Arca's beta-blocker Gencaro receives FDA complete response, further trials requested
This article was originally published in Scrip
Arca Biopharma has received a US FDA complete response letter for its lead candidate, the beta-blocker Gencaro (bucindolol HCl), which was filed for the treatment of patients with chronic heart failure.
Upon the news, the Colorado-based firm's share price plummeted by 44% to close at $5.13 on Nasdaq on June 1st.
In the letter, the FDA stated that it could not approve the NDA in its current form and instructed the company to conduct an additional clinical efficacy trial of the drug in patients with heart failure. The agency also requested further clinical and non-clinical studies to address the drug's pharmacological profile.
The agency said that the Phase III BEST study which, despite failing to meet its primary endpoint serves as the pivotal trial for the application, does not adequately demonstrate efficacy of Gencaro in reducing all-case mortality in patients with heart failure.
The letter raises concerns about the integrity of the BEST data based on its audit of certain clinical sites involved in the trial.
The agency also raised doubts over the statistical significance of some of the pharmacogenetic data relied upon by the company to assert that individual patient responses to Gencaro may be predicted by genotype.
Bucindolol hydrochloride has been in development at other companies since the 1980s.
The company believes that additional data that it submitted to the FDA in May, which the agency has acknowledged was not reviewed before sending the complete response letter, may address some of the issues raised.
BEST was conducted by Interneuron between 1995 and 1999 – when it was prematurely terminated, due to a lack of survival benefit in patients with moderate-to-severe heart failure.
The double-blind trial randomised 2,708 patients with heart failure designated as New York Heart Association (NYHA) functional class III and IV to receive Gencaro or placebo, in addition to standard therapy.
The trial failed to meet significance on its primary endpoint of reduction of mortality – which saw a 13% reduction (p=0.0053). The company added that all of the trial's secondary endpoints were met.
A 13% reduction in mortality is modest compared with other beta-blockers.
Arca claims that the patient response to Gencaro is dependent on genotype, and patients who have two copies of the Arg-389 variant of the beta1-adrenergic receptor had a 38% reduction in death rate, and patients with the Gly-389 variant had no response to the drug.