D1.377 - Berotralstat effectively controls a type 2 Hereditary Angioedema patient, refractory to other long-term prophylaxis treatments – Case report

Background: Hereditary angioedema (HAE) is a rare, potentially life-threatening, genetic disorder characterized by recurrent swelling of subcutaneous/submucosal tissues. In type 2 HAE, the C1 esterase inhibitor (C1-INH) protein is functionally impaired, leading to dysregulated plasma kallikrein activity and uncontrolled production of bradykinin, a potent vasodilator.

Innovative therapies target plasma kallikrein to block this pathway and provide long-term prophylaxis (LTP).

Case Report: We present the case of a 47-year-old woman with type 2 HEA (functional C1-INH of 2-15%). She presented in 2012 with recurrent angioedema of the face, hands, arms, legs, feet and, most frequently, of the tongue and upper airway.

She began LTP with danazol 400mg/day, substituted during pregnancy and breastfeeding by C1-INH concentrate. Despite good symptom control with the androgen, important side-effects included significant increase of cholesterol, triglycerides and liver enzymes. A tapering of danazol to 100mg/day resulted in a restart of weekly angioedema episodes.

Danazol was stopped and, due to a new pregnancy, C1-INH concentrate was restarted. After breastfeeding ended, danatrol 200mg/day was tried. Good control was achieved, with only minor episodes of peripheral angioedema occurring, but Danatrol was stopped due to significant cholesterol increase.

A change was made to tranexamic acid 500mg/day in 2021. It was only effective in reducing the intensity of the exacerbations. However, in 2023, the frequency and intensity of the exacerbations increased. Weekly episodes of upper airway angioedema occurred, with need for icatibant as rescue medication.

In 2023, Lanadelumab 300mg every 2 weeks was initiated, with no response. Tranexamic acid 500mg/day was added to Lanadelumab and control of upper airway angioedema was achieved, but peripheral episodes still occurred.

A change was made back to C1-INH concentrate 2500U/week.

In 2024, berotralstat 150mg/day was started, and complete symptom control was achieved.

Comparison of AECT scores showed: 9 (androgens), 11 (C1-INH), 6 (Lanadelumab), 15 (berotralstat). For AE-QoL scores: 6% (androgens), 9% (C1-INH), 9% (Lanadelumab), 4% (berotralstat).

Conclusion: In this patient, berotralstat achieved the best control and quality of life of all LTP treatments. Even though Lanadelumab and berotralstat both inhibit plasma kallikrein, they do so in different ways. In face of a Lanadelumab failure, Berotralstat may be a valuable alternative.