Entresto Sinks 38%; Novartis Bets on Leqvio

On July 7, 2015, the FDA approved Novartis's heart failure drug Entresto six weeks ahead of schedule.

Eleven years later, on October 27, Novartis reported third-quarter results. Entresto sold $1.165 billion, down 38% from a year earlier.

While its best-selling heart drug was being eaten by generics, Novartis watched both of its succession bets in heart and muscle disease fail within a single week in September.

The quarter also carried a $1.9 billion impairment.

That leaves one card in the cardiovascular hand: Leqvio, the cholesterol-lowering shot given twice a year. Its outcomes trial, ORION-4, is due to read out in the fourth quarter.

ORION-4 will succeed. Leqvio will significantly cut heart attacks, strokes and other major cardiovascular events, and the reduction will be at least the 15% that Amgen's Repatha delivered.

The reason is simple. Leqvio hits a target that has already been proven. Pelacarsen lost on a target that never was.

01 | A ten-year blockbuster, halved in one summer

Entresto was supposed to be Novartis's model investment.

Heart failure is a large, chronic market. When the drug was approved, Novartis said nearly 6 million Americans lived with the condition.

It was built on PARADIGM-HF, an 8,442-patient trial in which it cut the risk of cardiovascular death by 20% versus the older drug enalapril. The trial stopped early. The FDA approved early.

That is the kind of evidence a heart drug needs: fewer deaths, not just a better lab value.

Over the next nine years it grew into Novartis's largest product. In 2024 it sold $7.822 billion, still growing 31% at constant currency.

Then came July 22, 2025.

It was the day the patent wall came down.

That day Novadoz launched MSN's generic version of Entresto in the United States. Torrent followed two days later.

For a pill taken every day for years, a cheaper copy changes prescriptions quickly. Pharmacies switch, insurers push, and the brand keeps only part of the market.

The numbers fell fast. In the first nine months of 2026, Entresto sold $3.651 billion, against $6.495 billion a year earlier. That is more than $2.8 billion gone in nine months.

The group did not fall with it. Third-quarter net sales were $14.5 billion, up 4% at constant currency. Core operating income rose 10%, and Novartis raised its full-year profit guidance.

The breast cancer drug Kisqali is carrying the load.

It sold $5.032 billion in the first nine months, $1.57 billion more than a year earlier.

Its third-quarter sales of $1.821 billion trailed the psoriasis drug Cosentyx, at $1.857 billion, by a hair.

CEO Vas Narasimhan said Kisqali "continued to outperform the CDK4/6 market," and management reiterated its peak sales outlook for the drug.

At that pace, Kisqali is on track to pass Cosentyx and become Novartis's largest drug.

None of that growth comes from the heart, though.

Figure 1 | Entresto has dropped to fourth place, Kisqali is right behind Cosentyx, and Leqvio is still the smallest line.

On October 6, in our Chinese-language piece on Novartis's succession problem, we wrote that the third-quarter report would have to answer one question: which revenue arrives, and when.

On cancer, Novartis has an answer. On the heart, the answer is narrower than it was a month ago.

02 | Two succession bets, both lost in one week of September

Novartis had two routes lined up to inherit Entresto's place in cardiovascular and serious disease.

The first was pelacarsen, an antisense drug licensed from Ionis that lowers lipoprotein(a), or Lp(a), in the blood.

People with high Lp(a) carry higher heart risk, and diet and statins barely move it. Proving that lowering Lp(a) prevents heart attacks would have opened the largest new lipid market in a decade.

On September 4, the answer arrived.

Lp(a)HORIZON enrolled 8,323 patients with established cardiovascular disease and elevated Lp(a). Lp(a) fell sharply. In a mid-stage study, pelacarsen had cut Lp(a) by up to 80% versus placebo.

The combined risk of cardiovascular death, heart attack, stroke and urgent revascularization did not fall significantly versus placebo.

Ionis CEO Brett Monia put it plainly: "we are disappointed that this did not translate to cardiovascular risk reduction."

The industry had bet heavily on that hypothesis. William Blair noted that "a large focus across the biotech industry has been paid to lowering Lp(a) levels."

BMO Capital Markets called the result "a meaningful setback for dedicated Lp(a)-lowering therapies."

Four days later, the second card turned over.

On September 8, del-desiran, the lead asset from Novartis's $12 billion purchase of Avidity, missed its primary endpoint of hand-muscle relaxation in the Phase 3 HARBOR trial in myotonic dystrophy type 1.

Novartis shares fell 12% in premarket trading that day.

Novartis had agreed to pay $72 a share for Avidity in October 2025, a premium of about 46%.

On October 27 the bill landed in the accounts. Novartis booked a $1.9 billion partial impairment on del-desiran, cutting its carrying value to $5.5 billion.

Narasimhan told reporters, "We remain very, very happy with the Avidity acquisition."

He called the write-down "the mathematical shift of our assumption," because another pivotal study will be needed.

The rest of the Avidity pipeline is still moving.

Del-zota has priority review in certain forms of Duchenne muscular dystrophy, and Novartis is discussing a possible accelerated approval for del-brax in FSHD with the FDA.

None of those are heart drugs, though.

Pelacarsen's status is blunter.

In the third-quarter presentation's submission table, its U.S. filing column reads "Will not be submitted."

Full data come at the American Heart Association meeting in November.

Figure 2 | Entresto took a decade to become a blockbuster and lost half of it in one summer; both successors fell in the same week.

03 | Two RNA drugs, one proven target

Novartis's heart franchise now rests on Leqvio.

It has been on the US market since December 2021, sold as a twice-yearly shot given in the clinic. It looks a lot like pelacarsen, and differs in the one place that matters.

Both are RNA drugs. Both work in the liver. Both block an RNA message before the cell can turn it into protein.

Pelacarsen blocks the message for apo(a), the protein that makes Lp(a). Leqvio blocks PCSK9.

PCSK9 acts as a demolition crew for LDL receptors on liver cells. With less PCSK9, the liver keeps more receptors that pull "bad" LDL cholesterol out of the blood.

In its December 2021 approval, Leqvio lowered LDL by up to 52% on top of statins, dosed at day one, month three, then every six months.

Figure 3 | Pelacarsen lowers Lp(a), a target never proven to cut events; Leqvio blocks PCSK9 to lower LDL, a proven cause of heart disease.

The marker is not the outcome. A drug can push a number down and still leave heart attacks where they were. HORIZON just showed that for Lp(a).

Here is the difference. The PCSK9 route has already been walked end to end.

In 2017, Amgen's PCSK9 antibody Repatha cut LDL by 59% in the 27,564-patient FOURIER trial and reduced major cardiovascular events by 15%.

After the first year, the drop in cardiovascular death, heart attack or stroke reached 25%.

ORION-4 is testing a mechanism that a 27,000-patient trial has already vouched for.

Leqvio lowers LDL a bit less than Repatha did, up to 52% versus 59%. It makes up for that with time on drug.

That is the core of the call.

Pelacarsen had no such precedent. HORIZON was the first outcomes trial of any Lp(a)-lowering drug, so it was a bet on the hypothesis that Lp(a) causes heart disease at all.

ORION-4's design also leans the right way. According to the UK Health Research Authority, it planned to enroll 15,000 people and treat them for about five years.

The benefit of lower LDL accumulates over time, so longer follow-up makes a difference easier to see.

That second FOURIER number matters most here. The longer patients stay on treatment, the wider the gap between the arms, and a five-year trial gives that curve room to separate.

The bear case deserves a hearing. Narasimhan himself noted that ORION-4 was partly run during the pandemic, when missed visits and missed doses could dilute the effect.

That risk is real, but it affects the size of the benefit, not its direction. Leqvio is given by a healthcare provider twice a year, which makes it harder to skip than an antibody patients inject at home.

04 | After the readout: how big a hole can Leqvio fill?

Even if ORION-4 succeeds, Leqvio cannot fill Entresto's hole.

It sold $506 million in the third quarter, up 64%, and management guides to more than $4 billion at peak. Entresto peaked at $7.8 billion.

What ORION-4 decides is how fast Leqvio gets there.

Most patients start with a statin. For any add-on drug, the question is always the same: does it prevent events, or does it only move a lab number?

The growth so far has come on LDL numbers alone. Q3 sales were up from $308 million a year earlier, without any outcomes data on the label.

Today its label says it lowers LDL. It does not say it prevents heart attacks.

Novartis's pipeline table puts the Leqvio secondary-prevention filing in 2027, and a second outcomes trial, VICTORION-2P, also reads out in 2027. ORION-4 is the first step for both.

The Lp(a) question now passes to others.

Truist analysts said the failure turns Amgen's olpasiran into a "higher-risk/higher-reward" bet rather than an outright write-off.

Amgen expects the olpasiran outcomes readout in 2028, and Eli Lilly's lepodisiran trial in 2029.

Novartis's own next-generation Lp(a) drug, DII235, is listed as "under assessment."

That leaves Novartis in an unusual spot. It ran the first Lp(a) outcomes trial, and now it will watch Amgen and Lilly decide whether that field exists.

For the next two years, its heart franchise is an LDL franchise.

That is not a bad place to be. LDL is the one lipid target where lowering the number has repeatedly meant fewer heart attacks.

Figure 4 | Repatha passed, pelacarsen failed, and Leqvio is sitting the same exam Repatha passed, on the same target.

If ORION-4 succeeds, Leqvio gets the one sentence its label is missing: it prevents heart attacks.

If it fails, Novartis's heart business shrinks to a declining generic-era Entresto and a cholesterol shot without an outcomes claim.

The evidence says the first outcome is far more likely.

Eleven years ago, Entresto won approval six weeks early. This time, Novartis has to wait for five years of heart events in 15,000 patients.

This article is industry and company analysis, not investment or medical advice.

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