NOTUS Trial Confirms Dupixent Benefit in COPD with Type 2 Inflammation

Use of dupilumab (Dupixent) was associated with reduced exacerbations and greater lung function than use of placebo therapy among patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation, according to the NOTUS study.

Presented at the 2024 American Thoracic Society International Conference, results of the study suggest patients with COPD and a blood eosinophil count of 300 cells per microliter achieved a 34% reduction in rate of exacerbations as well as a statistically significant benefit for prebronchodilator forced expiratory volume in 1 second (FEV1) change relative to placebo.¹

“In my more than 20 years of practice, there have been limited advancements for patients struggling with the debilitating effects of uncontrolled COPD, and too many patients experience a vicious cycle of exacerbations that can result in loss of lung function and greatly diminish their quality of life,” said coprincipal investigator Surya Bhatt, MD, MSPH, professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Alabama at Birmingham. “In NOTUS, dupilumab reduced exacerbations by a magnitude never seen before with an investigational biologic in a phase 3 COPD clinical trial. These comprehensive results reinforce that, if approved, dupilumab could provide a first-of-its-kind medical advancement for the COPD community.”

A fully human monoclonal antibody blocking the IL-4 receptor alpha antagonist, dupilumab boasts a multitude of indications from the US Food and Drug Administration dating back to its initial approval in 2017 for management of eczema in adult patients. In 2024, the agent became the first treatment indicated for the treatment of pediatric patients aged 1 to 11 years with eosinophilic esophagitis.^2,3

In February 2024, Regeneron and Sanofi announced it would be seeking a sixth indication, with the submission supplement Biologics License Application for dupilumab as an add-on maintenance treatment in certain adult patients with uncontrolled COPD, which had been granted a Priority Review by the FDA and had received a PDUFA date of June 27, 2024. In their announcement, the company noted their application, as well as receipt of the Priority Review designation, were based on results from the NOTUS and BOREAS trials, which are replicate trials evaluating dupilumab in adults who were current or former smokers with moderate-to-severe COPD aged 40 to 85 years (NOTUS) and 40 to 80 years (BOREAS).⁴

An international, double-blind, randomized, placebo-controlled trial, the phase 3 NOTUS trial was conducted across 329 sites in 29 countries. In the NOTUS trial, which was presented at ATS 2024, patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher were randomized to receive subcutaneous dupilumab 300 mg or placebo every 2 weeks. In total, 935 patients underwent randomization, with 470 randomized to dupilumab and 465 randomized to placebo therapy.¹

Of note, patients were considered eligible if they 40 to 85 years of age, had physician-diagnosed COPD for at least 12 months, and had been receiving background triple inhaler therapy for at least 3 months and at a stable dose for at least 1 month. Additional inclusion criteria required patients to have had at least 2 moderate or 1 severe exacerbation in the year prior to screening for eligibility with at least 1 of these exacerbations resulting in the need for treatment with systemic glucocorticoids and at least 1 occurring while the patient was receiving background triple inhaler therapy.¹

The trial’s primary outcome of interest was the annualized rate of moderate or severe exacerbations. The trial’s secondary outcomes of interest, which were assessed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator FEV1 at weeks 12 and 52 and in the St. George’s Respiratory Questionnaire (SGRQ) total score at week 52. Investigators pointed out the primary analysis was performed after a positive interim analysis and included all available data for the study cohort, which included 721 with 52 weeks of data.¹

Upon analysis, results of the NOTUS trial suggested the annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo (Rate ratio [RR], 0.66; 95% CI, 0.54 to 0.82; P <.001). Further analysis demonstrated these results were similar across prespecified demographic and disease subgroups.¹

Analysis of secondary outcomes of interested indicated improvements in prebronchodilator FEV1 were baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) relative to placebo therapy (least-squares mean change, 57 ml; 95% CI, 23 to 91). Investigators observed significant least-squares mean difference of 82 ml at week 12 (P <.001) and 62 ml at week 52 (P = .02).¹

In prespecified analyses involving patients with FeNO levels at baseline of 20 ppb or higher, results suggested the least-squares mean change from baseline in the prebronchodilator FEV1 at week 12 was 221 ml (95% CI, 148 to 294) with dupilumab relative to 81 ml (95% CI, 8 to 153) with placebo (least-squares mean difference, 141 ml; 95% CI, 58 to 223; P = .001). Additional analysis of secondary outcomes revealed no significant difference in change for SGRQ from baseline to week 52 (least-squares mean difference, –3.4 points; 95% CI, –5.8 to –0.9).¹

“These results further confirm the role of type 2 inflammation in the pathobiologic disease mechanisms in a subgroup of patients with COPD and the role of dupilumab in treating this distinct COPD endotype,” investigators wrote.¹

References:

1. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. New England Journal of Medicine. Published online May 20, 2024. doi:10.1056/NEJMoa2401304.
2. Sanofi. Press release: DUPIXENT® FDA approved as first and only treatment indicated for children aged 1 year and older with eosinophilic esophagitis (EOE). Sanofi. March 28, 2017. Accessed May 20, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-01-25-19-30-00-2817342.
3. Sanofi. Press release: DUPIXENT® FDA approved as first and only treatment indicated for children aged 1 year and older with eosinophilic esophagitis (EOE). Sanofi. January 25, 2024. Accessed May 20, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-01-25-19-30-00-2817342.
4. Sanofi. Press release: Dupixent® SBLA accepted for FDA Priority Review for treatment of COPD with type 2 inflammation. Sanofi. February 24, 2024. Accessed May 20, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-02-23-06-00-00-2834219.