Orladeyo (Berotralstat)

Orladeyo (berotralstat) is an oral 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 European Commission granted approval to Orladeyo for the same indication in April 2021, with a similar decision in the U.K. following soon after. Prior to these approvals, the therapy was available to eligible patients in France through a temporary authorization for use program, and in the U.K. under an early access to medicines scheme.

Regulators in Japan approved the therapy for patients 12 and older in January 2021, and added it to that country’s National Health Insurance System, making it available at low or no cost. Orladeyo will be marketed there by BioCryst’s partner, Torii Pharmaceutical.

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 body’s immune response, lead to the excessive production of bradykinin. This inflammatory mediator regulates blood pressure and inflammation by encouraging small blood vessels to dilate. Its excessive production can lead to sudden swelling and pain attacks.

Given as an oral capsule (150 mg) once a day, Orladeyo works by suppressing plasma kallikrein, a precursor of bradykinin, and preventing bradykinin levels from rising too high and triggering an attack.

Orladeyo in clinical trials

An international Phase 2 clinical trial (NCT02870972) evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and effectiveness of four doses of Orladeyo against a placebo in 75 adults with HAE. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body; pharmacokinetics assesses its effects in the body. The study, called APeX-1, aimed to assess the preventive potential of the medicine to reduce the frequency of HAE attacks. Results showed that Orladeyo was generally safe and led to a significant reduction (by more than 70%) in HAE attacks, compared with a placebo.

These positive findings prompted the launch of the international, Phase 3 APeX-2 trial (NCT03485911), which is evaluating Orladeyo’s safety and effectiveness in preventing angioedema attacks in 121 adults and adolescents, ages 12 and older, with HAE. Patients, who had at least two confirmed HAE attacks in the two months preceding enrollment, were recruited at sites in North America and Europe. Participants were randomly assigned to a daily capsule of either Orladeyo (110 or 150 mg) or a placebo for 24 weeks (nearly six months). All 108 participants completing treatment entered the trial’s extension phase, in which all received one of Orladeyo’s two doses for at least 24 weeks, totaling one year of treatment or longer for those initially assigned to the therapy.

Results showed that both doses met the trial’s main goal of significantly lowering the frequency of monthly angioedema attacks after six months, compared with a placebo. However, the higher dose (150 mg) showed the greatest benefits, reducing HAE attacks by 44%. These reductions were sustained at least until week 48, at which point patients on the higher dose had a mean of one attack per month, compared with 2.9 monthly attacks before starting treatment.

Orladeyo-treated patients also reported meaningful improvements in quality of life and overall satisfaction, in addition to needing significantly less standard-of-care treatment and experiencing more symptom-free days than those given a placebo. The trial is expected to finish in September 2023.

A similar Phase 3 trial, called APeX-J (NCT03873116), is being conducted in Japan and recruited 19 HAE patients, ages 12 and older. Similar to APeX-2 data, six months of treatment with the higher dose of Orladeyo was found to significantly lower HAE attack frequency by 49%. Attack rate fell by 50% or more in more than half of these individuals (57%), and by at least 70% in nearly a third (29%). The trial is collecting data through about a year of treatment, and is estimated to finish in June 2021.

Eligible patients who completed previous Orladeyo trials were also given the option to enter the Phase 2/3 APEX-S extension trial (NCT03472040), which is assessing the long-term safety and efficacy of the therapy, given at a daily dose of 150 mg, for up to two years. In select countries, patients who in the opinion of a study investigator could derive benefit from an oral preventive treatment for angioedema attacks, were also allowed to enroll.

The trial has recruited a total of 386 patients, and preliminary data showed that those completing about one year of treatment had a mean of 0.8 attacks per month. APEX-S is expected to end in February 2024.

A joint safety analysis of APeX-2 and APeX-S, involving a total of 342 patients, showed the therapy was generally well-tolerated, with no new safety concerns identified, and with the most common adverse events being gastrointestinal problems. These events generally occurred soon after treatment initiation, became less frequent over time, and typically resolved on their own.

Three doses of a liquid formulation of Orladeyo were also tested against a placebo in a completed international, proof-of-concept Phase 2 trial, called ZENITH-1 (NCT03240133), which recruited 58 HAE adult patients. Participants treated three attacks with Orladeyo (two attacks) or a placebo (one attack) in a random sequence and in a blinded way.

Results showed that a dose-response occurred for all doses, which were well-tolerated by patients. The higher dose tested (750 mg) was found to be most effective, lessening symptoms and attack severity as early as one hour after oral dosing and through 24 hours, compared with a placebo. Orladeyo-treated patients also showed a 31.6% reduction in standard-of-care medication use relative to those given a placebo.

Other information

Orladeyo received fast track designation in the U.S., orphan drug status in the EU, and Sakigake designation in Japan, all meant to speed its development and regulatory review.

The most common side effects of taking Orladeyo are abdominal pain, vomiting, diarrhea, back pain, and heartburn. The therapy also may affect heart rhythm.


Last updated: May 18, 2021


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