High marks for novel LVEF-boosting agent stir hope in heart failure

The heart-failure drug development field is so strewn with casualties that researchers tend to express caution rather than optimism when discussing new candidates. Hopes are stirring again, however, for an LVEF-boosting drug with mechanistic underpinnings and safety data suggesting it could be an effective, lower-risk alternative to conventional inotropic agents, and perhaps more.

That potential was on display in two studies published in the August 20, 2011 issue of the Lancet, phase-1 and -2 evaluations aimed at pinning down the most effective and best-tolerated IV dosage of the novel myosin-activator omecamtiv mecarbil (Cytokinetics, San Francisco, CA). In earlier research, the drug was identified as CK-1827452.

Dr John R Teerlink (San Francisco Veterans Affairs Medical Center, CA), lead author of one of the studies, acknowledges that the drug is still early in development but is impressed enough with its positive effect on cardiac output and apparent safety to say that omecamtiv mecarbil "has the potential to completely replace dobutamine and milrinone," which are used only in the most seriously ill patients with heart failure.

But as the same molecule is under investigation in an oral form, Teerlink noted in an interview that it has potential for broader use in acute heart failure as well as stable, chronic heart failure.

Conventional inotropic agents are used sparingly in patients with advanced heart failure because of well-recognized adverse effects. With increased intracellular calcium as their mechanism in strengthening ventricular contractions, they also raise heart rate, are proarrhythmic, and can cause ischemia by raising myocardial oxygen demand.

Omecamtiv mecarbil apparently has none of those metabolic downsides, according to Teerlink. The drug potentiates the effect of myosin in myocyte contractions, boosting cardiac output not by strengthening contractile force but by prolonging systole, thereby making contractions more efficient. And, he says, the effects are predictable and "exquisitely dose-dependent."

The only significant adverse effect in the dose-ranging studies, according to Teerlink, was evidence of myocardial ischemia at the very highest dosages. "It prolonged systole to such an extent that it finally impinged upon coronary filling," he said. "So far, we have not seen any off-target effects or any adverse effects at what we consider now to be a reasonable dose range."