Also, more patients receiving the prophylactic, or preventive, treatment remained without an attack during the study’s four-week duration.
The study, “Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema,” was published in The New England Journal of Medicine.
Hereditary angioedema, caused by a deficiency in the C1-inhibitor protein, is marked by recurrent episodes of swelling, which can be painful and life-threatening if the airways are involved.
If lacking (in HAE type 1) or functioning abnormally (HAE type 2), patients experience episodes of swelling due to the excessive production of a pro-inflammatory protein fragment called bradykinin.
BioCryst Pharmaceuticals developed BCX7353 to inhibit kallikrein, a precursor of bradykinin, which was expected to reduce angioedema attacks.
To determine if BCX7353 could prevent angioedema attacks in patients with HAE types 1 or 2, the company designed the APeX-1 Phase 2 trial (NCT02870972), where patients received daily BCX7353 — 62.5 mg, 125 mg, 250 mg, or 350 mg — or a placebo for 28 days.
The trial included 77 patients who were not receiving any other preventive treatments for angioedema. Additional assessments included adverse events and measures of quality of life.
The 125 mg dose yielded the best results, reducing the rate of angioedema attacks by 73.8% compared to placebo. And while 43% of patients receiving this dose remained attack-free for the 28 days of the trial, only 9% of those receiving a placebo did.
The 250 mg and 350 mg doses also decreased angioedema attacks, but reductions were lower — 44.6% and 45.5%, respectively. In these groups, 21% of patients taking 250 mg, and 39% taking 350 mg, did not experience any attacks during the study period.
Peripheral attacks — those affecting hands, arms, legs, feet, or genitals — were reduced with all BCX7353 doses. However, attacks affecting the stomach or gut were only reduced with the 125 mg dose.
Patients receiving the 125 mg dose also reported better health-related quality-of-life — assessed using an angioedema-specific quality-of-life (AE-QoL) questionnaire — compared to placebo-treated patients. Improvements were seen in functioning, fatigue and mood, fears and shame, and food.
Gastrointestinal adverse events were the most common adverse effects, particularly in the 250 mg and 350 mg dose groups — 50% and 44%, respectively. In the 125 mg dose group, only 29% of patients developed these side effects.
Researchers believe that the higher incidence of adverse effects in higher dose groups may have masked the therapy’s effectiveness.
Overall, these results show that “once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo,” researchers wrote.
BioCryst is currently recruiting participants for two additional clinical trials. The APeX-2 Phase 3 trial (NCT03485911) is investigating the long-term safety of two BCX7353 doses — 110 mg and 150 mg — as a preventive therapy for angioedema attacks.
The ZENITH-1 study is a Phase 2 proof-of-concept clinical trial (NCT03240133) evaluating a liquid formulation of BCX7353 for acute angioedema attacks.
In May 2018, the European Medicines Agency issued a positive opinion on BioCryst’s application for orphan drug status of BCX7353 to treat HAE. Orphan drug status grants, among other incentives, 10-year market exclusivity in Europe.