A pair of pivotal Phase 3 placebo-controlled trials that evaluated dupilumab (Dupixent, Sanofi and Regeneron) for adults with inadequately-controlled chronic rhinosinusitis with nasal polyps met all primary and secondary endpoints.
All primary and secondary endpoints were met in a pair of pivotal Phase 3 placebo-controlled trials that evaluated Sanofi and Regeneron's dupilumab product (Dupixent®) for adults with inadequately-controlled chronic rhinosinusitis with nasal polyps (CRSwNP).1
On the coprimary endpoints for both trials at 24 weeks, patients treated with dupilumab added to a standard-of-care corticosteroid nasal spray experienced a 51% and 57% improvement in their nasal congestion/obstruction severity compared to 15% and 19% improvement with nasal spray alone (placebo) (-1.25 and -1.34 for dupilumab compared to -0.38 and -0.45 for placebo, on a 0-3 scale ). Dupilumab treated patients had a 27% and 33% reduction in their nasal polyps score compared to a 4% and 7% increase for placebo (-1.71 and -1.89 for dupilumab compared to 0.10 and 0.17 for placebo, on a 0-8 scale that measures bilateral polyps size by endoscopy).1
Dupixent, an injectiable medication,2 also met all secondary endpoints in both trials, including demonstrating a significant reduction in the need for systemic corticosteroids or surgery, and improvements in smell and chronic rhinosinusitis symptoms. In a pre-specified group of patients with comorbid asthma, dupilumab significantly improved lung function and asthma control (p < 0.0001 for all primary and secondary endpoints in both trials). Dupilumab blocks the IL-4 and IL-13 signaling pathways.1
According to George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer of Regeneron, Dupixent has demonstrated significant late-stage efficacy in 3 Type 2 or allergic inflammatory diseases, indicating that IL-4 and IL-13 are required drivers of Type 2 or allergic inflammation in general.1
“With these data, Dupixent has now been shown to address this inflammation across the complete airway, which manifests in the upper respiratory tract as polyps and congestion, and in the lower airway as asthma," said Yancopoulos, in a prepared statement.1 "We look forward to U.S. regulatory action on our moderate-to-severe asthma application later this month, and (we) 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."
CRSwNP is a chronic disease in which Type 2 or allergic inflammation causes nasal polyps. Current treatments are limited and include intranasal corticosteroids, oral corticosteroids and surgery, with high recurrence rates after treatment. Among the patients involved in the pair of Phase 3 Dupixent trials, more than half had previously undergone surgery for their nasal polyps and nearly 3/4 of trial participants had used systemic corticosteroids within the past two years.1
"Living with inadequately controlled nasal polyps carries a heavy burden with patients experiencing pain, nasal discharge, difficulty breathing and the inability to smell. The standard of care, which includes the use of oral and intranasal corticosteroids, often alongside surgery, has not changed for decades," said John Reed, MD, Executive Vice President, Global Head of Research & Development, Sanofi, in a prepared statement.1 "For the first time, we have Phase 3 data showing that a biologic can help address the underlying Type 2 or allergic inflammation that causes chronic rhinosinusitis with nasal polyps and we look forward to working with regulatory authorities around the world to make Dupixent an option for people living with this chronic condition."
The pivotal Phase 3 trials, known as SINUS-24 (n=276) and SINUS-52 (n=448), had the same co-primary endpoints, which were change from baseline in nasal congestion/ obstruction severity based on the patient's daily morning assessment, and change from baseline in nasal polyposis score after 24 weeks, as assessed by nasal endoscopy. An additional co-primary endpoint in Japan, a key secondary endpoint in other countries, was change from baseline in sinus opacification, as assessed by computed tomography scan. The trials were randomized double-blind, placebo-controlled trials evaluating dupilumab when added to the corticosteroid mometasone furoate nasal spray (MFNS), compared to MFNS alone.1
The trials enrolled patients who were aged 18 years or older with bilateral nasal polyps who, despite treatment with systemic corticosteroids in the previous 2 years or a history of surgery, continued to have ongoing moderate or severe symptoms of nasal congestion, blockage, loss of smell or nasal discharge. Consistent with the overlap seen among patients with Type 2 or allergic inflammatory diseases, more than 3/4 of participants also suffered from other conditions, including asthma (approximately 59%), allergic rhinitis (approximately 58%) and NSAID-exacerbated respiratory disease (approximately 28%). Patients with co-morbid asthma and CRSwNP tend to have more severe disease.1
Dupilumab can cause serious adverse effects, including allergic reactions and eye problems, such as pain, conjunctivitis, and change in vision, The most common adverse effects include injection site reactions, eye and eyelid inflammation, including redness, swelling and itching; and cold sores in the mouth or on the lips.1,2
The rates of adverse events were generally similar across dupilumab and placebo, and no new or unexpected side effects related to the drug were observed. The rates of conjunctivitis were: 1.4% dupilumab versus 0.8% placebo in SINUS-24; 2.7% dupilumab every 2 weeks and 2.0% dupilumab every 2-4 weeks versus 1.3% placebo in SINUS-52. Overall rates of serious adverse events were lower with dupilumab: 4.2% dupilumab versus 14.4% placebo in SINUS-24; 5.4% dupilumab every 2 weeks and 6.8% dupilumab every 2-4 weeks versus 10.0% placebo in SINUS-52.1
In the United States, Dupixent was approved by the FDA in 2017 with Priority Review and Breakthrough Therapy designations. Dupixent was indicated in its approval for treating adult patients with moderate-to-severe eczema that is not well controlled with topical prescription therapies, or who cannot use therapies on the skin.2
The safety and efficacy of dupilumab in CRSwNP is investigational and has not been evaluated by any regulatory authority. Detailed results from the SINUS-52 and SINUS-24 trials will be submitted for presentation at future medical meetings, and will form part of the companies' regulatory submissions.1