Orladeyo (berotralstat) for hereditary angioedema

 

What is Orladeyo for hereditary angioedema?

Orladeyo (berotralstat) is an approved oral therapy used for the prevention of swelling attacks in adults and adolescents with hereditary angioedema (HAE).

It was developed and is marketed by BioCryst Pharmaceuticals.

Therapy snapshot

Brand name:	Orladeyo
Chemical name:	Berotralstat
Usage:	Prevention of swelling attacks in people with hereditary angioedema
Administration:	Oral capsules

 

How does Orladeyo work?

HAE is caused by genetic mutations that generally lead to the overproduction of bradykinin, a molecule that regulates blood pressure and inflammation by causing blood vessels to dilate, or expand. Its excess can cause blood vessels to widen too much, allowing fluid to leak to nearby tissues, which leads to the sudden swelling attacks that characterize HAE.

Orladeyo works by suppressing kallikrein, an enzyme needed to generate bradykinin from its precursor molecules. By inhibiting kallikrein, the medication lowers bradykinin production, thereby preventing swelling attacks.

Who can take Orladeyo?

Orladeyo was approved by the U.S. Food and Drug Administration in December 2020 as a prophylactic (preventive) therapy to reduce the frequency of swelling attacks in HAE patients, ages 12 and older. With that decision, Orladeyo became the first and only oral therapy to be approved to prevent HAE attacks.

Similar approvals were granted in the European Union, U.K., and Japan in 2021. Orladeyo has since been approved for adults and adolescents in several other countries around the globe, including Canada, Switzerland, Israel, Saudi Arabia, Argentina, and Chile.

Who should not take Orladeyo?

Orladeyo’s prescribing information lists no contraindications. However, the medication is not indicated for the on-demand treatment of acute HAE attacks.

How is Orladeyo administered?

Orladeyo is available in the form of oral capsules that come in two dosage strengths:

• 150 mg capsules with a white opaque body with a black imprint “150” and a light blue opaque cap imprinted with “BCX”
• 110 mg capsules with a light blue opaque body and cap and a white imprint “110” on the body and “BCX” imprinted on the cap.

The recommended dose is a single 150 mg capsule, taken once daily with food. That dosage should not be exceeded, as that may cause patients to develop heart rhythm abnormalities.

The lower-dose capsules (110 mg) may be used in certain cases where dose adjustments are needed, including for patients with moderate to severe liver impairments or for those experiencing persistent gastrointestinal side effects when given the higher dose.

Orladeyo in clinical trials

Orladeyo’s approvals for hereditary angioedema were mainly supported by data from an international Phase 3 clinical trial called APeX-2 (NCT03485911).

APeX-2 trial

APeX-2 evaluated Orladeyo’s safety and efficacy against a placebo in 120 people with HAE types 1 or 2, ages 12 and older, who were recruited at sites in the U.S. and Europe. All participants had experienced at least two confirmed HAE attacks during an eight week run-in period before the trial.

APeX-2 consisted of three parts. In Part 1, participants were randomly assigned to a daily capsule of Orladeyo (110 or 150 mg), or a placebo, for 24 weeks (about six months). In Part 2, participants on Orladeyo continued at their assigned dose, and those on a placebo were randomly assigned to one of the two Orladeyo doses for another 24 weeks. Finally, in Part 3, all participants received Orladeyo at its approved 150 mg dose for up to another year.

Results from the trial’s first part showed both Orladeyo doses met the trial’s main goal of significantly lowering the frequency of angioedema attacks compared with a placebo, although greater reductions were observed with the higher dose.

Among patients treated at that dose, there was a 44% reduction in monthly attack rates relative to placebo after six months, and that reduction became evident within the first month of treatment. Half of the patients receiving 150 mg of Orladeyo experienced at least a 70% reduction in attack rates after six months, compared with 15% of those in the placebo group. These patients also experienced a significant, 54% reduction in the need for rescue medications compared with a placebo.

In Part 2, the benefits of Orladeyo continued to be observed for up to 48 weeks, or nearly one year. Patients who switched to Orladeyo from the placebo saw drops in their attack rates in a magnitude similar to that observed in Part 1, while patients originally assigned to Orladeyo experienced further declines. These reductions were accompanied by life quality improvements.

Again in Part 3, attack rate reductions were sustained, with an overall 86% reduction in HAE attack rates observed after 96 weeks (nearly two years) of treatment among patients who received the higher dose of Orladeyo for the entire trial. Reductions were observed regardless of patients’ initial responses at the start of the trial. Quality of life improvements also were observed after 96 weeks on treatment, with patients reporting reduced impairments associated with HAE in their day-to-day life.

APeX-J trial

Data from a similarly designed Phase 3 clinical trial, called APeX-J (NCT03873116), supported Orladeyo’s approval in Japan. APeX-J recruited 19 HAE patients, ages 12 and older, at 10 sites in Japan.

As in APeX-2, six months of treatment with the higher dose of Orladeyo significantly lowered HAE attack frequency by 49% compared with a placebo. Attack rates fell by 50% or more in more than half of these individuals (57%), and by at least 70% in nearly a third (29%), while zero patients on placebo achieved such reductions.

Data from subsequent portions of the trial showed long-term treatment with Orladeyo continued to effectively reduce swelling attacks and improve patient-reported outcomes, with no new safety concerns being identified.

APeX-S trial

Eligible patients who completed previous Orladeyo trials were given the option to enter the Phase 2/3 APEX-S open-label extension trial (NCT03472040), wherein the therapy’s long-term safety and efficacy was monitored. In some countries, patients not included in earlier trials could enroll if a study investigator deemed they could benefit from the therapy.

Patients initially received Orladeyo at a dose of either 110 or 150 mg, but when the superior efficacy of 150 mg was confirmed, all switched to the higher dose. Patients always treated with the higher dose of Orladeyo experienced significant reductions in attack rates over a period of 96 weeks, with median attack rates of zero for most of the trial. These benefits were observed regardless of patients’ age, sex, or prior use of prophylactic therapies.

Ongoing trials

An open-label Phase 3 clinical trial called APeX-P (NCT05453968) is testing the safety and pharmacological properties of Orladeyo oral granules in up to 30 pediatric HAE patients, age 2-11. Its goal is to establish the appropriate dose of Orladeyo in this patient population, with an expected completion in 2027.

Another ongoing open-label Phase 3b trial called APeX-A (NCT04933721) is monitoring the long-term safety of daily Orladeyo in HAE patients who participated in previous clinical trials. It is designed to enable access to the therapy for patients in countries where Orladeyo has not yet become commercially available.

Common side effects of Orladeyo

The most common side effects associated with Orladeyo include:

• abdominal pain
• vomiting
• diarrhea
• back pain
• gastroesophageal reflux disease, or acid reflux.

Heart rhythm abnormalities

Doses of Orladeyo above what is recommended — 150 mg once daily — can lead to a type of heart rhythm abnormality referred to as QT prolongation. Patients should not use Orladeyo at higher doses, and should not take additional doses of the medication during acute HAE attacks.

Use in pregnancy and breastfeeding

It is not known whether Orladeyo is safe for use during pregnancy. In animal studies, there was no evidence of fetal harm with Orladeyo when used at doses higher than the recommended maximum dose in humans. Patients who are pregnant or may become pregnant while using Orladeyo should discuss the matter with their healthcare providers.

It also is not known if Orladeyo passes into human breast milk, but low levels of the therapy were found in breast milk during animal studies. The mother’s clinical need for Orladeyo, along with the potential risks to the infant, should be considered by patients and their doctors when deciding if the therapy should be used during breastfeeding.

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