LabCorp last week said it plans to develop a genetic test that can identify patients most likely to benefit from ARCA Discovery’s beta-blocker bucindolol, and those who are likely to be at greater risk of dying from the drug.
Terms of the agreement call for LabCorp to develop the genetic test as ARCA’s drug is being reviewed by the US Food and Drug Administration for approval, the companies told Pharmacogenomics Reporter by e-mail this week. Ultimately, the firms hope that both products win regulatory approval simultaneously so they can market the test and drug as companion products.
ARCA said it plans to submit its application to the FDA for its next-generation beta-blocker this year. The company said it has garnered Phase III efficacy and safety data, including genetic data, in heart failure patients on bucindolol. The company published a genetic substudy in this regard in the Proceedings of the National Academy of Sciences, which
shows that a common genetic variation in the beta-1 adrenergic receptor may help doctors identify heart failure patients who may benefit most from the drug.
ARCA has exclusive, worldwide rights to bucindolol. Financial terms of the agreement were not disclosed.
LabCorp said it will consult the FDA “on the appropriate regulatory path for the test.”
“The regulatory filings for drug and test will be closely coordinated in any event,” a LabCorp spokesperson said. “The clinical support for the usefulness of the test in prescribing bucindolol will be part of the bucindolol application.
“A substantial percentage of heart failure patients have weak or negative responses to current therapy,” the spokesperson added. “The companion test will give doctors an analytic tool to address this problem, and thus allow patient care to become more personalized.”
LabCorp’s test will identify common genetic variations of the alpha-2c and the beta-1 adrenergic receptors that regulate the human heart.
“A patient’s response to bucindolol appears to be affected by these genetic variations,” the companies said in a statement. “Certain variants are associated with a strong positive benefit in the majority of patients, while others are associated with side effects and no benefit.”
The adrenergic receptor system modulates the activity of the human heart, and is activated by norepinephrine released from cardiac adrenergic nerve terminals. Norepinephrine binds to different adrenergic receptors, two of which impact how patients metabolize bucindolol.
The post-junctional beta1-adrenergic receptor reacts to norepinephrine by raising patients’ heart rate and contractility, and by mediating long-term myopathic effects, LabCorp said.
The hyperfunctional Arg variant of the beta1-AR is carried by about 50 percent of the general population, and it is also the receptor that helps to identify patients who are superior responders to bucindolol.
LabCorp estimates there are roughly 6 million heart failure patients in the US. With the help of the genetic test, approximately 90 percent of patients with systolic heart failure are likely to benefit from this therapy, with about half of them showing the strongest therapeutic response.
Meanwhile, genetic testing can also identify patients who may negatively react to bucindolol treatment.
“Patients with heart failure have very high levels of systemic and myocardial norepinephrine that contribute to compensation of the failing heart, but which ultimately produce cardiac damage in the form of progressive cardiomyopathy,” the LabCorp spokesperson explained.
“A substantial percentage of heart failure patients have weak or negative responses to current therapy. The companion test will give doctors an analytic tool to address this problem, and thus allow patient care to become more personalized.”
Beta-blockers, like bucindolol, achieve a therapeutic effect by binding to the myocardial beta-1 receptor and ameliorating some of the adverse effects of increased norepinephrine, he said.
However, there is also a genetic variant to the pre-junctional alpha-2c-adrenergic receptor, marked by deleted or missing amino acids 322-325. People with these variants, which account for about 10 percent of the general population, “lack the ability to respond to norepinephrine or epinephrine, and the tonic inhibition of norepinephrine release ordinarily imparted by the alpha2c receptor is lost,” LabCorp said.
Patients who have deletions in the alpha2c polymorphism produce a large reduction in norepinephrine, which may increase the risk of death.
“Bucindolol appears to have higher efficacy in the 90 percent of patients without this deletion polymorphism and, conversely, an unfavorable response in the subgroup that carries this variation,” the company said.
However, LabCorp suggested that this mortality risk can be attenuated in patients who carry “the normal, ‘wild type’ version of the alpha2c receptor, where bucindolol produces only a mild reduction in norepinephrine that is likely to be uniformly beneficial.”
The companies said they are also interested in homing in on patients who have the greatest risk of norepinephrine reduction due to interaction between bucindolol with the alpha2c receptor deletion polymorphism, but who also have hyperfunctioning beta-1 receptors.
“In these patients the loss of norepinephrine coupled with a low functioning receptor leaves the failing heart without adequate contractility support, and predisposes patients to sudden death,” LabCorp said.
However, the hyperfunctioning arginine form of the beta-1 receptor in these patients protects them from “marked loss of adrenergic support, as even low levels of norepinephrine can produce a positive inotropic effect through this receptor. Thus, bucindolol can be genetically targeted by selecting patients based on genetic polymorphisms in these two adrenergic receptors.”
Labcorp is currently considering various technology platforms for the test. “The genetic tests are straightforward and the platform chosen will be one of several highly reliable platforms commonly used in the industry,” LabCorp said.
The company has yet to determine a brand name for the diagnostic.
ARCA said it is conducting phamacoeconomic analyses that “preliminarily appear to show that bucindolol, [genetically] targeted, substantially reduces both the number and duration of hospital stays.”