Berotralstat Available to Eligible Patients in UK Through Early Access Program

Berotralstat — an oral therapy by BioCryst Pharmaceuticals for preventing swelling attacks in people with hereditary angioedema (HAE) — will be available to patients, 12 and older, in the U.K. through an Early Access to Medicines Scheme (EAMS) before its potential regulatory approval.

An EAMS gives patient access to therapies not yet approved for commercial use to people with life-threatening or seriously debilitating conditions and a clear unmet medical need.

“There are many patients in the U.K. that don’t have a realistic option for effective HAE prophylaxis [preventive treatment],” Sorena Kiani, MD, PhD, a consultant immunologist at Royal London Hospital, in London, said in a press release.

“The addition of berotralstat through the EAMS will bring a much needed option for HAE patients suffering with this debilitating disease,” he added.

The decision was based on a positive scientific opinion granted by the country’s Medicines and Healthcare Products Regulatory Agency (MHRA), which controls the EAMS process.

The opinion is designed to provide physicians and patients with information on the therapy’s benefit-risk balance based on available data, to help them decide on whether or not to use an unapproved treatment. The opinion stands for one year and can be renewed.

“HAE patients around the world are waiting for an oral, once-daily therapy to prevent attacks and reduce their burden of therapy,” said Jon Stonehouse, BioCryst’s CEO, noting that with this MHRA’s decision, “the wait for many HAE patients in the U.K. can end sooner.”

Berotralstat (BCX7353), given as an oral capsule once a day, is a 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, the therapy is thought to lower bradykinin levels, potentially treating and preventing angioedema attacks.

Berotralstat received fast track designation in the U.S., orphan drug status in Europe, and Sakigake designation in Japan — all meant to accelerate the therapy’s development and review.

The European Medicines Agency (EMA) is reviewing BioCryst’s application requesting the approval of berotralstat (to be marketed under the brand name Orladeyo) as a prophylactic for people with HAE. An opinion from EMA’s Committee for Medicinal Products for Human Use is expected by March 2021; its recommendations on a therapy’s approval are usually followed by the EMA.

Similar applications were also filed to regulatory agencies in other countries, including the U.S. and Japan. Decisions in both countries are expected this December.

The application to the EMA was based on positive data from two ongoing clinical trials — the placebo-controlled APeX-2 Phase 3 trial (NCT03485911) and the open-label APeX-S Phase 2/3 trial (NCT03472040).

Both are evaluating berotralstat’s safety and effectiveness at preventing HAE attacks in people, 12 and older, with type 1 or type 2 HAE (those who lack a normal C1 inhibitor protein).

In APeX-2, 121 patients were randomly assigned to receive a daily capsule of berotralstat (110 mg or 150 mg) or a placebo for 24 weeks (nearly six months).

Results showed that a greater proportion of berotralstat-treated participants (between 51% and 58%) experienced a 50% or greater drop in their rate of HAE attacks, compared with those given a placebo (25%).

In addition, participants receiving the higher dose of berotralstat were about six times more likely to have a 70% or greater reduction in attack rate than those on a placebo.

Compared with a placebo, berotralstat also appeared to lessen the severity of the swelling episodes by significantly dropping the rate of attacks needing standard treatment — by 36.9% with the lower dose and 49.2% with the higher dose.

All 108 participants who completed treatment entered the trial’s extension phase, in which all would receive one of berotralstat’s two doses for an additional 24 weeks at least.

Results from nearly a year of treatment (48 weeks) showed that berotralstat induced a rapid and sustained decrease in attack frequency over time.

Those receiving the therapy’s higher dose for the whole year showed a drop in their attack rate from a mean of 2.9 attacks per month to one attack per month, while those who switched from a placebo to the therapy’s higher dose saw their attack rate decline to less than one per month (mean of 0.4).

Also, among the 73 patients who completed nearly one year of treatment with the higher dose (150 mg), most remained attack-free for at least six months. Clinically meaningful improvements in patients’ quality of life were observed after four weeks of treatment and maintained up to 12 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 concerns identified.