Myosin-Activating Agent Boosts Systolic Function, but Please Don't Call it an "Inotrope"

September 26, 2008

September 26, 2008 (Toronto, ON)— Would that which is called an inotrope, by any other name, be safer in heart failure? A small dose-ranging study in patients with stable heart failure supports animal research suggesting that an obscure drug, a selective activator of cardiac myosin, can amplify contractile function without increasing myocardial oxygen demand [1]. Investigators hope that CK-1827452 (Cytokinetics), as it's called for now, will offer the benefits of conventional inotropic agents without the effects that can ultimately harm patients taking them.

They also don't want the myosin activator, still technically a positive inotropic agent, to carry the drug class's stigma by being lumped with {:beta:}1-adrenergic agonists like dobutamine or phosphodiesterase-3 inhibitors like milrinone. Those drugs strengthen myocardial contractions and are used sparingly for short-term symptom relief in some high-risk populations, but at a high metabolic cost and increased arrhythmic and mortality risk.

"There's been a discussion about what to call this drug. I, together with my Greek colleagues, have been looking for the right word," Prof John GF Cleland (University of Hull, Kingston-upon-Hull, UK) told heartwire at the Heart Failure Society of America 2008 Scientific Meeting after he presented the dose-ranging study.

Whatever descriptive name they eventually choose, he said, should reflect the key difference between the more familiar inotropes and CK-1827452. "This is a drug that prolongs systole," he said. "It doesn't increase the velocity of myocardial contraction, which is how all other inotropic agents work. This is a completely different mode of action, not only at the molecular level, but the physiological effect it has on the ventricle is also radically different from anything there has been before."

He said the drug has been studied in IV form for the early-phase studies, but there is also an oral version under evaluation for use in chronic HF.

CK-1827452 doesn't increase the heart's demand for energy, Cleland explained. Rather, it improves contractile performance by allowing the myocardium to make more efficient use of available energy. "There's no theoretical reason why it should increase myocardial oxygen consumption."

Commenting formally on Cleland's presentation of the study, Dr Mihai Gheorghiade (Feinberg School of Medicine, Chicago, IL) observed that many patients hospitalized for acute heart failure present in a low-cardiac-output state. "Except for possibly digoxin, none of the drugs we have to take care of this are both effective and safe in directly and immediately improving cardiac function."

Based on research in animals and human studies, Gheorghiade said, CK-1827452 "may fulfill an unmet need for patients in a low-cardiac-output state," as it appears to increase stroke volume and reduce LV diastolic pressure and heart rate, with no increase in myocardial oxygen demand, "all excellent attributes for an agent that we may in the future use in acute and chronic heart failure."

But the current study, he cautioned, didn't actually test the drug in a group that really "needs" it, such as those with low cardiac output. Also still to be adequately explored, he said, are the drug's effects on diastolic function and myocardial perfusion, the latter especially in patients with coronary artery disease, and the maximum tolerated dosage.

In the randomized, controlled, double-blind study, 28 patients with stable, chronic systolic heart failure were randomized to receive IV infusions of CK-1827452 or a placebo in four phases, with each patient receiving the active drug during three of the phases at ascending dosage levels while a placebo dose was given during one "randomly interpolated" phase, Cleland reported.

He and his colleagues observed "all the pharmacologic effects" of CK-1827452 at concentrations >100 mg/mL, Cleland said, including "statistically significant, concentration-dependent, clinically meaningful increases in systolic ejection time, stroke volume, fractional shortening, and cardiac output, and these are associated with reductions in heart rate, which we believe is not a direct pharmacologic effect of the drug but rather a secondary effect."

Adverse events were as common when patients were on placebo as on the active drug, Cleland reported.

"In the doses intended for therapeutic use, CK-1827452 is well tolerated," Cleland said. In studies in healthy subjects, given increasing dosages to the point of toxicity, they experienced chest pain, tachycardia, and small elevations in troponin, "indicating that if you prolong systole enough, you can have adverse effects on myocardial perfusion."

There was a strong relationship between plasma concentrations of the drug and its pharmacologic effects, and "a sense that patients with heart failure had a steeper dose-response relationship than the healthy volunteers," he said. "Indeed, there is some evidence that the sicker the patient is, the greater the response to a particular plasma concentration of the drug."

Cleland discloses that he has consulted for and received research grants and honoraria from Amgen and Cytokinetics. Gheorghiade reports consulting for Debiopharm, Errekappa, Terapeutici, GlaxoSmithKline, Protein Design Laboratories, and Medtronic; receiving research grants from Otsuka, Sigma Tau, Merck, and Scios; and receiving honoraria from Abbott, AstraZeneca, GlaxoSmithKline, Medtronic, Otsuka, Protein Design Laboratories, Scios, and Sigma Tau.

  1. Cleland JGF. The selective cardiac myosin activator CK1827452 increases systolic function in a concentration-dependent manner in patients with stable heart failure. Heart Failure Society of America 2008 Scientific Meeting; September 24, 2008; Toronto, ON. Late Breaking Clinical Trials II.



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