AHA 2020 – look out for the omecamtiv fault lines

The full Galactic-HF data were supposed to have suggested a path forward. Instead they point the way to disagreement.

Hopes that a subgroup benefit might point a way forward for Amgen/Cytokinetics’ heart failure project omecamtiv mecarbil have taken a knock. Full data from the Galactic-HF study, unveiled on Friday at the American Heart Association meeting, confirmed the worst fears, and omecamtiv looks dead in the water.

Undeterred, Cytokinetics reckons it has seen enough to plough on, however, highlighting a subgroup of patients with baseline low ejection fraction. But Amgen has been reticent, and recent success with the asthma project tezepelumab means that the group is less dependent on omecamtiv than before; what happens to the collaboration if Cytokinetics cannot get Amgen's buy-in?

The companies’ deal, signed at the end of 2006, would not be easy to unwind, being structured not as a straight licence but as a broad alliance to develop cardiac myosin activators. There appears to be no easy way for Amgen to opt out, should this be what Amgen wants to do.

The decision on whether to proceed with further development will be taken jointly, and if Amgen says no Cytokinetics could still go it alone. But to do this the junior company would have to buy back from Amgen full rights to the data, which were generated jointly, and then find a new licensee.

Not only do the Galactic-HF results provide an unconvincing lure for a partner, omecamtiv’s key US patent is believed to expire in 2027, according to US regulatory filings. By the time any new trial was run in a predefined subgroup the asset would face being launched with virtually no intellectual property protection.

Galactic irrelevance

Of course, these are theoretical considerations. For now the focus is on Galactic-HF, which last month was toplined as borderline positive in its primary endpoint, a composite of death or heart failure events, and negative on cardiovascular death, the key secondary (Primary omecamtiv win is not enough, October 9, 2020).

The full AHA data, also published today in the NEJM, lay bare the extent of the disappointment. Cardiovascular death shows not even the hint of a numerical benefit versus placebo, with the survival curves virtually superimposable and a hazard ratio of 1.01 (p=0.86). Rate of all-cause mortality is identical is both groups, at 25.9%.

For the primary endpoint the reduction in risk is just 8%, with the upper bound of the confidence interval almost 1.00; in a study as large as Galactic-HF, which enrolled 8,256 subjects, such unconvincing data cast serious doubt on omecamtiv – even before you consider the relatively stellar results Astrazeneca’s Farxiga boasts in its corresponding Dapa-HF trial.

Source: NEJM & Farxiga label.

The comparison against Farxiga makes it obvious that omecamtiv has no real-world use in all-comers. So what about subgroups?

On a Friday analyst call Cytokinetics played up the benefit of omecamtiv versus placebo in subjects with relatively low left ventricular ejection fraction (LVEF). These patients saw a 16% reduction in risk versus placebo, against a 4% increase in those with LVEF above the median, and though comparing the difference between the two was post hoc the group cited an "interaction p value" for it of 0.003. 

However unconvincing this seems as a basis for continuing development, which would now presumably involve running yet another large trial, this time enrolling only those subjects with LVEF at or below 28%, Cytokinetics stated that the subgroup finding gave it "a clear roadmap for omecamtiv becoming standard of care".

Neither company has so far said anything about a filing strategy, and there has apparently been no discussion with the US FDA of the Galactic-HF result. Over to Amgen.

This is an updated version of a story first published on Friday.

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