Richard Glen Gower

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable localized episodes of edema, which is frequently managed with long-term prophylactic medications. Until recently, long-term prophylaxis has predominantly required regular intravenous or subcutaneous administration, however the recent approval of berotralstat (Orladeyo™) offers an orally administered prophylactic which may be associated with a lower burden of treatment compared to injectable options for some patients.Case presentation: This report describes four participants in the APeX-S trial who transitioned from subcutaneously administered lanadelumab (Takhzyro^®) to daily oral berotralstat for long-term HAE prophylaxis. Lanadelumab dosing continued after berotralstat commencement in all patients and was tapered before discontinuation in three of the four patients. No substantial increases in HAE attack rates were observed after the transition to berotralstat monotherapy. One patient experienced a treatment-related adverse event (dyspepsia), which was mild and self-resolving.Conclusions: All four patients described in this case series successfully transitioned from lanadelumab to berotralstat monotherapy for long-term prophylaxis without significant complications and without the use of a complex transition protocol. The decision to transition to berotralstat monotherapy and how the transition should be achieved was discussed between patient and physician, ensuring that the comfort and perspectives of the patients were considered during the treatment transition. This report highlights the importance of individualization of HAE management plans to address both the disease and treatment burdens of HAE, and thus to provide the best possible quality of life for each patient.

Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, –2.42 attacks per month; 95% confidence interval [CI], –3.38 to –1.46; and mean difference with 60 IU, –3.51 attacks per month; 95% CI, –4.21 to –2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10, and ClinicalTrials.gov number, NCT01912456.)

Background: Human plasma‐derived nanofiltered C1 esterase inhibitor (C1 INH‐nf) is used to treat acute angioedema attacks in patients with hereditary angioedema (HAE), but data regarding use in children are sparse.Methods: Patients 2 to 25 kg). Each weight category included 2 dosing levels: C1 INH‐nf (500 units [U], 1000 U) and C1 INH‐nf (1000 U, 1500 U), respectively. Patients experiencing an angioedema attack were given a single intravenous dose. Primary efficacy end‐point was the onset of unequivocal relief of the defining symptom within 4 h following initiation of C1 INH‐nf treatment.Results: Nine children were treated: 3 (10–25 kg) received 500 U; 3 (>25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. The lower weight/higher dose category (10–25 kg, 1000 U) was not successfully enrolled. All patients completed the study. Most angioedema attacks (n = 5) were abdominal. All patients met the primary end‐point; median time to unequivocal symptom relief was 0.5 (range: 0.25–2.5) h. Doses of C1 INH‐nf ranged from 20.8 to 51.9 U/kg.Conclusions: Treatment of a single angioedema attack with C1 INH‐nf doses of 500 U (in patients 10–25 kg), 1000 U, and 1500 U (in patients >25 kg) were well tolerated. Doses of C1 INH‐nf <1000 U may be appropriate in some pediatric patients.