within pancreatic tissue
Credit: Louisa Howard
The US Food and Drug Administration (FDA) has granted fast track designation for BCX4161, an oral inhibitor of plasma kallikrein intended to treat hereditary angioedema (HAE).
Uncontrolled activation of plasma kallikrein, caused by deficiency of its physiological inhibitor (C1 inhibitor) in HAE, results in acute systemic edema.
By inhibiting plasma kallikrein, BCX4161 suppresses the production of bradykinin, the mediator of acute swelling attacks in HAE patients.
HAE is a severely debilitating and potentially fatal condition that occurs in approximately 1 in 50,000 people. Symptoms include recurrent episodes of edema in various locations, as well as bouts of excruciating abdominal pain, nausea, and vomiting that are caused by swelling in the intestinal walls.
HAE patients have a defect in the gene that controls C1 inhibitor, and this results in the production of inadequate or non-functioning C1 inhibitor protein.
Normal C1 inhibitor helps regulate the biochemical interactions of blood-based systems involved in disease-fighting, inflammatory response, and coagulation.
Because defective C1 inhibitor does not adequately perform its regulatory function, a biochemical imbalance can occur and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissue, causing edema.
BCX4161 trials
In May 2014, BioCryst Pharmaceuticals, the company developing BCX4161, announced results from the phase 2a OPuS-1 trial.
OPuS-1 investigators evaluated 400 mg of BCX4161 administered 3 times a day for 28 days in HAE patients with a high angioedema attack frequency (≥ 1 per week), in a randomized, placebo-controlled, 2-period cross-over design.
BCX4161 demonstrated a significant reduction in mean attack rate compared to placebo. The mean attack rate per patient-week was 0.82 on BCX4161 treatment and 1.27 on placebo (P<0.001).
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 to none during the placebo period.
BCX4161 was generally well-tolerated, BioCryst reported, with an adverse event profile similar to that observed for placebo. There was one serious adverse event reported, an abdominal HAE attack during the placebo period.
In December, the first patient was dosed in the OPuS-2 trial, a double-blind, randomized, placebo- controlled trial conducted in the US and European Union.
Study investigators will evaluate the efficacy and safety of BCX4161 treatment for 12 weeks in patients with HAE. BioCryst expects to report results from OPuS-2 by the end of 2015.
About fast track designation
The FDA’s fast track process is designed to facilitate the development and expedite the review and approval of drugs intended to treat serious or life-threatening conditions that also address unmet medical needs.
A drug that receives fast track designation is usually eligible for more frequent written communication and meetings with the FDA to discuss the drug’s development plan and the collection of appropriate data supporting drug approval.
Priority review and rolling review may be granted if relevant criteria are met. Rolling review allows a drug company to submit completed sections of its new drug application on an ongoing basis, rather than wait until the entire application is complete.
