FDA Agrees to Review Berotralstat as Preventive Treatment for HAE Attacks

The U.S. Food and Drug Administration (FDA) agreed to review BioCryst Pharmaceuticals‘ application requesting approval of oral berotralstat as a once-daily treatment to prevent swelling attacks in people with hereditary angioedema (HAE).

ByoCryst submitted the new drug application (NDA) to the FDA in December 2019, and the agency has set a Prescription Drug User Fee Act action date for Dec. 3, meaning that a decision is due by then.

“HAE patients and their physicians tell us they have been waiting for a once-daily oral therapy to prevent attacks, and the acceptance of our submission, with a PDUFA date this year, means their wait is nearly over,” BioCryst CEO Jon Stonehouse said in a press release.

“We are sharply focused on building out a very experienced commercial team and executing our commercial plan, so we are ready to go fast when we get approval,” he said.

HAE patients produce too much of an inflammatory molecule called bradykinin, causing blood vessels to dilate and leading to episodes of swelling and pain.

Berotralstat is an oral inhibitor of plasma kallikrein, a precursor of bradykinin, and is expected to treat or prevent angioedema attacks by lowering the amount of bradykinin in people with HAE.

Berotralstat is being developed in two formulations: an oral capsule to prevent angioedema attacks, and an oral liquid for the treatment of acute HAE attacks.

The recent application was based on data from two ongoing 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.

APEX-2 enrolled 121 patients with type 1 or 2 HAE and tested two oral doses of berotralstat against a placebo. Initially, 41 patients received the lower (110 mg) dose, 40 the higher, 150 mg dose, and 40 others were on placebo. All were given as once-daily capsules for 24 weeks.

All 108 patients who completed treatment continued into the trial’s ongoing 48-week extension phase, where those previously on placebo continued to receive one of the therapy’s two doses.

The results showed that patients on berotralstat experienced a rapid and sustained drop in attack frequency over 48 weeks.

Among the 30 patients who completed 48 weeks of treatment with the therapy’s 150 mg dose, the monthly attack rate dropped from a mean of 2.9 to 1.4 after one month of treatment. Within a year of therapy, the mean number of attacks reached one per month.

Among those who switched from placebo to 150 mg of berotralstat at week 24, the frequency of attacks fell to a mean of 0.4 a month at the end of 12 months of therapy.

Results from APeX-S, an open-label study evaluating the agent’s long-term safety and efficacy, confirmed berotralstat’s effectiveness at preventing HAE flares. In that trial, most of the 73 patients who completed 48 weeks on 150 mg berotralstat remained attack-free for six of the study’s 12 months.

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

Common cold was the most common side effect, occurring in the treated as often as in the placebo group. Gastrointestinal events led 3% of patients on berotralstat to leave the study. Serious adverse events related to treatment occurred in three people (0.9%) and resolved after stopping berotralstat.

BioCryst is also seeking the approval of oral berotralstat in Japan, based on findings from APEX-2 and another Phase 3 trial – APeX-J (NCT03873116) – conducted in Japan.