Orladeyo Approved in Japan to Prevent Swelling Attacks Due to HAE

Japan’s Ministry of Health, Labor and Welfare (MHLW) has approved oral Orladeyo (berotralstat), at a daily dose of 150 mg, to prevent hereditary angioedema (HAE) attacks in individuals ages 12 and up.

According to the therapy’s developer, BioCryst Pharmaceuticals, Orladeyo is the first prophylactic, or preventive, HAE medication approved in Japan. It will be marketed there by Biocryst’s partner, Torii Pharmaceutical, which plans to launch the medication after pricing negotiations with the Japanese National Health Insurance System (NHI) are completed.

“Until now, HAE patients in Japan had no therapies approved to prevent attacks, so the approval of Orladeyo marks a significant advance in HAE treatment,” Goichi Matsuda, president of Torii, said in a press release. “We are pleased to have the opportunity to bring the first oral treatment option to Japanese HAE patients and are actively preparing for the commercialization.”

Orladeyo is a small molecule that blocks plasma kallikrein, a precursor of bradykinin — an inflammatory molecule produced in excess in HAE patients, leading to sudden and recurrent swelling episodes. By suppressing plasma kallikrein, the medication is expected to lower bradykinin levels, helping to treat and prevent angioedema attacks.

The medication was approved in the U.S. late last year. BioCryst is also seeking approval in the EU; a decision is expected by mid-year.

BioCryst applied for approval of Orladeyo in Japan early last year. The medication had both orphan drug and sakigake designations in that country, which aim to facilitate its development.

MHLW approval was based on results from two similar Phase 3 clinical trials sponsored by BioCryst: APeX-J (NCT03873116) and APeX-2 (NCT03485911). APeX-J took place in Japan, while APeX-2 was conducted in North America and Europe.

Both enrolled children and adults, ages 12 and above, with type 1 or type 2 HAE — meaning their disease was caused by mutations that lower the levels or activity of the C1 inhibitor protein.

Those enrolled had at least two confirmed HAE attacks in the two months leading up to the trial. All were randomized to treatment with Orladeyo at one of two doses (110 mg or 150 mg), or to a placebo, given orally once each day.

Previously reported results from APeX-2, which enrolled 121 people, showed that treatment at the 150 mg dose lowered the frequency of HAE attacks significantly compared with placebo — by 44% after 24 weeks (about six months).

Results from APeX-J were recently published in Allergy. This trial enrolled 19 people, 18 of whom completed the 24-week study — one placebo group participant left due to adverse events.

“The efficacy and safety data from the APeX-J trial are consistent with the results of the global phase 3 APeX-2 study,” the researchers wrote.

Specifically, after 24 weeks in APeX-J, daily treatment with 150 mg of Orladeyo was found to lower the rate of HAE attacks by 49% — from 2.3 to 1.11 attacks per month, on average. The lower dose, given to six patients, also decreased attack rates compared with placebo, though the difference here was not statistically significant.

Among the seven patients treated at 150 mg, over half (57%) had a decrease in attack frequency of 50% or more, and nearly a third (29%) had a decrease of 70% or more. No one given placebo showed similar decreases in attack frequency.

Treatment with Orladeyo was also associated with more symptom-free days, fewer attacks that required treatment, and improvements to quality of life. Not all differences were statistically significant, and the researchers noted that the trial’s statistical power to find such differences was limited by its small size.

The most common adverse events (side effects) associated with Orladeyo in APeX-J included nasopharyngitis (the common cold), cough, abdominal pain, diarrhea, and fever. No serious side effects were reported among Orladeyo-treated participants.

“Overall, this study supports the use of oral berotralstat [Orladeyo] 150 mg once daily as an effective prophylactic treatment for the prevention of angioedema attacks in patients with HAE in Japan,” the researchers concluded.

APeX-J is continuing to collect data through 52 weeks (about a year) of treatment. An open-label extension study, APeX-S trial (NCT03472040), which is enrolling individuals who completed earlier Orladeyo trials or are recommended by a study investigator in select countries, is assessing the treatment’s long-term safety and efficacy.

“Today’s approval of Orladeyo in Japan represents important progress towards our goal to bring an oral, once-daily treatment to HAE patients around the world,” said Jon Stonehouse, president and CEO of BioCryst.

“Thank you to the HAE patients who participated in our APeX-J trial, to the investigators who conducted it, and to Torii and OrphanPacific [BioCryst’s representative partner in Japan] for their partnership to achieve this milestone to offer a much-needed new treatment option to HAE patients and physicians in Japan,” Stonehouse added.