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Study Suggests Two-Gene Combo Predicts Spectrum of Response to ARCA's Beta Blocker Gencaro

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Originally published Oct. 23.

ARCA Biopharma's personalized beta blocker for cardiac patients is poised to move into phase III testing after a study demonstrated the feasibility of using a multimarker strategy to identify best responders, intermediate responders, and non-responders to the drug.

In a paper published in PLOS One earlier this month, researchers from Duke University Medical Center, ARCA Biopharma, and elsewhere published data from a retrospective pharmacogenetic analysis showing that the combination of two polymorphisms can be useful in determining which patients respond especially well, have an average response, or have virtually no response to the investigational beta blocker Gencaro (bucindolol).

Beta blockers like Gencaro target beta receptors on heart tissue. When stimulated by the stress hormones epinephrine or norepinephrine, these receptors cause the heart rate and blood pressure to increase. Beta blockers mediate the effect of these stress hormones by blocking their binding with the receptors.

Previous studies have shown variability in response to Gencaro in patients with two different adrenergic receptor polymorphisms: one that results in a change in at amino acid position 389 from Arg to Gly in the drug's primary target, beta1 AR; and another that results in a four-amino-acid deletion of positions 322 through 325 in the drug's secondary target, alpha2c AR.

Specifically, prior studies indicated that patients with the beta1-389 Arg/Arg genotype had better response to Gencaro than Gly carriers, and that patients who were alpha2c wildtype homozygotes responded better to the drug than did those with the four-position deletion. "Thus, the question arises as to whether the combination of two major allele genotypes would yield an even greater therapeutic response than in either monotype alone," the researchers posited in the paper.

The authors found that beta1-389 Arg homozygotes, regardless of alpha2c status, were the best responders to Gencaro; those who were beta1-389 Gly carriers and alpha2c 322–325 wildtype homozygotes were intermediate responders; and those who were carriers of both beta1-389 Gly and the alpha2c 322–325 deletion had no response to the drug.

"The goal of pharmacogenetic targeting is to identify subgroups with large differences in treatment efficacy, or 'outliers', so that the more responsive group can be offered the likelihood of benefit that is better than that in the general population, and the less-responsive group can avoid treatment exposure," the authors wrote. "In this regard, the use of beta1-389 and alpha2c combination genotypes yielded numerically greater degrees of high-low response differential efficacy compared with beta1 or alpha2c monotypes, by respective absolute amounts of 54 percent and 94 percent."

Derek Cole, ARCA's VP of investor relations, noted that previously published data suggest that in the general patient population, approximately 50 percent of patients have the very favorable genotype combination, approximately 40 percent have a favorable genotype and 10 percent have a genotype that suggests they should not receive the drug candidate.

ARCA is planning to conduct a Phase III clinical trial to evaluate Gencaro as a potential treatment for the prevention of atrial fibrillation in patients with the genotype combinations discussed in the PLOS One publication, Cole told PGx Reporter. "The findings are the basis for our belief in the current regulatory strategy, including the potential drug/test combination," Cole said in an email.

Three years ago, the US Food and Drug Administration granted fast-track status to Gencaro. ARCA filed an initial special protocol assessment with the FDA, but the agency requested additional information. To this, ARCA submitted a revised SPA filing in March 2010 for a pivotal trial (PGx Reporter 5/19/2010).

ARCA is collaborating with the Laboratory Corporation of America to advance a companion test for Gencaro that gauges variants in the beta1 and alpha2c receptors (PGx Reporter 2/21/2007).

Although ARCA and LabCorp plan to simultaneously seek approval for Gencaro and the companion diagnostic, Cole couldn't provide a timeline for when the companies expect to file for regulatory approval. "We plan to initiate the Phase III trial approximately 12 months after securing funding for the trial," he noted.

BEST Substudy

In the study reported in PLoS One, researchers analyzed more than 1,000 samples from patients previously enrolled in the Beta Blocker Evaluation of Survival Trial, or BEST, which investigated whether Gencaro improved mortality rates among chronic heart failure patients compared to placebo. BEST results published in 2006 in the Proceedings of the National Academy of Sciences indicated that patients with certain genotypes responded better to bucindolol — data that provided the basis for Gencaro's development (PGx Reporter 7/26/2006).

In the PGx substudy, called “Pharmacogenomics of Beta-Adrenergic Receptor Polymorphisms and Response to Beta-Blockers in Heart Failure,” researchers hypothesized that patients harboring certain combinations of polymorphisms in the cardiac beta1 and alpha2c adrenergic receptors would see an especially good response to Gencaro while others could have a severely limited response to the drug.

The investigators divided patients into four genotype combinations: patients with beta1-389 Arg/Arg and alpha-2c Wt/Wt genotypes (Group 1); patients who had beta1-389 Arg/Arg but were alpha-2c deletion carriers (Group 2); those who were beta1-389 Gly carriers and alpha-2c Wt/Wt (Group 3); and patients who were beta1-389 Gly and alpha-2c deletion carriers (Group 4).

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Researchers previously observed that beta1-389 Arg genotypes have greater affinity for norepinephrine than the beta1-389 Gly variant. Since Gencaro targets and lowers norepineprhine levels, patients with the beta1-389 Arg polymorphism were expected to respond better to Gencaro than Gly carriers.

Meanwhile, alpha2c adrenergic receptors are involved in the release of norepinephrine. The study authors expected that patients with loss-of-function alpha2c deletions would have limited benefit from Gencaro compared to those who were alpha2c wild type. However, in the PGx substudy, the researchers were surprised to find that the alpha2c deletion didn't have a negative effect on Gencaro's efficacy in the presence of the beta1-389 Arg/Arg variant.

The study authors found that Gencaro was 70 percent and 132 percent more efficacious in Group 1 and Group 2, respectively, than it was for the entire DNA substudy population. For example, 165 patients out of 420 in Group 1 and 32 patients out of 74 in Group 2 experienced no heart failure events after treatment with Gencaro. The number of patients in Group 2 was too small to reach statistical significance for measuring the impact of the drug on patient outcomes, and only Group 1 reached statistical significance for measuring the efficacy of Gencaro in reducing heart failure progression and hospitalizations due to heart failure.

Despite the small number of patients in Group 2, the researchers observed that patients with beta1-389 Arg/Arg polymorphisms who also had the alpha2c deletion didn't seem to experience a reduced response to Gencaro even though the alpha2c 322-325 Del variant is associated with significant decreases in norepinephrine, previously shown to be a sign of poor response to the drug.

According to the study authors, this is likely due to the fact that the 389 Arg version of the beta1 adrenergic receptor has better agonist binding ability and therefore can support cardiac function in heart failure patients by targeting norepinephrine even when levels of the hormone are low. "The sympatholytic effects of bucindolol therefore preferentially inhibit beta1-389 Arg signaling, providing a basis for the selective clinical effects of bucindolol in beta1-389 Arg/Arg genotypes versus any Gly-containing genotype," the study authors wrote in the paper.

The researchers explained further that "in contrast, the hypofunctioning, lower-norepinephrine affinity beta1-389 Gly version of the beta1 adrenergic receptor needs higher norepinephrine levels to support the failing heart, and in the presence of the alpha2c 322–325 Del-associated marked sympatholysis, likely cannot adequately support cardiac function, leading to an increase in mortality and hospitalizations that cancels bucindolol efficacy."

Noting that the effect sizes for Group 1 and Group 2 overlapped, the researchers combined the two cohorts, and reported that the hazard ratios, relative change ratios, and p-values of the combined group were similar to Group 1.

Meanwhile, Group 3 didn't seem to respond as well to Gencaro as Group 1 or Group1/2, but the subgroup's average effect size (22 percent) was similar to that of the overall patient cohort in the DNA study (26 percent). "Strikingly, Group 4 … exhibited hazard ratios/relative change ratios of [around] 1 with an average effect size of negative 5.5 percent, or no evidence of any efficacy," the study authors wrote.

Although estimates for Gencaro's effect on certain patient outcomes were statistically significant only for Group 1, the study showed that Group 1/2 and Group 3 had differential efficacies of 190 percent and 97 percent compared to Group 4. The authors note that these findings will need further exploration in prospective analyses.

"Combinatorial genotyping led to improvement in pharmacogenetic differentiation of drug response compared with monotype genotyping," the study authors concluded. "The unexpected results of this study … emphasizes that combinations of response-altering polymorphisms may behave in unpredictable ways and in silico predictions of combinatorial genetic effects will need to be supported by empirical data."

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