Orally Administered Berotralstat in the Prevention of Hereditary Angioedema Attacks

HAE and its treatment options

Hereditary angioedema is an autosomal dominant hereditary disease characterized by a deficiency of the C1 inhibitor due to mutations in the SERPING1 gene. Reduced functional levels of the C1 inhibitor lead to excessive production of bradykinin in patients, which is responsible for the development of soft tissue edema.

HAE is a rare disease manifested by recurrent subcutaneous and mucosal angioedema. Angioedema attacks significantly reduce the quality of life of patients, increase morbidity, and in the case of laryngeal edema, represent a life-threatening condition.

Therapeutic options for hereditary angioedema have significantly progressed in recent decades. A drawback of previously available medications was the requirement for parenteral administration. A promising new treatment in this regard is berotralstat. It is a highly specific oral kallikrein protease inhibitor, which releases bradykinin from binding to plasma proteins. With a favorable pharmacokinetic profile, berotralstat can be administered once daily. The APeX-2 clinical trial evaluated the efficacy and safety of two dosing regimens of this medication compared to placebo in patients with HAE aged 12 years and older.

Study methodology and objectives

This randomized, double-blind, placebo-controlled phase III clinical trial included patients from 40 centers in 11 countries. Inclusion criteria were age ≥ 12 years (United States, Canada) or ≥ 18 years (European Union) and a confirmed HAE attack during the study's entry prospective period. Patients were evenly randomized to receive berotralstat at a dose of 110 or 150 mg once daily, or placebo.

The primary objective of the study was to evaluate the rate of confirmed HAE attacks during the 24-week treatment period. Secondary objectives included assessing the safety profile of the therapy.

Results 

A total of 121 patients were randomized to treatment, with 120 receiving at least one dose of the study drug (41 in the 110 mg berotralstat group, 40 in the 150 mg berotralstat group, and 39 in the placebo group). The majority of the study participants were women. At study entry, patients experienced an average of about 3 attacks per month across all treatment groups. Some participants did not complete the study, but average compliance in all groups was high (≥ 97%).

Administration of berotralstat showed a significant reduction in attack rates compared to placebo (1.65 attacks per month with 110 mg berotralstat, p = 0.024; 1.31 attacks per month with 150 mg berotralstat, p < 0.001; 2.35 attacks per month in the placebo group). Reduction in the average attack rate was observed as early as the first month of therapy and persisted throughout the 24-week treatment period.

In participants randomized to the higher dose of the drug, significant reduction in attack rates compared to placebo was observed in patients with ≥ 2 attacks per month as well as those with < 2 attacks per month (stratified based on the study entry period). Administration of the lower dose of berotralstat achieved a statistically significant reduction in attack rates only among patients with ≥ 2 attacks per month. Both groups achieved a statistically significant reduction in the rate of confirmed attacks requiring standard on-demand therapy.

A similar proportion of patients in all groups experienced at least one treatment-related adverse event (83% with the lower dose, 85% with the higher dose, 77% with placebo). Treatment-related adverse events more commonly associated with berotralstat included abdominal pain, vomiting, diarrhea, and back pain. Gastrointestinal symptoms were mostly transient and classified as grade 1 or 2 in intensity. They occurred primarily during the first month of therapy. No serious treatment-related adverse events were observed during the study.

Conclusion

The study results indicated that administering berotralstat at doses of 110 and 150 mg provides an effective and safe approach to preventing attacks in patients with hereditary angioedema. A slightly more favorable benefit-risk ratio was observed with the higher dose. The significant advantage of this medication is its oral administration and, thanks to its favorable pharmacokinetic profile, its once-daily dosing.

(holi)

Source: Zuraw B., Lumry W. R., Johnston D. T. et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol 2021; 148 (1): 164–172.e9, doi: 10.1016/j.jaci.2020.10.015.