International Rhinologic Society Rhinology 0300-0729 2026 07 17 Dupilumab in chronic rhinosinusitis without nasal polyps: randomized phase 2 trial (ORION) EN S.E. Lee Department of Otolaryngology–Head and Neck Surgery, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, United States A.T. Peters Feinberg School of Medicine, Northwestern University, Chicago, IL, United States P. Gevaert Upper Airways Research Laboratory, Department of Head and Skin, Ghent University, Ghent, Belgium J.K. Han Department of Otolaryngology and Head and Neck Surgery, Eastern Virginia Medical School, Norfolk, VA, United States C. BachertDepartment of Otorhinolaryngology—Head and Neck Surgery, University Hospital of Münster, Münster, Germany First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China F. Moreira da Silva Department of Otorhinolaryngology, Hospital Senhora da Oliveira, Guimarães, Portugal A. Rosenblüt Unidad de Otorrinolaringologia, Hospital Dr Sotero del Rio, Puente Alto, Santiago, Chile C.C Hu Sanofi, Morristown, NJ, United States J. Maloney Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States P. CaferraSanofi, Amsterdam, The Netherlands Department of Pharmacy, University of Pisa, Pisa, Italy A. Michalak Sanofi, Toronto, ON, Canada A.P. Fontenot Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States L.B. Robinson Sanofi, Cambridge, MA, United States N.A. Phadke Sanofi, Cambridge, MA, United States Journal Article 3487 10.4193/Rhin25.660 BACKGROUND: Chronic rhinosinusitis (CRS) is often driven by type 2 inflammation and is characterized by nasal obstruction/ discharge, facial pain/pressure, and/or reduced smell, either with or without nasal polyps (CRSwNP or CRSsNP). OBJECTIVE: To test whether dupilumab improves radiographic features in CRSsNP. Methods: ORION (NCT04678856), a phase 2, randomized, multicenter, double blind, placebo-controlled study, assessed dupilumab efficacy and safety in adults with uncontrolled CRSsNP. Patients were randomized 1:1 to dupilumab or placebo for 24 to 52 weeks. Endpoints included changes from baseline at week 24 in Lund–Mackay computed tomography (LMK-CT) score (dupilumab only [primary] and vs placebo [secondary]), sinus Total Symptom Score (sTSS), University of Pennsylvania Smell Identification Test (UPSIT) score, and 22-item Sino-Nasal Outcome Test(SNOT-22) score. Primary analysis was conducted in the intention-to-treat population with screening blood eosinophil count (sBEC) ≥300 cells/μL. Safety data were evaluated in all patients. RESULTS: Seventy-one patients were randomized (dupilumab, n = 38; placebo, n = 33). In the dupilumab group with sBEC ≥300 cells/μL (n = 16), mean (95% CI) week 24 change from baseline in LMK-CT was -6.63 (-8.71 to -4.54); week 24 mean differences vs placebo (95% CI) for LMK-CT, sTSS, UPSIT, and SNOT-22 were -5.95 (-8.38 to -3.51), -1.43 ( 3.28 to 0.41), 5.91 (-1.56 to 13.38), and -14.71 (-34.35 to 4.94). Treatment-emergent adverse events were balanced between treatment groups. CONCLUSION: Dupilumab was associated with improvement in LMK-CT score and a trend toward improvement in sinonasal symptoms at week 24 in adults with severe, uncontrolled CRSsNP with sBEC ≥300 cells/μL.