Avoralstat Disappoints in Patients With Hereditary Angioedema

By Will Boggs MD

June 02, 2016

NEW YORK (Reuters Health) - A just-published trial suggests the oral plasma-kallikrein inhibitor avoralstat may cut the frequency of attacks in patients with severe hereditary angioedema (HAE). But as-yet-unpublished data from a subsequent, larger study dash those hopes, at least for the liquid formulation.

In OPuS-1, Dr. Marcus Maurer from Charité - Universitätsmedizin Berlin, Germany, and colleagues investigated the efficacy of avoralstat in preventing angioedema attacks in a randomized, crossover study of 24 patients with severe HAE.

There were 79 HAE attacks during avoralstat treatment, compared with 123 attacks during placebo treatment, they report in the Journal of Allergy and Clinical Immunology, online May 11.

This translated into a weekly attack rate of 0.82 per patient on avoralstat, compared with 1.27 attacks per patient on placebo (p<0.001).

Adverse events occurred with similar frequency during the avoralstat period and during the placebo period.

"This study provides proof of concept that a targeted oral prophylaxis works in preventing attacks in HAE patients," Dr. Maurer told Reuters Health. "That's a big step forward. HAE patients have been looking forward to this for a long time. To have a safe and effective oral prophylaxis would greatly improve the management of HAE."

Several authors, including Dr. Maurer, reported financial ties to BioCryst Pharmaceuticals Inc., which is developing avoralstat. Some are employees of the company.

Dr. Marc Riedl from the University of California, San Diego, who has published several reports about HAE but was not involved in the new work, told Reuters Health by email, "For a number of years, both physicians and patients have been extremely interested in the concept of a non-androgen oral medication that would effectively prevent HAE episodes. This study served as an important 'proof-of-concept' that this may be an achievable goal."

The larger OPuS-2 trial of 110 less severely affected HAE patients, however, failed to demonstrate a reduced HAE attack rate among those assigned to avoralstat 300 mg or 500 mg three times daily.

According to a BioCryst presentation on this study, which has not yet been published, the criterion for eligibility was >=0.45 HAE attacks/week versus >=1.0 HAE attacks/week in OPuS-1, and the actual qualifying rate was 0.93 attacks/week versus 1.5 attacks/week in OPuS-1. (The presentation is available here: http://bit.ly/1r2DGXP.)

The confirmed attack rate per week in OPuS-2 was 0.63 in patients on avoralstat 500 mg, 0.71 in those on 300 mg and 0.61 in those on placebo. Corresponding subject-reported attack rates were 0.66, 0.77 and 0.67.

"The exposure profile achieved by the liquid formulation of avoralstat was insufficient for efficacy in this study, and is not suitable for further development," the presentation states.

"Unfortunately, this particular compound did not prove to be effective in a subsequent larger, longer clinical trial," Dr. Riedl said. "But it has spurred continued interest in this approach of orally bioavailable kallikrein inhibitors, as treatment could dramatically change the clinical management of HAE."

Robert Bennett, vice president of Investor Relations & Operations for BioCryst, told Reuters Health by email, "Following the OPuS-2 outcome, our team has evaluated a number of alternative avoralstat drug formulations with the goals of improving drug exposure and lengthening the interval between dosing."

"In addition, we are planning to start a phase 2 trial of our second-generation HAE compound, BCX7353," Bennett said. "The trial, called APeX-1, will start this summer, and we plan to report results from the trial at the end of 2016. The compound has a superior pharmacokinetics trial, as we have shown in recent presentations."

SOURCE: http://bit.ly/1TJGYY6

J Allergy Clin Immunol 2016.