Novartis' Entresto gains steam with cardiologists despite stinging heart failure trial flop

Entresto
Entresto will likely face sales challengers from the SGLT2 diabetes class and other candidates in the pipeline. (Novartis)

Novartis' blockbuster Entresto missed a big opportunity last year with a failed late-stage trial in certain heart failure patients without a current approved treatment. Despite that loss, and a slow start to market, analysts say Entresto is picking up steam with cardiologists—and it could translate into a major sales boost.

Cardiologists are betting on Entresto to race out to a big sales lead in the coming years as Novartis overcomes conservative physician opinion and payer roadblocks that dogged the drug's early days, SVB Leerink analysts said in a Wednesday note.

In a discussion with key opinion leaders, analysts found an overall positive view of Entresto's clinical efficacy in heart failure patients with a reduced ejection fraction (HFrEF) and a consensus opinion that the drug's uptake would rapidly build in the coming years as physicians grow more comfortable prescribing it to patients.

"Our specialists suggested that heart failure is a relatively conservative community with physicians and patients who are cautious about adopting new therapies," the analysts wrote. "(Heart failure) patients are also reluctant to rock the boat and look for new treatments when they are doing relatively well."

Leerink estimated that between 15% and 20% of HFrEF patients are currently treated with Entresto and expected that figure to "grow more rapidly" in the coming years. Entresto posted $569 million in the first quarter, up 62% from the same time period in 2019. Analysts have pegged the drug's sales to hit $4 billion by 2025.

What's more, cardiologists are holding out hope that Novartis' drug could get the nod in the currently untreated heart failure with a preserved ejection fraction (HFpEF) population, despite Entresto flopping a pivotal trial in that indication last year.

RELATED: AHA: Novartis hoping for 2nd go at broader use with 'profound' Entresto subdata

In June 2019, Novartis unveiled results from a phase 3 trial showing Entresto had posted a statistically insignificant 13% reduction in heart failure hospitalizations or death in HFpEF patients, seemingly shutting down the drug's $5 billion peak sales goal.

Later in the year, though, Novartis pointed to subgroup analyses from that trial as a possible avenue for future studies and a more limited approval—data that seems to have resonated with cardiologists, according to Leerink.

In November, the Swiss drugmaker said heart failure patients with an ejection fraction below 57% showed a stronger clinical response on Entresto than patients with ejection fractions above that threshold.

RELATED: ESC: Novartis looks for the bright side in flopped Entresto heart failure study

A month before, another unveiled analysis showed patients with a left ventricular ejection fraction equal to or below the median of 57% saw a 22% reduction in total CV events, and female patients showed a 27.5% reduction in the same measure.

Heart failure ejection fractions below 40% are usually defined as "reduced"––an indication in which Entresto is already approved to slash the risk of CV death and hospitalizations––while fractions above 40% are defined as "preserved," an indication which currently has no approved treatment.

Competitors looming

But Entresto isn't the only drug in the space, and at least one challenger—AstraZeneca's diabetes med Farxiga—is making a hard push at Entresto's lead.

RELATED: AstraZeneca's Farxiga scores landmark FDA nod in heart failure patients with or without diabetes

In May, Farxiga became the first SGLT2 inhibitor to win an FDA approval to reduce the risk of cardiovascular death or hospitalization in HFrEF patients with or without Type 2 diabetes. The FDA based its review on data from the phase 3 Dapa-HF trial, which showed Farxiga could cut CV risks by 26% over standard of care in patients with and without diabetes.

Cardiologists told Leerink that Farxiga's results were "impressive" and could secure a spot for AstraZeneca's drug—and maybe the rest of the SGLT2 class—as a standard-of-care add-on to Entresto.

Even better for Farxiga, what cardiologists described as a "resistance" to SGLT2s from endocrinologists isn't much of an issue for heart failure prescribers. Leerink's specialist predicted that heart failure patients with diabetes would most likely be referred to cardiologists who "prefer" using SGLT2s to manage patient outcomes.

Like Entresto, Farxiga is also chasing a vaunted approval in HFpEF with its phase 3 Deliver and Determined-Preserved trials, the first of which could read out by the end of the year.

RELATED: Merck, Bayer's trial win for heart failure rival could actually boost Novartis' Entresto

Cardiologists believe Farxiga has the best chance to play second fiddle in sales to Entresto by 2024 after a slow buildup period, but two investigational challengers could test that dynamic.

In November, Merck & Co. and Bayer posted a surprise phase 3 trial win for vericiguat, a novel oral guanylate cyclase stimulator, as an addition to standard of care for worsening HFrEF patients.

But cardiologists were less than blown away by vericiguat's results in that trial, saying a 10% risk reduction—even in a harder-to-treat patient population—wouldn't cut the mustard for prescribing physicians.

"Although the trial enrolled sicker patients than previous trials, the physicians cautioned against assuming a role for vericiguat for severe patients as the benefit of other HF therapies in this population could be just as good or better," the analysts wrote.

Meanwhile, Leerink pointed to Amgen's omecamtiv, a selective cardiac myosin activator, as a possible "highly overlooked asset" for cardiologists due to its unique mechanism of action. The drug received a fast-track designation from the FDA in May and is currently running a phase 3 outcomes trial of 8,000 HFrEF patients.

Because its mechanism of action is so different—omecamtiv increases interactions between myosin heads and actin filaments to boost pumping of the heart—cardiologists told Leerink that anything better than a 10% risk reduction and positive results in reducing death and hospitalizations could make the drug "highly competitive." Leerink put the drug's peak sales at around $900 million by 2025.