Orladeyo (berotralstat) is a treatment developed by BioCryst Pharmaceuticals to prevent swelling attacks in people with hereditary angioedema (HAE).
The U.S. Food and Drug Administration approved Orladeyo in December 2020 for use in adults and children, ages 12 and older. The treatment also is available in the U.K. under an early access to medicines scheme.
BioCryst licensed Orladeyo to Torii Pharmaceuticals in 2019 for commercialization in Japan.
How does Orladeyo work?
HAE is a rare inherited disease in which defects in the C1 inhibitor, a protein that plays a role in the immune response, lead to excessive production of bradykinin. This inflammatory mediator regulates blood pressure and inflammation by encouraging small blood vessels to dilate. Excessive bradykinin leads to angioedema and pain.
Orladeyo is an oral antagonist of plasma kallikrein, a precursor of bradykinin. Researchers think that Orladeyo treats and prevents angioedema attacks by inhibiting plasma kallikrein and reducing the amount of bradykinin.
Orladeyo in clinical trials
A Phase 2 clinical trial (NCT02870972) evaluated the effectiveness, safety, tolerability, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of Orladeyo in 75 patients with HAE. The study, called APeX-1, aimed to assess the preventive potential of the medicine to reduce the frequency of attacks.
The results, which appeared in the journal Annals of Allergy, Asthma & Immunology, showed that Orladeyo 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 Orladeyo capsules in preventing acute angioedema attacks in patients with HAE. The study enrolled 121 patients.
Its primary goal was to determine Orladeyo’s ability to reduce the frequency of angioedema attacks after 24 weeks (nearly six months) of treatment. It achieved that endpoint in both dosages that researchers tested: 110 mg and 150 mg. The researchers found that the 150 mg dose reduced HAE attacks by 44% compared with a placebo. No serious adverse events related to the treatment were reported. The results were published in the Journal of Allergy and Clinical Immunology,
Three doses of liquid Orladeyo also were studied in a proof-of-concept Phase 2 clinical trial (NCT03240133), called ZENITH-1, as a treatment for acute angioedema attacks in HAE patients. The effectiveness of the different doses of Orladeyo was evaluated by assessing the patient-reported composite visual analog scale scores — a test for gauging pain intensity — as well as the participants’ global assessments, any change in symptoms, and the use of rescue medications. The trial tested 250 mg, 500 mg, and 750 mg oral suspensions of Orladeyo versus a placebo in 95 patients.
A dose-response occurred for all of the concentrations, and patients tolerated each of the three dosages well. The single 750 mg dose was found to be most effective, improving HAE endpoints better than the placebo, with improvements as early as one hour after treatment, according to the company.
BioCryst has stated that it plans to initiate a Phase 3 trial to further investigate the 750 mg oral suspension.
Ongoing clinical trials
A Phase 2/3 extension trial, APeX-S (NCT03472040) is testing the long-term effect of Orladeyo. Participants receive one of two doses of Orladeyo — 110 mg or 150 mg — once a day for 48 weeks. Researchers are assessing the long-term safety and effectiveness of the treatment on patients’ quality of life. They also will evaluate the durability of any response.
APeX-J, a Phase 3 trial (NCT03873116), is currently underway in Japan, with recruitment completed. The 24 participants receive 110 or 150 mg doses of Orladeyo or a placebo once a day. The number of HAE attacks are be monitored over a 24-month (two year) period, and the trial is expected to be completed in June 2021.
BioCryst submitted applications for Orladeyo’s approval in Japan in February 2020 and in the EU in April 2020. The company expected to hear back from Japan’s Pharmaceutical and Medical Devices Agency in December 2020, but that date was pushed back to January 2021.
Meanwhile, an opinion from the EU’s Committee for medicinal products for human use is expected in March 2021.
The treatment received fast track designation in the U.S., orphan drug status in the EU, and Sakigake designation in Japan. These designations will all speed up the therapy’s regulatory review in that country.
The most common side effects of taking Orladeyo are abdominal pain, vomiting, diarrhea, back pain, and heartburn. Orladeyo also may cause problems with heart rhythm.
Last updated: Jan. 11, 2020
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