Dupilumab Hits Phase 3 Pivotal Marks for Chronic Rhinosinusitis with Nasal Polyps

A pair of pivotal phase 3 trials have indicated benefits for dupilumab (Dupixement) in the treatment of adults with poorly-controlled chronic rhinosinusitis with nasal polyps (CRSwNP).

The trial results come just days before the US Food and Drug Administration (FDA) is required to rule on the drug’s supplemental biologics application (sBLA) for the indication as an add-on therapy for asthma in adults and adolescent patients—and a week after Sanofi and Regeneron Pharmaceuticals’ presented LIBERTY ASTHMA trial results showing the monoclonal antibody’s benefit in adolescents with uncontrolled, moderate-to-severe asthma.

The biologic, with capabilities of blocking the pathways to interleukin (IL) 4 and 13, has been previously approved for improperly controlled atopic dermatitis (AD), and is being investigated for the treatment of pediatric AD and eosinophilic esophagitis—as well as CRSwNP.

In the new results from the SINUS-24 and SINUS-52 phase 3 pivotal trials, patients treated with dupilumab as an add-on therapy to standard-of-care corticosteroid nasal spray reported improvements each above 50% (51%, 57%) in nasal congestion/obstruction over 24 weeks, compared to improvements of just 15% and 19% in patients treated with lone nasal spray and placebo.

SINUS-24 (n= 276 patients) and SINUS-52 (n= 448 patients) both carried the same co-primary endpoints: change from baseline in congestion/obstruction severity based on the a daily morning assessment from the patient, and change from baseline nasal polyposis score after 24 weeks, as per a nasal endoscopy. Patients were randomized in the double-blind trials to receive either dupilumab plus mometasone furoate nasal spray (MFNS) or lone MFNS.

Patients were required to be 18 years of age or older, with bilateral nasal polyps treated for at least 2 years with systemic corticosteroids or surgery but continued moderate or severe symptoms of nasal congestion, blockage, loss or smell or nasal discharge.

Investigators noted that, in trends consistent with the overlap observed in patients with Type 2 or allergic inflammatory diseases—theorized as the atopic march—more than three-fourths of the patient population were diagnosed with other conditions. Among the most prominent comorbidities were asthma (59%), allergic rhinitis (58%), and nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (28%). As investigators have previously found, patients with both CRSwNP and asthma more commonly suffer from a severe form of the former disease.

Using a scale from 0 to 8 (with greater scores indicating severity), patients on dupilumab reported -1.71 and -1.89 reductions in bilateral nasal polyps size scores. These reductions were worth 27% and 33% from baseline, compared to 4% and 7% increases in patients on lone MFNS, respectively.

In secondary endpoints including significant reduction of need for systemic corticosteroid or surgery, as well as improvements in smell and chronic rhinosinusitis symptoms, patients on dupilumab met their goals. A pre-specified group of patients with comorbid asthma administered the therapy also reported improved lung function and asthma control (P < .0001).

Adverse events across all treatment groups were generally similar, with no new observed side effects related to dupilumab.

With these new findings, dupilumab has been proven to be efficacious at late clinical stages in 3 different Type 2 or allergic inflammatory diseases, George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer of Regeneron, said in a statement. It’s further evidence that IL-4 and IL-13 inhibitors such as dupilumab have benefits across the complete airway.

In an interview with MD Magazine® at the 2018 CHEST Annual Meeting in San Antonio, TX, last week, Monica Kraft, MD, Deparment of Medicine Chair at the University of Arizona College of Medicine — Tuscon, called the antibody an exciting biologic in the asthma community if not only for its interleukin targeting.

“IL-4 is really important in the allergic response, in IgE (immunoglobulin E) formulation, and that side of things,” Kraft explained. “IL-13 has a lot of effects on the airway, in terms of collagen deposition. It affects smooth muscle, increases contraction of smooth muscle, increases production of mucus—all the things that are abnormal in the asthmatic airway.”

Looking forward to the October 20 sBLA decision date and future clinical assessment, Yancopoulos expressed excitement for the future of dupilumab.

“We look forward to US regulatory action on our moderate-to-severe asthma application later this month, and are continuing our development program in additional Type 2 or allergic inflammatory diseases with high unmet need including pediatric asthma, pediatric and adolescent atopic dermatitis, eosinophilic esophagitis, and food and environmental allergies,” Yancopoulos said.