], giving those with COPD a novel option that has demonstrated the unprecedented ability to help patients experience fewer exacerbations, while also helping them breathe better and improve quality of life in phase 3 trials.”1
REFERENCES
1. Regeneron. Dupixent® (dupilumab) Approved in the U.S. as the First-ever Biologic Medicine for Patients with COPD. News release. September 27, 2024. Accessed September 27, 2024. https://www.globenewswire.com/en/news-release/2024/09/27/2954552/0/en/Dupixent-dupilumab-Approved-in-the-U-S-as-the-First-ever-Biologic-Medicine-for-Patients-with-COPD.html
2. Ferruggia, K. FDA Approves Dupilumab for Pediatric Patients with Eosinophilic Esophagitis. Pharmacy Times. January 25, 2024. Accessed September 27, 2024. https://www.pharmacytimes.com/view/fda-approves-dupilumab-for-pediatric-patients-with-eosinophilic-esophagitis
3. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. N Engl J Med. 2023;389(3):205-214. doi:10.1056/NEJMoa2303951
4. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med. 2024;390(24):2274-2283. doi:10.1056/NEJMoa2401304
