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By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first treatment for chronic rhinosinusitis with nasal polyposis (CRSwNP). Dupilumab is a human monoclonal IgG4 antibody that inhibits the actions of interleukin-4 (IL-4) and interleukin-13 (IL-13) by binding to the alpha subunit of the IL-4 receptor (IL-4R alpha). Previously, dupilumab was approved to treat moderate-to-severe asthma with an eosinophilic phenotype and moderate-to-severe atopic dermatitis. The FDA granted priority review and fast-track breakthrough designation. The drug is distributed as Dupixent.
Dupilumab should be prescribed as an add-on maintenance treatment for adults with inadequately controlled CRSwNP.1 Dupilumab also can be prescribed to treat inadequately controlled moderate-to-severe asthma with eosinophilic phenotype or oral corticosteroid-dependent asthma as well as moderate-to-severe atopic dermatitis.
The recommended dose for CRSwNP is 300 mg administered subcutaneously every other week.1 Dupilumab is available in 200 mg and 300 mg prefilled syringes.
The is the first FDA-approved treatment for inadequately controlled CRSwNP.
Adverse outcomes, compared to placebo, include injection site reactions (6% vs. 4%), conjunctivitis (2% vs. 1%), arthralgia (3% vs. 2%), and gastritis (2% vs. 1%).1 Approximately 5% of patients taking the drug developed antibodies to dupilumab, with approximately 2% neutralizing antibodies.1
The efficacy of dupilumab was evaluated in two randomized, double-blind, placebo-controlled studies.1-3 The trials included subjects with CRSwNP on background intranasal corticosteroid, despite prior sinonasal surgery (63%) or treatment with systemic corticosteroid (74%) in the past two years. Those who were ineligible or intolerant to corticosteroids also were included. At the investigators’ discretion, surgery or rescue corticosteroids were allowed during the studies. All subjects showed evidence of sinus opacity based on CT scans (73-90% exhibited opacification of all sinuses).
In trial 1, subjects were randomized to either dupilumab (n = 143) or placebo (n = 133) every other week for 24 weeks. In trial 2 (three arms), subjects were randomized to dupilumab every other week for 52 weeks (n = 150), dupilumab every other week for 24 weeks and then every four weeks until week 52 (n = 145), or placebo for 52 weeks (n = 153). The co-primary efficacy endpoints were mean change from baseline to week 24 in bilateral endoscopic nasal polyps score (NPS; 0-8 scale) and change in nasal congestion (NC)/obstruction score (averaged over 28 days; 0-3 scale) assessed by the subjects’ daily diary. Polyps on each side of the nose were graded as such: 0 = no polys; 1 = small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2 = polyps reaching the lower border of the middle turbinate; 3 = large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; 4 = large polyps causing complete obstruction of the inferior nasal cavity. Total NPS was the sum of both sides of the nose. NC was graded by severity category (0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms).
Dupilumab showed a significant mean difference from placebo in NPS of -2.06 (95% confidence interval [CI], -2.42 to -1.69) for trial 1 and -1.89 (95% CI, -2.10 to -1.51) for trial 2. The overall mean reduction across both studies was 32% from an overall baseline score of 5.96. NC showed a 37% mean reduction vs. placebo from an overall baseline mean of 2.40. In trial 2, improvement continued at week 52 with every-other-week dosing. However, mean NPS improvement diminished in trial 1 after discontinuation of the drug and moved toward baseline. NC improved with dupilumab as early as week 4 and maintained at week 52. Dupilumab also improved the ability to smell and alleviated sinonasal symptoms. The drug reduced the use of systemic corticosteroids and/or the need for sinonasal surgery by 76%. The benefit seems to be consistent in patients with or without prior sinonasal surgery.1
Chronic rhinosinusitis is a heterogenous inflammatory condition characterized by worse sense of smell, facial pain-pressure fullness, nasal obstruction, or mucopurulent drainage.4 It is divided into two phenotypes: with and without polyps. The condition is estimated to affect about 12% of the U.S. population.5 CRSwNP patients tend to exhibit elevated levels of eosinophils and interleukins 4, 5, 10, and 13.6 Atopy and asthma are common comorbidities and seem to share pathophysiology with CRS, which can result in significant healthcare costs and diminished quality of life.4 The recommendation by the American Academy of Otolaryngology-Head and Neck Surgery Foundation for initial treatment is saline nasal irrigation and/or intranasal corticosteroids.4 For those with persistent symptoms, medical treatment (systemic corticosteroids, anti-inflammatory antibiotics) and sinonasal surgery are options.4,7 However, there are patients who are refractory to medical treatment and are candidates for surgery; some patients still suffer after surgery (recalcitrant).7 Several biologics are under investigation for CRS. Dupilumab is the first biologic treatment to be approved for CRSwNP and is effective in reducing nasal polyp size, improving symptoms (e.g., nasal congestion, loss of smell), and reducing the need for oral steroids and surgery. The cost is $3,019.50 for a four-week supply or $39,253 for a one-year supply.
Financial Disclosure: Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott, Acadia, Allergan, AstraZeneca, Avadel, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mylan, and Salix; he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Editorial Group Manager Leslie Coplin; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.