Association of muscle instability and long-term prophylaxis in hereditary angioedema.

Introduction: Hereditary angioedema (HAE) types 1 and 2 are caused by C1 inhibitor deficiency or dysfunction, leading to increased prekallikrein activity and bradykinin production. HAE causes vasodilation and edema resulting in obstruction of the upper airway, gastrointestinal symptoms, and skin swelling. Evidence of involvement of other organ systems has been sparse. Herein, we demonstrate evidence of creatinine kinase (CK) elevation in HAE patients suggesting an effect of bradykinin on skeletal muscle with subsequent improvement with long term prophylaxis (LTP). Methods: CK levels from participants with type 1 or 2 HAE enrolled in the Phase 2 and 3 clinical trials evaluating the safety and efficacy of donidalorsen for LTP in patients with HAE, was measured at baseline (before treatment initiation) and Week 17 (for participants enrolled in Phase 2 Study) and Week 25 (for participants enrolled in Phase 3 study). Mixed effect model with repeated measures was used to assess the influence of time and treatment (donidalorsen vs. placebo) on serum CK levels. Results: CK levels were available from 20 patients enrolled in the Phase 2 study and the mean CK level was numerically lower by Week 17; however, these results were not statistically significant. Among the 90 participants enrolled in the Phase 3 study who had CK levels checked at baseline and Week 25, a significantly lower CK level at Week 25 was observed among those receiving Q4W donidalorsen, but not among those receiving donidalorsen Q8W or placebo. Conclusion: Bradykinin appears to cause instability of skeletal muscle, causing CK release with even minor exercise. The effect of increases in bradykinin in HAE on muscle needs further research but may account for some of the atypical HAE symptoms patients often describe and which are noted in quality-of-life assessments. LTP, therefore, may confer additional benefits beyond reduction of HAE symptoms, potentially contributing to stabilization of skeletal muscle and improvement of fatigue and weakness.