Originally published May 17.
ARCA Biopharma said today that it has reached an agreement with the US Food and Drug Administration on the design of a clinical trial to assess the safety and efficacy of an investigational heart failure drug the company is developing with a genomic marker.
Separately, the cash-strapped firm indicated it is still exploring options to raise enough capital to fund the nearly four-year trial.
ARCA said the FDA has approved a special protocol assessment that green lights a trial investigating bucindolol in approximately 3,200 chronic heart failure patients who have a genotype associated with response to the beta-blocker and mild vasodilator bucindolol. The study will be an international, multi-center, randomized, double-blind clinical trial that will compare bucindolol to the beta-blocker metoprolol CR/XL.
The genotype of interest is described by ARCA as the "homozygous state for arginine (Arg/Arg) at amino acid position 389 of the beta-1 adrenergic receptor." Metoprolol CR/XL, marketed in the US by Novartis under the brand name Lopresor, is indicated for the treatment of heart failure and has not been shown to have any differentiated impact on patients with beta-1 389 Arg/Arg genotypes versus those with another common genotype of the beta-1 receptor known as 389 Gly.
Last November, FDA granted fast-track status to ARCA's bucindolol development program for the reduction of cardiovascular mortality and cardiovascular hospitalizations in a genotype-defined heart failure population. A month later, ARCA filed an initial SPA with the FDA, but the agency requested additional information, which it submitted in a revised SPA filing in March (PGx Reporter 03/31/10).
"This SPA agreement with the FDA, the latest in a series of important milestones for ARCA, provides us with a clearly defined development and regulatory pathway for bucindolol in the treatment of genotype-specific heart failure patients," said ARCA CEO Michael Bristow in a statement. "If the planned study confirms previous observations made in the BEST trial, bucindolol has the potential to become the first genetically targeted heart failure treatment for what we estimate to be the approximately 1.5 million heart failure patients with systolic dysfunction and the genotype that appears to respond most favorably to bucindolol."
The Beta-Blocker Evaluation of Survival Trial, or BEST, was a study originally published in 2006 in the Proceedings of the National Academy of Sciences that showed that patients with certain genotypes respond better to bucindolol. This study provided the basis for bucindolol development (PGx Reporter 07/26/06).
ARCA's FDA-cleared pivotal trial will have a composite endpoint of cardiovascular mortality and cardiovascular hospitalization, and will include two interim data analyses of primary endpoints. "If the results of either of the interim analyses meet the pre-specified criteria, ARCA would be able to formally submit a complete response to the FDA's May 2009 Complete Response Letter and the results of the interim analysis could serve as the clinical effectiveness basis for FDA approval," ARCA indicated in a statement.
The first interim data analysis is planned when 630 study participants have reached the primary endpoint, which the company estimates will occur within the first 24 to 30 months into the trial. FDA's approved SPA also requires that ARCA analyze bucindolol's efficacy in terms of patient survival, which should meet the hazard ratio criteria with a 95 percent confidence interval upper bound of less than 0.999 and with a p-value of approximately 0.050. ARCA will also evaluate bucindolol's safety as compared to metoprolol CR/XL.
If any of the interim analyses yield positive results, the estimated 3.5-year trial will "proceed to conclusion," ARCA said.
"In order to not influence the planned trial's subsequent completion, if the results of an interim data analysis are adequate to support potential approval of bucindolol, ARCA's goal would be to have bucindolol commercially available no sooner than immediately after the conclusion of the trial," the company added in a statement.
For patients with the Arg/Arg genotype, beta-1 receptors have high function and high affinity for norepinephrine, with a relatively large fraction of the receptors having constitutive activity, all of which are properties that the company believes predispose these patients to an enhanced clinical response to bucindolol.
ARCA said that bucindolol has been shown to lower systemic norepinephrine levels and facilitate conversion of constitutively active beta-1 Arg receptors to an inactive state — pharmacologic properties that may explain the favorable response in the beta-1 389 Arg/Arg genotype versus the response in 389 Gly genotypes.
In March, ARCA was awarded a patent on methods of treating heart failure patients with bucindolol based on genetic testing. ARCA also holds exclusive worldwide rights to the therapeutic. The company is working with Laboratory Corporation of America to develop a companion genetic test for bucindolol (PGx Reporter 02/21/07).
With FDA's go-ahead of its clinical trial plan, the company's next challenge is garnering enough funding to actually conduct the trial. On March 12, ARCA received a notice from Nasdaq that its stockholder equity as of Dec. 31, 2009, did not meet the minimum requirement of $10 million for continued listing on the stock exchange.
ARCA reported research and development expenses totaling $10 million for 2009 compared to $11 million for 2008. As of Dec. 31, 2009, ARCA had total cash and cash equivalents of $7.8 million. In its annual report for 2009, filed with the SEC on March 4, the company said it has implemented a "restructuring plan in connection with its strategy to seek strategic alternatives for further development of [bucindolol] and to lower operating expenses to preserve its capital resources."
In announcing the approval of its clinical trial plan, ARCA said today that it is "continuing to evaluate several options for funding the proposed clinical trial," including "strategic partnership, license and/or government funding."
According to the company, in the first quarter of this year, it raised approximately $6.8 million, net of offering costs, to provide additional time to effectively pursue its strategic options related to bucindolol's development. "Subject to the company's ability to obtain sufficient funding, the company currently expects it could begin the proposed trial in the second half of 2011," ARCA said.
Meanwhile, the development of bucindolol's companion genetic test is underway in collaboration with LabCorp.
ARCA has licensed to LabCorp the rights to commercialize a receptor genotype diagnostic for the beta-1 adrenergic receptor and the alpha-2C adrenergic receptor genotype. In return, LabCorp has agreed to develop the test, obtain FDA approval, and commercially launch it in parallel with the commercial launch of bucindolol.
LabCorp filed a premarket approval application for the companion test in January 2009, but according to ARCA that review is currently "under extension," as the test's clearance through the FDA is contingent on the drug's approval.