Berotralstat, also known as BCX7353, is an investigational therapy being developed by BioCryst Pharmaceuticals to prevent swelling attacks in people with hereditary angioedema (HAE).

BioCryst filed an application for berotralstat’s approval with the U.S. Food and Drug Administration (FDA) in December 2019.

BioCryst announced in November 2019 that it has licensed berotralstat to Torii Pharmaceuticals for commercialization in Japan.

The medicine is available in two formulations: an oral capsule as a preventive treatment to avoid angioedema attacks, and as an oral liquid for the treatment of acute HAE.

How berotralstat works

HAE is a rare inherited disease in which mutations in the C1 inhibitor, a protein involved in the immune response, lead to excessive production of bradykinin. This inflammatory mediator, or molecule, that promotes inflammation regulates blood pressure and inflammation by encouraging small blood vessels to dilate (widen). Excessive bradykinin leads to angioedema and pain.

Berotralstat is an oral antagonist of plasma kallikrein, a precursor of bradykinin. By inhibiting plasma kallikrein, berotralstat is thought to reduce the amount of bradykinin in HAE patients, potentially treating and preventing angioedema attacks.

Berotralstat in clinical trials

The effectiveness, safety, tolerability, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of berotralstat were first evaluated in a Phase 2 clinical trial (NCT02870972). The study, called APeX-1, aimed to assess the preventative potential of the medicine to reduce the frequency of attacks in people with HAE. The results of the trial, published in the scientific journal Annals of Allergy, Asthma & Immunology, showed that berotralstat was generally safe, well-tolerated, and associated with a significant reduction in HAE attacks.

APeX-2, a Phase 3, placebo-controlled trial (NCT03485911) evaluated the effectiveness and safety of berotralstat capsules in preventing acute angioedema attacks in patients with type 1 and type 2 HAE. The primary goal of the trial was to determine berotralstat’s ability to reduce the frequency of angioedema attacks after 24 weeks of treatment. The study recruited 121 patients and achieved its primary endpoint of reducing HAE attack rate in both tested dosages (110 mg and 150 mg). The 150 mg dosage reduced HAE attacks by 44% compared to placebo. No serious adverse events related to the drug were reported.

A Phase 2/3 extension trial, APeX-S (NCT03472040), will test the long-term clinical ability of berotralstat as a preventive treatment for HAE patients. Participants will receive one of two doses of berotralstat (110 mg or 150 mg) once a day for 48 weeks. The researchers then will assess the long-term safety and effectiveness of the treatment on patients’ quality of life, as well as the durability of any response.

The trial aims to enroll up to 160 patients in Austria, Denmark, the U.K., Germany, and Macedonia. Patients who already had participated in a previous berotralstat trial will have priority, followed by those who have never had berotralstat therapy.

Interim results of the APeX-S and APeX-2 study at 48 weeks, showed a continued decrease in HAE attack rates with no new safety concerns.

A Phase 3 trial (NCT03873116), called APeX-J, is underway in Japan. The study has completed recruitment of 24 participants who will be given 110 or 150 mg doses of berotralstat or placebo once a day. The number of HAE attacks will be monitored over a 24 month period. The study is expected to be completed in June 2020.

Based on the results of the APeX-2 and APeX-S studies, BioCryst submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) in December of 2019 seeking approval of the oral formulation of berotralstat for daily treatment to prevent HAE attacks.

ZENITH-1, a proof-of-concept Phase 2 clinical trial (NCT03240133), studied three doses of liquid berotralstat as a treatment for acute angioedema attacks in patients with HAE. Researchers evaluated the effectiveness of the different doses of berotralstat by assessing the patient-reported composite visual analog scale scores (a test for gauging pain intensity), patients’ global assessment, any change in symptoms, and the use of rescue medication. The trial tested 250, 500, and 750 mg oral suspensions of berotralstat versus placebo in 95 patients. The results showed a dose-response for the 3 drug concentrations. All 3 dosages were well tolerated and the 750 mg dose was found to improve HAE endpoints better than placebo and improvements were seen as early as 1 hour after treatment. BioCryst has stated that it plans to initiate a Phase 3 trial to further investigate the 750 mg oral suspension.


Last updated: Dec. 15, 2019.


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