Journal of Asthma and Allergy (Mar 2023)
A Review of Randomized Controlled Trials of Hereditary Angioedema Long-Term Prophylaxis with C1 Inhibitor Replacement Therapy: Alleviation of Disease Symptoms Is Achievable
Abstract
Hilary J Longhurst,1,* Anna Valerieva2,* 1Department of Medicine, University of Auckland and Department of Immunology, Auckland City Hospital, Auckland, New Zealand; 2Department of Allergology, Medical University of Sofia, Sofia, Bulgaria*These authors contributed equally to this workCorrespondence: Hilary J Longhurst, Department of Immunology, Auckland City Hospital, 2 Park Road, Grafton, Auckland, 1023, New Zealand, Tel +64 (0)9 367 000 ext 22986/22971, Email [email protected]: Through its fluctuating disease activity and unpredictable attacks, hereditary angioedema (HAE) imposes a substantial patient burden. To minimize HAE burden and improve quality of life, treatment should involve individualized management strategies that address on-demand therapy and short-term/long-term prophylaxis. Goals of long-term prophylaxis include reducing the number, severity, and burden of HAE attacks. The best characterized forms of HAE arise from deficiency or dysfunction of C1-inhibitor (C1-INH; types I/II), and C1-INH replacement therapy is a first-line intervention for on-demand (acute) treatment of HAE attacks, short-term prophylaxis before high-risk procedures, and long-term prophylaxis. Randomized, double-blind, placebo-controlled crossover trials have shown dose-dependent efficacy with plasma-derived C1-INH (pdC1-INH) 40– 60 IU/kg subcutaneously, pdC1-INH 1000 U intravenously, and recombinant human C1-INH (rhC1-INH) 50 IU/kg (maximum 4200 IU) intravenously, all administered twice weekly, as long-term prophylaxis in patients with a history of 2 to ≥ 4 attacks/month. Overall, up to 83% (pdC1-INH 60 IU/kg) of patients experienced an HAE attack reduction threshold of ≥ 70%, and up to 58% (pdC1-INH 60 IU/kg) achieved an attack reduction threshold of ≥ 90%. Lower-dose intravenous pdC1-INH therapy (1000 U) was seemingly less effective, with 45% of 22 patients experiencing an HAE attack reduction threshold of ≥ 70%, and up to 23% achieving an attack reduction threshold of ≥ 90%. Higher-dose intravenous rhC1-INH 50 IU/kg (maximum, 4200 IU) twice weekly was of intermediate benefit. Despite a baseline mean attack frequency of 17.9 (during the 3 months prior to study treatment) and a mean attack frequency during a 4-week placebo period of 7.2, 52% of 23 patients experienced ≥ 70% reduction in attack frequency and 26% of 23 patients experienced ≥ 90% reduction in attack frequency. The increasing patient percentages treated with C1-INH replacement therapy as long-term prophylaxis meeting these high thresholds reinforces hopes and expectations that “attack freedom” is achievable, including for those with moderate or severe disease.Keywords: hereditary angioedema, complement C1 inhibitor protein, clinical trial design, clinical outcomes, prophylaxis
