Another inotropic “Failure in Failure?”

CK-1827452 is a novel inotropic drug being developed for heart failure.

Inotropic drugs have “failed” in long-term treatment of heart failure because they increase mortality.

Virtually all prior similar agents looked “promising” when at the same stage as CK-1827452 is now.

The mechanism of inotropic effect is probably not as important as the effect itself, which is harmful.

All potent inotropic drugs, like CK-1827452, are suspect for long-term treatment of heart failure.

There is little reason to be optimistic about the chances for success of CK-1827452.

Amgen has recently allied with Cytokinetics in the development of a new drug for heart failure (HF). The drug involved, CK-1827452, is an inotropic agent that acts through a novel mechanism to make the heart contract more forcefully. So far the drug has been given only to animals and normal human volunteers, and has performed as expected, i.e., improved cardiac contractility in both. The drug is about to enter the next stage (Phase II) in humans with HF, i.e., small trials as “proof of concept”, to be followed by Phase III, or large clinical trials in HF to assess general efficacy and safety if Phase II is successful.

There are many inotropic drugs and all have “failed” in large long-term clinical trials in HF because of their propensity to cause cardiac arrhythmias and an excess of deaths in patients with HF. The list includes amrinone, milrinone, flosequinon, beta-blockers with intrinsic agonist activity (xamoterol, bucindolol), etc. Each of these (and others) acts through different mechanisms, all thought to be unique early on and unlikely to produce harmful effects. They all looked very promising early in development, i.e., at the stage where CK-1827452 is now. So far there is nothing “unique” about CK-1827452.

Having a novel inotropic mechanism may not be important. What seems important is that making the failing heart muscle contract more forcefully, regardless of how this is done, may actually harm the heart muscle, analogous to “beating a dying horse.” The only inotropic drug used for long-term treatment of HF is digitalis (digoxin), and it has not been shown to reduce mortality, but has also not increased mortality, probably because it is a relatively weak inotropic agent compared to the others mentioned. Many HF experts would question the logic of anyone developing a new inotropic agent in this day and age. Such agents are limited to very short-term use in acutely decompensated HF, for which many agents already exist.