BCX4161 (plasma kallikrein inhibitor)
BCX4161 is being developed as an oral prophylactic treatment for patients suffering from Hereditary Angioedema (HAE). In July 2013, BioCryst successfully completed a randomized, placebo-controlled, Phase 1 clinical trial of orally-administered BCX4161 in healthy volunteers. The safety, tolerability, drug exposure and on-target kallikrein inhibition results of this trial strongly supported advancing the development program into a Phase 2a trial in high-attack frequency HAE patients.
In November 2013, the OPuS-1 (Oral ProphylaxiS-1) Phase 2a proof of concept clinical trial enrolled its first subject and enrolled 24 HAE patients with a history of HAE attack frequency of 1 per week. On May 27, 2014 BioCryst announced that OPuS-1 met the primary efficacy endpoint, several secondary endpoints and all other objectives established for the trial. Treatment with BCX4161 demonstrated a statistically significant mean attack rate reduction of 0.45 attacks per week versus placebo, p<0.001. The mean attack rate per week was 0.82 on BCX4161 treatment, compared to 1.27 on placebo.
In December 2014, BioCryst initiated enrollment in OPuS-2 (Oral ProphylaxiS-1) Phase 2a. OPuS-2 is a 12-week, three-arm, parallel cohort design trial to evaluate the efficacy and safety of two different dose regimens of BCX4161 administered three-times daily, 300 mg and 500 mg, compared with placebo. The trial, to be conducted in the U.S. and selected European countries, is expected to enroll approximately 100 HAE patients whose average historical attack rate is lower than that observed for patients enrolled in OPuS-1. The primary efficacy endpoint for the trial will be the mean angioedema attack rate for each BCX4161 dose group compared to placebo
BCX4161 inhibits plasma kallikrein and suppresses bradykinin production. Bradykinin is the mediator of acute swelling attacks in HAE patients. In preclinical experiments, BioCryst has confirmed the potency of BCX4161 using human plasma and established a predicted therapeutic window to prevent HAE attacks. The oral bioavailability of BCX4161 in preclinical experiments was sufficient to support its continued development. More information is available at the links below:
- "BCX4161, an Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results of a Phase 1 Study in Healthy Volunteers," P-138, presented at the 2014 AAAAI Annual Meeting, San Diego, CA.
- "A Simple, Sensitive and Selective Fluorogenic Assay to Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma," P-143, presented at the 2014 AAAAI Annual Meeting, San Diego, CA.
- "BCX4161, a small molecule orally bioavailable plasma kallikrein inhibitor for the treatment of hereditary angioedema," presented at the 2013 AAAAI Annual Meeting, San Antonio, TX.
Second Generation plasma kallikrein inhibitors
In December 2013, BioCryst selected two optimized next generation kallikrein inhibitors to advance into preclinical development for the treatment of HAE. Its scientists are moving forward based on evidence of superior bioavailability and selectivity, as well as comparable or better potency compared to BCX4161.
About Hereditary Angioedema (HAE)
HAE is a rare, severely debilitating and potentially fatal genetic condition that occurs in about 1 in 10,000 to 1 in 50,000 people. HAE symptoms include recurrent episodes of edema in various body parts including the hands, feet, face, genitalia and airway. In addition, patients often have bouts of excruciating abdominal pain, nausea and vomiting that is caused by swelling in the intestinal wall. Airway swelling is particularly dangerous and can lead to death by asphyxiation. Current treatments include potentially toxic oral anabolic steroids for prophylaxis or medicines that are delivered by injection or infusion to either prevent or treat acute attacks. Daily, oral administration of a safe and efficacious prophylactic drug would revolutionize treatment for patients suffering from this serious condition.
For more information on hereditary angioedema, please visit the following websites: