Novartis Heart Drug Failure Rattles Market for Rival Treatments

(Bloomberg) — Few new ideas in heart-drug research appeared to have as much going for them as Lp(a).

The inherited form of cholesterol, which affects roughly one in five people, has been closely linked to heart disease by decades of population and genetic research. That made it a tantalizing opportunity for the world’s biggest drugmakers, who’ve raced to design medicines to lower the particle.

On Friday, the first big test of whether those drugs could prevent cardiovascular problems failed. The results from Novartis AG’s trial stunned competitors and scientists, raising questions about rival medicines from Amgen Inc. and Eli Lilly & Co. and prompting analysts to shave billions of dollars from their forecasts.

“This is a major and genuinely surprising setback for the field,” said Harlan Krumholz, a cardiologist and scientist at Yale University and Yale New Haven Hospital. “We were all expecting we would have a new treatment soon.”

Akash Tewari, an analyst from Jefferies, cut his peak sales estimate for Amgen’s drug olpasiran to just $1.3 billion from about $4 billion. The company’s market value shrank by about $24 billion after Novartis’s announcement.

Lp(a), short for lipoprotein(a), is a cholesterol-carrying particle that circulates in the blood. High levels are largely determined by genetics, meaning diet and exercise don’t have much effect. People can have dangerously elevated Lp(a) even when their conventional cholesterol numbers look relatively normal, and high levels have been linked to a greater risk of heart attacks, aortic valve disease and other cardiovascular problems.

Genetic studies provided another layer of evidence: People born with variants that produce higher levels face greater lifetime risk, while those predisposed to lower levels appeared to be protected.

For decades, doctors could identify the risk but had few ways to address it directly. Then drugmakers developed medicines designed to interfere with production of a protein needed to make the particle, in some cases driving Lp(a) levels down by more than 90%.

Novartis was the furthest ahead with pelacarsen. While the experimental drug successfully lowered Lp(a) levels, that didn’t translate into meaningful outcomes for patients.

Novartis didn’t disclose details from the trial, and drug development is notoriously risky.

But the failure has left cardiologists, drugmakers and investors trying to understand what went wrong. The hypothetical explanations range from questions about the drug’s potency and study design to a much more troubling possibility for the entire field.

One option is that pelacarsen simply didn’t lower Lp(a) enough. The drug produced reductions of roughly 80% in earlier tests, while the newer medicines from Amgen and Lilly have achieved reductions of more than 90%. Genetic modeling has suggested that a steep reduction may be needed to produce a measurable benefit, particularly over the short span of a clinical trial.

The choice of patients in the Novartis trial could also have made success difficult. The study enrolled people who already had cardiovascular disease and were receiving other treatments to lower their risk. By then, decades of exposure to elevated Lp(a) may already have contributed to plaque and other damage that can’t easily be undone.

Stroke Questions

“This first and foremost demonstrates that it’s very difficult to alter something in the short term,” said Pia R. Kamstrup, professor and head of the department of clinical biochemistry at Copenhagen University Hospital – Herlev Gentofte.

There are also questions about the way Novartis designed the clinical trial. Its main measure of success included cardiovascular death, heart attacks, strokes and urgent procedures to restore blood flow to the heart. But Lp(a)’s association with stroke is weaker than its link to coronary disease. Amgen, which is testing its rival drug olpasiran, didn’t include stroke in the main goal of its trial, which is still ongoing.

Those differences leave room for another drug to succeed, experts say. Before the Novartis news, Amgen research chief Jay Bradner cautioned against treating a pelacarsen failure as a final verdict on the field.

But there’s one more fundamental possibility that would cast doubt on the entire Lp(a) field: When does overwhelming evidence that something predicts disease become sufficient evidence that it should be targeted with a drug?

Some cardiologists like Kausik Ray, a professor at Imperial College London, argue that Lp(a) is clearly more than an innocent marker of cardiovascular risk. Others doubt whether lowering the particle in other trials will yield different results.

“The data weren’t sufficient to turn a risk marker into a therapeutic target,” according to Mahir Karakas, a professor at University Medical Center Hamburg-Eppendorf. “One thing is to mark risk; another is to cause it.”

–With assistance from Robert Langreth.

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