Donidalorsen Treatment of Hereditary Angioedema in Patients Previously on Long-Term Prophylaxis

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BACKGROUND: Hereditary angioedema (HAE) is a rare, potentially life-threatening disorder characterized by episodes of tissue swelling. Donidalorsen, an investigational ligand-conjugated antisense oligonucleotide, reduces plasma prekallikrein production. OBJECTIVE: We report an interim analysis on safety, efficacy, quality of life (QoL), and treatment preference and satisfaction from an ongoing open-label phase 3 study (OASISplus Switch cohort, NCT05392114). METHODS: Patients with HAE receiving stable doses (≥12 weeks) of lanadelumab, complement protein 1 inhibitor, or berotralstat switched to donidalorsen 80 mg subcutaneously every 4 weeks, using a predefined algorithm. The primary end point was the incidence and severity of treatment-emergent adverse events. Other end points included change in HAE attack rate, angioedema-QoL score, disease control (≥10 points on the Angioedema Control Test), and treatment preference and satisfaction at week 16, compared with baseline on prior treatment. RESULTS: A total of 65 patients were enrolled; 32 switched from lanadelumab, 22 from complement protein 1 inhibitor, and 11 from berotralstat. At cutoff, 58 were ongoing in the study (89%). Forty-five patients (70%) reported treatment-emergent adverse events; 62% were unrelated to donidalorsen. At week 16, total HAE attack rates had decreased by 62%. Hereditary angioedema attack rates decreased by 65%, 41%, and 73%, and mean angioedema-QoL scores improved by 8.4, 9.6, and 17.1 points for patients switching from lanadelumab, C1INH, and berotralstat, respectively. More patients reported well-controlled disease (93% vs 67%), and most patients preferred donidalorsen over their prior treatment, with improved treatment satisfaction. CONCLUSIONS: Donidalorsen was well tolerated, decreased HAE attack rate, and improved QoL and disease control. Most patients preferred donidalorsen over their prior treatment. Further analyses are planned at week 52.

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