Entresto approval revives heart failure sector

The progress of Novartis’ Entresto to yesterday’s approval has sparked interest in treatments for congestive heart failure, an area that has been stagnant since so many molecules modulating the renin-angiotensin system have lost market exclusivity.

While much of the recent excitement has been around advanced therapies like Celyad’s C-Cure, small molecule approaches like Bayer’s vericiguat are also advancing through the pipeline (see table below). The payoff is clear – Entresto alone will outsell all other heart failure drugs combined in 2016.

Innovation, sort of

The pill formerly known as LCZ696 gained US approval six weeks early on the strength of its benefit in reducing the risk of cardiovascular death or hospitalisation when compared to the ACE inhibitor Vasotec. It marks the second FDA heart failure approval this year, following Amgen’s Corlanor.

Entresto is on track to be the 18th-biggest drug by sales in 2020, ringing up $4.5bn, according to EvaluatePharma’s consensus forecasts. This will be made possible by its ability to meet a clear need in a disease that leads to death in 30-40% of patients within a year of diagnosis, and the failure of approved therapies to reduce that risk.

Entresto’s pivotal trial was terminated early because of an efficacy benefit in its head-to-head trial against an ACE inhibitor – it reduced the risk of cardiovascular death by 20%, death from any cause by 16% and heart failure hospitalisations by 21% (ESC– Novartis heart failure pill scores big, August 30, 2014).

This should make its discussions with payers a little less fraught, as it ought to be able to show an economic benefit as well as a clinical one. Novartis set a list price of $12.50 a day, or about $4,600 for a year of therapy.

Yet Entresto is novel only in the sense that it combines two types of agents known to modulate blood pressure. It combines Diovan’s active ingredient valsartan with sacubitril, an inhibitor of the enzyme neprilysin, which breaks down two peptides to achieve reductions in blood volume. Neprilysin inhibitors have been unsuccessful as single agents in hypertension and heart failure, however.

Thus heart failure must be seen as a huge target for innovators, stimulating a decent pipeline of contenders looking to take a share of a market estimated at $9.6bn in 2020.

Stem cells and more

The stem-cell therapies NeoFuse from Mesoblast and C-Cure from Celyad figure prominently in the phase III pipeline. Because heart failure results from diseased tissues, regenerative approaches like cell therapies have been thought of as a promising approach.

Mesoblast’s allogenic project, licensed to Teva Pharmaceutical Industries as a result of its buyout of Cephalon, entered its late-stage studies last year. Celyad, which floated on the Nasdaq last month, started phase III testing of its autologous therapy in 2012.

In keeping with the advanced therapy theme, Celladon’s gene therapy Mydicar failed in a phase II trial in April, and the company has cancelled the programme and initiated a strategic review with an eye toward sale or liquidation (Celladon spoils the gene therapy party, April 27, 2015).

Others are still alive in phase II, however. Some important readouts are due in the next few months for the Bayer candidate vericiguat and Cytokinetics’ Amgen-licensed omecamtiv mecarbil, which also had an unfortunate miss in 2013 (ESC – Heart failure miss knocks wind from Cytokinetics, September 3, 2013).

Bayer has a second shot on goal in this space with finerenone, which aims to block the negative effects of aldosterone on heart tissue. Phase II trials have reached their scheduled completion date, so if it is to advance to phase III news should be forthcoming soon.

Finally, in acute heart failure Trevena’s Allergan-partnered TRV027 has passed an interim analysis in a phase IIb trial and is expected to report topline data in the first half of 2016. This project is a more conventional angiotensin receptor antagonist, like Diovan, but has a signalling profile that makes it suitable for use in the acute phase of heart failure.

Novartis has shown that there is opportunity yet in heart failure. However, Entresto has set a high benchmark for innovative agents to surpass.

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