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Positive Results Reported for Kallikrein Inhibitor in Patients With Hereditary Angioedema

Mid-stage trial shows reduced angioedema attack rate compared with placebo

Positive results have been reported from the OPuS-1 (Oral ProphylaxiS-1) proof-of-concept phase IIa clinical trial of orally administered BCX4161 (BioCryst Pharmaceuticals) in patients with hereditary angioedema (HAE). The trial met its primary efficacy endpoint and several secondary endpoints.

The OPuS-1 study evaluated 400 mg of BCX4161 administered three times daily for 28 days in HAE patients with a high attack frequency (one or more per week) in a randomized, placebo-controlled, two-period cross-over design. The study’s primary goals were to determine the efficacy of BCX4161 in reducing the frequency of angioedema attacks and to evaluate the safety and tolerability of 28 days of treatment with BCX4161.

Twenty-four patients received the study drug, and all completed the trial. The primary efficacy endpoint was the by-subject difference in the mean angioedema attack rate with BCX4161 compared with placebo. Treatment with BCX4161 demonstrated a statistically significant mean reduction in the attack rate of 0.45 attacks per week compared with placebo (P < 0.001). The mean attack rate per week was 0.82 for BCX4161 compared with 1.27 for placebo.

Oral administration of BCX4161 was generally safe and well tolerated, with an adverse event profile similar to that observed for placebo. One serious adverse event was reported — an abdominal HAE attack during the placebo period. Patient dosing compliance was 98%.

The mean number of attack-free days during each treatment period improved from 19 for placebo to 22 for BCX4161 (P = 0.008). Three subjects were attack-free during the BCX4161 period compared with none during the placebo period.

Quality of life was measured by the Angioedema Quality of Life (AeQoL) questionnaire, and disease activity was measured by the Angioedema Activity Score (AAS28). For BCX4161, the mean total AeQoL score improved by 8.4 units from baseline compared with 0.5 units for placebo (P = 0.004). Moreover, the AAS28 was 21.4 for BCX4161 compared with 28.8 for placebo (P = 0.022).

BCX4161 is a selective inhibitor of plasma kallikrein in development for the prevention of attacks in patients with HAE. By inhibiting plasma kallikrein, BCX4161 suppresses bradykinin production. Bradykinin is the mediator of acute swelling attacks in HAE patients.

HAE is a rare, severely debilitating, and potentially fatal genetic condition that occurs in approximately 1 in 10,000 to 1 in 50,000 people. The symptoms of HAE include recurrent episodes of edema in various locations, including the hands, feet, face, genitalia, and airway. In addition, patients often have bouts of excruciating abdominal pain, nausea, and vomiting that are caused by swelling in the intestinal wall. Airway swelling is particularly dangerous and can lead to death by asphyxiation.

Source: BioCryst Pharmaceuticals; May 27, 2014.

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