Event – Novartis writing second act in heart failure

When the sector last saw the acute heart failure infusion serelaxin, regulators were unconvinced by findings of symptom relief and intriguing signs of a mortality benefit, and told Novartis to resubmit an application after completing another clinical trial. Data from this study will emerge early in 2017.

Preventing death in the six months after an acute episode would represent a step forward over the symptomatic relief offered by current therapies. However, the recent failure of another vasodilator, Cardiorentis’s ularitide, should raise doubts over whether an in-hospital treatment like serelaxin can show any long-lasting clinical value.

Mixed picture

Serelaxin, which carries the trade name Reasanz in its only approved jurisdiction, Russia, is being tested in more than 10,000 patients in three trials in the phase III Relax-AHF programme. The largest, at 6,500, is the global Relax-AHF-2 study aimed at gaining US approval, with co-primary endpoints of time to cardiovascular death and worsening heart failure.

The size of the trial should make it better powered to detect a significant difference between serelaxin plus standard of care over standard of care alone than was the case in the initial Relax-AHF study used to support the first submissions to the US and the EU.

The 37% mortality benefit shown in Relax-AHF was called into question because of small numbers – 41 serelaxin patients and 64 placebo patients had died of any cause at 180 days (AHA – Two hits and several misses with Novartis’s serelaxin, November 7, 2012).

On cardiovascular mortality, serelaxin showed a numerical benefit at 60 days following treatment but, as that endpoint was neither prespecified nor significant, the FDA viewed it sceptically.

Matching or exceeding the 37% threshold set in the first Relax-AHF trial would probably be sufficient to win approval, although that seems ambitious. As a comparison, Novartis’s chronic heart failure drug Entresto won approval with a 20% reduction in cardiovascular death.

Another vasodilatory in-hospital infusion for acute heart failure, Natrecor, won approval based on its effects on breathlessness, but in a post-approval outcomes study it failed to show any mortality benefit, or indeed any breathlessness benefit. Diuretics, meanwhile, relieve volume overload, but long-term outcomes data are scant.

Thus, should serelaxin prove that it can significantly reduce cardiovascular death, even if it does not necessarily match Entresto’s standard it should have a good shot at approval.

Second string to the bow

Success in the trial could allow Novartis to build out a heart failure franchise anchored by Entresto. That agent, a combination of an angiotensin II antagonist and a neprilysin inhibitor, has had a slow start – one of several factors in Novartis’s difficult year – but is still reckoned to sell $4.7bn in 2022, according to EvaluatePharma’s consensus of sellside analysts.

The same analysts forecast $1.4bn in sales from serelaxin. Taken together, the agents will account for more than three quarters of the total sales growth Novartis will see between 2015 and 2022.

Success in symptomatic endpoints and signs of a mortality benefit, despite the scepticism that the first Relax-AHF trial generated, was enough for Novartis to justify investing more in serelaxin. However, the ularitide findings raise questions about the ability of a short-term, in-hospital AHF treatment to prevent cardiovascular death over a longer follow-up. Novartis clearly believes that serelaxin can succeed where ularitide failed.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @ByJonGardner on Twitter