NEW YORK (GenomeWeb) – ARCA Biopharma has seen its share of challenges in its quest to develop the first pharmacogenetically targeted atrial fibrillation drug in the beta-blocker Gencaro (bucindolol).
The latest, according to a company announcement in March, was the trouble investigators were having enrolling the Phase IIb/III Genetic-AF clinical trial investigating Gencaro as a treatment to reduce atrial fibrillation in patients with heart failure and left ventricular systolic dysfunction, who also have the beta-1 389 arginine homozygous genotype — the population ARCA believes will respond most favorably to the drug.
ARCA estimates 50 percent of patients have the best responder genotype, and that requirement limits the trial population at the start. A bigger problem, though, has been the initial inclusion criteria, which required patients to be in persistent atrial fibrillation at the time of randomization, a condition that study investigators believe was too restrictive.
"The original patient population was probably an overly pristine type of patient population," Derek Cole, head of investor relations for ARCA, told GenomeWeb. "We had patients that met all the criteria, went through the screening process, went through genotyping, and were at their randomization visit and weren't in atrial fibrillation that day, so they dropped out of eligibility."
Based on the original enrollment criteria for Genetic-AF, study investigators screened 37 patients and randomized 12 patients into the trial, the company reported in mid-March. The Phase IIb portion of the trial has a target enrollment of 200 patients.
Atrial fibrillation is a heart arrhythmia that is associated with poor blood flow, and can confer up to a five-fold increase in the risk of stroke and two-fold increased risk of death. Patients often have atrial fibrillation and heart failure, but the treatment options for those with both conditions are limited. Many of the atrial fibrillation drugs can cause cardiovascular side effects and carry warnings about their use in heart failure patients. ARCA is hoping to bridge this unmet need by developing Gencaro for heart failure patients with atrial fibrillation who are pharmacogenomically characterized to respond well to the drug.
In the Genetic-AF trial, investigators are randomizing patients to receive either Gencaro or another beta blocker, metoprolol succinate. After a 24-week follow-up period, investigators will compare the two arms to see which group has less symptomatic atrial fibrillation, atrial flutter, or death due to any cause. The data safety monitoring board for the trial will evaluate the outcomes from the Phase IIb portion and determine whether the drug should continue to be studied in a Phase III trial involving more than 400 patients.
However, since investigators were having trouble getting going with the Phase IIb portion, ARCA discussed the issue with the clinical trial steering committee and decided to expand the enrollment criteria to include patients who in the last 120 days before screening experienced atrial fibrillation. Patients can have normal heart rhythm at the time of enrollment.
"We do expect this [amendment] will have a significant impact on eligibility and enrollment," principal investigator Jonathan Piccini, an associate professor of medicine at Duke University's cardiology division, told GenomeWeb. But since each enrollment site must garner institutional review board approval for the new protocol, it will be several months before ARCA will be able to gauge whether this amendment had the desired effect of easing the enrollment process.
Cole expects that the sites will achieve their IRB's go ahead and begin enrollment using the amended criteria starting in June. Currently, ARCA has activated 38 trial sites in the US and Canada, but is hoping to activate a total of 65 sites.
Even though the trial criteria would now allow enrollment of patients who aren't experiencing atrial fibrillation at the time they enter the study, Cole doesn't expect this will create a higher bar for proving Gencaro's efficacy over metropolol. The treatment evaluation period is 24 weeks, during which time patients are at risk of experiencing a recurrence of atrial fibrillation, and this will enable investigators to track how well Gencaro impacts outcomes. "So, [the trial] goes out fairly long," Cole noted. "Normally the recurrence of atrial fibrillation is within six-to-eight weeks."
The trial enrollment difficulty is ARCA's latest challenge in its already protracted development program for Gencaro, a drug originally created by Bristol-Myers Squibb. Incara Pharmaceuticals and Indevus Pharmaceutical outlicensed the drug to ARCA in 2003, around the time ARCA founders Michael Bristow and Stephen Liggett performed a DNA substudy from a large, Phase III trial for Gencaro, which suggested that patients with the beta-1 389 arginine homozygous genotype experienced a 34 percent reduction in mortality and 48 percent reduction in hospitalization due to heart failure.
Retrospective PGx analysis of data from this so called Beta-Blocker Evaluation of Survival Trial (BEST) was included in ARCA's new drug application (NDA) for Gencaro to the FDA in 2008. But the FDA wasn't satisfied, and in May 2009 it sent ARCA a letter asking for additional information. In response to the agency, the company laid out a study protocol amendment proposing to assess the safety and efficacy of Gencaro in 3,000 patients with chronic heart failure.
Several years later, the company still hasn't been able to start collecting the data from the study it needs to conduct for Gencaro's approval. ARCA now hopes to bring 200 patients into the Phase IIB portion of Genetic-AF by the end of 2016, and projects that the data safety monitoring board will finish its interim analysis to determine whether to continue into the Phase III portion by the first half of 2017.
In developing Gencaro with a pharmacogenetic strategy, ARCA is essentially attempting to resuscitate a drug that previously fell short of the mark in terms of efficacy. In BEST, which compared Gencaro against placebo in advanced heart failure patients, the drug failed to show a difference in overall mortality between the two arms. The trial, which was stopped early, did suggest efficacy, however, as Gencaro-treated patients had significantly lower rates of death from cardiovascular causes and lower rates of hospitalization due to heart failure.
As Cole recounts it, while the BEST study was ongoing, trials for two other beta blockers, metropolol and carvedilol, convinced the investigator community of their usefulness in heart failure. In its most recent 10-k filing with the US Securities and Exchange Commission, the company recounts the history of the BEST trial in some detail, noting that when the data on these other beta-blockers came out, some of the investigators in BEST began prescribing patients in the placebo arm these drugs, which "threatened to destroy the trial's integrity," and lead to its early termination.
In Cole's review of the published data on Gencaro and these other beta blockers, the treatments are "roughly equivalent" in terms of efficacy in the all-comer population, he said. But he believes that because BEST was stopped early, before the planned cohort was fully enrolled, the trial wasn't the optimal test for proving Gencaro's efficacy in heart failure.
Industry observers have opined that drugmakers are reluctant to use pharmacogenetics to resuscitate drugs that have previously shown to lack efficacy in clinical trials. Once a drug has failed to meet a primary endpoint in a pivotal trial, it can be increasingly challenging to shed that reputation when enrolling a new trial with the same drug.
Cole maintains there is no such hurdle for Gencaro, and the company remains committed to using a pharmacogenetic strategy to home in on the patients that are most likely to benefit from the treatment. ARCA is working with Laboratory Corporation of America to develop a companion diagnostic that will detect from a blood sample whether a patient has the favorable beta-1 adrenergic receptor genotype. He estimated that the test will likely cost around $200 and won't be a barrier to the uptake of the drug.
If Gencaro gets through clinical trials and into the market, the drug may be appropriate for 1.5 million heart failure patients with systolic dysfunction who have the favorable genotype, according to ARCA's prior projections. Despite the difficulties with the Gencaro trial, investigators remain committed to it because heart failure patients with atrial fibrillation lack treatment options, according to lead investigator Piccini.
"The investigators I've spoken to and the patients I've spoken to very much appreciate the lack of treatment options," Piccini said. "One of the dark secrets of heart failure medicine is that there are few options available to these patients and most of the options have significant toxicities."
While guidelines recommend the use of beta blockers for patients with atrial fibrillation, data from recent studies go against this advice for heart failure patients with atrial fibrillation. Researchers led by Dipak Kotecha of the University of Birmingham analyzed data from studies involving more than 18,000 heart failure patients. Among the 3,000 patients in the cohort with atrial fibrillation, Kotecha et al. found that beta blockers didn't reduce mortality compared to placebo. Based on this finding, the study authors concluded that doctors should not consider beta blockers the standard treatment for patients with heart failure and atrial fibrillation over other rate-control medications.
These types of findings further emphasize the importance of the Genetic-AF study, in Piccini's view. "If we can find a patient population and treat them with a medication like a beta blocker and give them superior outcomes to the current established best practice, that is a very, very important thing," he said.
ARCA believes Gencaro is unique in that it only mildly dilates blood vessels, and so it might be better tolerated by cardiac patients than other beta blockers. Like other drugs in the class, Gencaro blocks beta-1 receptors involved in regulating the rate of heart contractions. But studies suggest that in patients with the beta-1389 arginine homozygous genotype the beta-1 receptor is more active, which can be harmful for heart failure patients. ARCA's development program is based on the hypothesis that Gencaro has a unique mechanism of action that enables it to block constantly active beta-1 receptors and lower atrial fibrillation and death particularly well in heart failure patients who have the beta-1 389 arginine homozygous genotype.
ARCA's commitment to developing the first PGx-guided atrial fibrillation treatment may be unwavering despite the challenges it has faced, but it faces the risk of not having enough funding to see the process through. According to its latest 10-k filing, ARCA raised $19.3 million in net proceeds through public equity offerings during 2013. In February 2014, the firm raised $7.9 million through another public equity offering to support the Phase IIb portion of Genetic-AF and company operations.
Cole noted that the company said last year it had enough cash to take ARCA through the end of this year. However, he acknowledged that the firm will need additional cash by the time the data safety monitoring board reviews the Phase IIb data and considers whether the drug should move on to Phase III.
"We have sufficient capital to go for a long ways, and we're not looking to raise capital in the short term," he said. "We can get the amended protocol up and running, and get some insights … prior to needing to raise capital."
Update 4/13/2015: After the pubilcation of this article, ARCA announced that the FDA had granted the Gencaro development program fast track status.