EMA to Review Berotralstat as Preventive Treatment for HAE Swelling Attacks

The European Medicines Agency has validated BioCryst Pharmaceuticals‘ application requesting the approval of berotralstat as a once-daily oral treatment to prevent swelling attacks in people with hereditary angioedema (HAE).

The Committee for Medicinal Products for Human Use, an advisory committee for the European Union’s regulatory agency, will now review the company’s marketing authorization application, and recommend whether or not the European Commission should approve the treatment. An opinion is expected within the next 12 months.

Similar applications have also been filed in the U.S. and Japan. The U.S. Food and Drug Administration is expected to make a decision by Dec. 3, and a decision by Japanese regulators is anticipated in the second half of 2020.

“Berotralstat would represent the first targeted oral therapy approved for HAE prophylaxis in Europe, and would deliver a major advance in therapy to HAE patients,” Jon Stonehouse, CEO of BioCryst, said in a press release.

Berotralstat (BCX7353) is an oral, small molecule that blocks plasma kallikrein, a precursor of bradykinin — an inflammatory molecule produced in excess in HAE patients, leading to swelling and pain. By suppressing plasma kallikrein, berotralstat is thought to lower bradykinin levels, potentially treating and preventing angioedema attacks.

The recent application was based on positive data from two clinical trials — the APeX-2 Phase 3 trial (NCT03485911) and the APeX-S Phase 2/3 trial (NCT03472040) — which are evaluating berotralstat’s safety and its ability to prevent HAE attacks in patients with type 1 or type 2 HAE (those who lack a normal C1 inhibitor protein).

APeX-2 data showed that treatment with berotralstat significantly reduced HAE attacks over 24 weeks — by 30% with the low dose (110 mg berotralstat), and by 44.2% with the high dose (150 mg berotralstat), compared with a placebo.

Also, about 22.5% of patients on berotralstat achieved a 90% or greater reduction in their attack rate compared to the study’s start.

Berotralstat also appeared to lessen the severity of the swelling episodes, as people taking the preventive treatment experienced significant reductions in the rate of attacks needing treatment with standard-of-care medication — a 36.9% reduction with the low dose, and a 49.2% drop with the high dose, compared to placebo.

Patients who completed the first, placebo-controlled part of APeX-2 continued to its 24-week extension phase, where all (including those previously on placebo) received one of the therapy’s two doses.

Results from this part showed that berotralstat induced a rapid and sustained decrease in attack frequency over 48 weeks (nearly one year). Those who received 150 mg of berotralstat saw their attack rate drop from a mean of 2.9 attacks per month to one attack per month after one year of treatment. Also, those who switched from a placebo to 150 mg of berotralstat saw their attack rate decline to less than one per month (mean of 0.4) at the end of the 12 months.

Berotralstat’s benefits for the prevention of swelling episodes was further confirmed in APeX-S, an open-label study evaluating the therapy’s long-term safety and efficacy. During the study’s 12 months, the majority of patients receiving 150 mg of berotralstat remained attack-free for at least six months.

A joint safety analysis of APeX-2 and APeX-S, comprising a total of 342 patients, showed that berotralstat was generally well-tolerated, with no new safety findings.