A 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 [1,2], 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 and previous heartwire coverage, 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."

Promise after "a lot of disappointment"

"The history of heart failure has been one of a lot of disappointment," Dr Stephen S Gottlieb (University of Maryland Medical Center, Baltimore), who was not involved in the studies, said to heartwire. "But this is a promising and completely new way of trying to improve cardiac function, and it's exciting."

No one is saying it's "anywhere near prime time," he cautions. It is an innovative approach, but historically, "acute improvement in cardiac output has not translated into clinical benefit."

In an accompanying editorial in the Lancet, Dr Kenneth Dickstein (University of Bergen, Stavanger University Hospital, Norway) agrees with both Gottlieb and the studies' authors in expressing cautious optimism [3]. The two studies "support further investigation of omecamtiv mecarbil's potential therapeutic role in appropriate patients," writes Dickstein. "However, very few new agents have survived the most rigorous test, the randomized clinical trial assessing clinical outcomes."

The drug should be tested in randomized trials of patients with chronic systolic dysfunction and NYHA class 3-4 symptoms, according to Dickstein. Regarding the myosin-activation approach to treating heart failure, he writes, "Let's find out how this theory performs in practice."

The search for a best dosage

In the dose-finding study by Teerlink and colleagues, 34 men with no signs of heart disease or other important disorders received six-hour infusions of omecamtiv mecarbil and placebo, one infusion per week for four weeks, at different dosages ranging from 0.005 to 1.0 mg/kg/h, in double-blind fashion and randomized order. They were regularly followed before and during the infusions and out to 24 hours from their second infusion; evaluations included two-dimensional, M-mode, color-Doppler, and tissue-Doppler echocardiography.

The maximum tolerated dose for which there were adequate data was 0.5 mg/kg/h. Omecamtiv mecarbil infusions were associated with mean increases of 85 ms in systolic ejection time, 15 mL in stroke volume, 8% in fractional shortening, and 7% in LVEF, all closely related to dosage and plasma concentrations (all differences, p<0.0001). There were no major effects on measures of diastolic function.

"Although signs and symptoms of myocardial ischemia began to emerge at plasma concentrations in excess of 1200 ng/mL, significant increases in ejection time and stroke volume were evident at much lower concentrations (from 0 to 100 ng/mL for ejection time and >200 ng/mL for stroke volume)," the group writes.

A simultaneously published study with a similar double-blind crossover design included 45 patients with chronic systolic heart failure who were stable while on therapy that included beta blockers and either ACE inhibitors or angiotensin-receptor blockers. They received a total of 151 infusions of omecamtiv mecarbil or placebo, with at least seven days between infusions, at escalating dosages that were tolerated in the previous study. The initial infusions were two hours, but subsequent ones went to 24 and 72 hours.

As reported by Dr John GF Cleland (Hull York Medical School, University of Hull, UK) and colleagues, "systolic ejection time, stroke volume, and fractional shortening increased in a concentration-dependent manner," compared with placebo.

Different parameters significantly improved at varying dosages and generally above 300 ng/mL. They included an increase in systolic ejection time by 80 ms; LV end-systolic volume dropped by 15 mL at >500 ng/mL (both p<0.01). But ejection-time increases were highly significant at dosages as low as 100 ng/mL to 200 ng/mL.

Absolute increase in LVEF was 7.9% with omecamtiv mecarbil 300 ng/mL to 400 ng/mL and 10% at >500 ng/mL (both p<0.0001). Stroke volume rose by 11 mL at 300 ng/mL to 400 ng/mL.

Heart-rate reduction of a few beats per minute (p<0.0001) observed at different dosage levels "is not thought to be mediated directly by omecamtiv mecarbil and more likely reflects a reflex action due to increases in stroke volume," according to the group.

Myocardial ischemia associated with the drug was seen in two patients at plasma concentrations of about 1750 and 1350 ng/mL, respectively. One of the patients had received an "unintended" excessive drug dose.

"This study suggests that omecamtiv mecarbil is generally well-tolerated in patients with stable heart failure over a broad range of plasma concentrations," write Cleland and colleagues. "Further studies are needed to establish whether the observed effects on cardiac function translate into benefits related to symptoms, quality of life, exercise capacity, morbidity, or mortality."

Still "a lot of questions"

"As long as the concentrations don't get high, the safety profile looks good," Gottlieb said, but added, "these are preliminary data, and there are a lot of questions about whether [omecamtiv mecarbil] will be at all helpful clinically and whether it will be safe."

Still, "I'm cautiously optimistic. The idea of improving cardiac output in a safe way is still appealing, but it has to be demonstrated. We have to keep trying new mechanisms, and this is a new mechanism."

Teerlink said other trials of the drug are ongoing, and he is chair of the executive committee for an upcoming randomized trial called Acute Treatment with Omecamtiv Mecarbil to Increase Contractility-Acute Heart Failure (ATOMIC-AHF).

Related link Myosin-activating agent boosts systolic function, but please don't ...
[Heart failure > Heart failure; Sep 26, 2008]

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