A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema

Remy S. Petersen, Laura Bordone, Marc A. Riedl, Raffi Tachdjian, Timothy J. Craig, William R. Lumry, Michael E. Manning, Jonathan A. Bernstein, Jason Raasch, Bruce L. Zuraw, Yiwen Deng, Kenneth B. Newman, Veronica J. Alexander, Cindy Lui, Eugene Schneider, Danny M. Cohn

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Background: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). Methods: In the OLE, the on-treatment study period consisted of fixed (weeks 1–13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17–105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. Results: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02–0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94–3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0–1.7; 95% CI, −0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. Conclusion: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

Original languageEnglish (US)
Pages (from-to)724-734
Number of pages11
JournalAllergy: European Journal of Allergy and Clinical Immunology
Issue number3
StatePublished - Mar 2024

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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