A Review of Randomized Controlled Trials of Hereditary Angioedema Long-Term Prophylaxis with C1 Inhibitor Replacement Therapy: Alleviation of Disease Symptoms Is Achievable

Abstract

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, shortterm 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%. Higherdose 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.

Letter in reply: network meta-analysis for indirect comparison of lanadelumab and for the treatment of hereditary angioedema

“…There is limited literature reporting on prognostic factors in HAE. A search in Pubmed ( https://pubmed.ncbi.nlm.nih.gov/ ) identified two studies reporting on prognostic factors (Banerji et al [ 5 ], Sundler Björkman et al [ 6 ]), as well as three studies reporting on confounders (Longhurst et al [ 7 ], Giacomini et al [ 8 ], Wang et al [ 9 ]). A study protocol published by the Paul Ehrlich Institute (by CENTOGENE AG 2020 [ 10 ]) reported on which variables were adjusted for in the statistical analysis.…”

“…In Longhurst et al [ 7 ], differences in route of administration and in baseline attack frequency are mentioned as confounders. The CENTOGENE AG study protocol [ 10 ] describes using statistical analysis such as Poisson regression adjusting for differences in follow-up duration, and potential confounders age, sex and number of attacks per year on standard therapy.…”

Androgen transition and management of hereditary angioedema long-term prophylaxis in real life: a single-center case series

“…Today, for adults, first-line LTP agents include pdC1-INH, lanadelumab and berotralstat; others include attenuated androgens (AAs) and tranexamic acid [ 10 ]. Lanadelumab, administered subcutaneously, and pdC1-INH, available in subcutaneous or intravenous formulations, are effective methods of LTP [ 11 , 12 ]. However, some patients and caregivers find injectable prophylactic treatments burdensome [ 5 , 13 ].…”

Lanadelumab demonstrates high efficacy in reducing the frequency of angioedema attacks in patients with severe HAE in real-life settings

“…They can still be life-threatening, unpredictable, and debilitating, significantly reducing patients' quality of life. This is why in recent years so much attention has been paid to long-term prophylaxis, where the goal is to achieve full control of HAE attacks and normalisation of patients' lives (7) . It has a significant impact not only on improving the quality of life, but also patients' safety.…”