Marc A. Riedl ¹ Petra Staubach ² Henriette Farkas ³ Andrea Zanichelli ^4,5 Hong Ren ⁶ Christina Nurse ⁷ Irmgard Andresen ⁸ Salomé Juethner ⁹ Ming Yu ⁷ Jingmei Zhang ^7*

• ¹ Division of Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, United States
• ² Department of Dermatology, University Medical Center Mainz, Mainz, Germany
• ³ Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
• ⁴ Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
• ⁵ Dipartimento di Scienze Biomediche per la Salute, University of Milan, Milan, Lombardy, Italy
• ⁶ Cytel Inc., Cambridge, Massachusetts, United States
• ⁷ Takeda Development Center Americas, Inc., Lexington, United States
• ⁸ Takeda Pharmaceuticals International AG, Zurich, Switzerland
• ⁹ Takeda Pharmaceuticals U.S.A., Inc., Lexington, United States

Background: Randomized controlled trial data for non-histaminergic normal C1 inhibitor (nC1INH) angioedema prevention are lacking. Methods: Patients aged ≥12 years with investigator-confirmed non-histaminergic nC1INH angioedema were enrolled in phase III, multicenter, randomized, placebo-controlled, double-blind CASPIAN Study (NCT04206605). Patients with ≥1 investigator-confirmed angioedema attack/4 weeks during observation period were randomized 2:1 to lanadelumab 300 mg every 2 weeks or placebo. Primary efficacy outcome was investigator-confirmed angioedema attack number during 26-week treatment period. Safety was analyzed as treatment-emergent adverse events (TEAEs). After completing treatment period, patients could roll over to CASPIAN open-label extension (CASPIAN OLE; NCT04444895) for additional 26-week lanadelumab treatment to assess long-term safety and efficacy. Results: Seventy-seven patients (mean ± SD age 42.8 ± 12.9 years, 80.5% female, 88.3% White) were enrolled (lanadelumab, 50; placebo, 27). Primary efficacy outcome was not different with lanadelumab versus placebo (1.82 vs. 1.78 attacks/month; rate ratio 1.02; p=0.90), with attack rate reduction from baseline in both groups. Subgroups meeting a clinical definition of HAE (known mutations [n=5] or family history and unknown mutations [n=13]) showed positive attack rate reduction trend with lanadelumab versus placebo. Angioedema attack rate reduction with lanadelumab was observed in CASPIAN OLE. In both studies, all treatment-related TEAEs were non-serious, most were non-severe; most frequent treatment-related TEAEs were similar to those previously reported in lanadelumab clinical trials. Conclusion: In patients with non-histaminergic nC1INH angioedema, lanadelumab safety was consistent with previous studies; efficacy remained inconclusive due to unmet CASPIAN primary endpoint. Overall results suggest potential clinical benefit in symptom control.