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Novartis' Game Changer: When Failure Turns To Success

This article is more than 9 years old.

Here's what two frequent skeptics have to say about the results of Novartis' new heart failure drug that were presented over the weekend. Stephen Nissen, chair of cardiology at the Cleveland Clinic and probably best known for highlighting safety problems with Merck's painkiller Vioxx, calls it "the first new heart failure drug in decades." Sanjay Kaul of Cedars-Sinai Health System, a stickler for procedure and nuance in the design of clinical trials, says that unless there are problems that only the Food and Drug Administration can uncover, it's "a major win."

This is a big deal. Heart failure, in which the heart pumps blood insufficiently, causing fluid to build up in the extremities and sometimes the lungs, afflicts 5.1 million Americans and costs $32 billion annually, according to the Centers for Disease Control & Prevention. Novartis' drug, still known by the codename LCZ696, was tested against a pill called enalapril, a member of a class of drugs called angiotensin-converting enzyme inhibitors, which are the standard therapy in the disorder. Patients who got LCZ696 were 20% less likely to be hospitalized for heart failure or die from cardiovascular causes -- a reduction of about three deaths and three hospitalizations for every 100 patients treated over the course of the study. For now, these benefits have only been shown in relatively sick heart patients, those whose hearts are pumping low amounts of blood per pump. A trial in patients whose hearts have trouble re-filling with blood will come next.

The financial impact for Novartis is obviously going to be big. Seamus Fernandez raised his 2026 forecast for LCZ696 sales from $3.2 billion to $6.4 billion, meaning that the drug could bring in $30 billion in revenue over the next decade. Even for a company with a stock market value of $220 billion, like Novartis, that's significant. It's more than likely that analysts are still underestimating how much Novartis will be able to charge for this drug, because it will have little in the way of competition, and how broadly it will be used.  As Nissen noted, new heart failure drugs mostly fail. There's not likely to be a lot of competition.

That also makes this a good time to think a bit about what it means when medicines fail. Because another drug that was based on the same basic idea as LCZ696 was one of the biggest clinical trial flameouts of the past couple decades, and it completely changed the direction of another large drug company, Bristol-Myers Squibb .

LCZ696 combines valsartan, the active ingredient in Diovan, with a new chemical to block neprilysin, which degrades chemicals that are involved in causing blood vessels to constrict. The result for both is less constricted blood vessels, and lower blood pressure.

Bristol-Myers, in fact, had the exact same idea with a drug, called Vanlev, that blocked both a class of hormones called endopeptidases (neprilysin is one) and the angiotensin-convering enzyme. Unfortunately, this resulted in a deadly side effect, a swelling of the throat and tongue that can cause patients to suffocate. Because Diovan blocks not the production of angiotensin (which, like it's name says, makes blood vessels tense) but the receptor it affects (it's an ARB , or angiotensin receptor blocker), Novartis' new combination does not cause those same side effects.

One lesson is that just because an approach failed before doesn't mean it will again, and that's important to remember. One group of medicines where this could be particularly important are what are known as the cholesterol ester transfer protein (CETP) inhibitors, designed to raise high-density lipoprotein, the so-called good cholesterol. Pfizer bet on one CETP inhibitor to be its replacement for Lipitor, which was the best-selling drug ever. Instead, it raised the death rate in clinical trials. Since then, a Roche CETP inhibitor has failed to do anything.

Studies of genetics have raised doubts about whether raising HDL with a drug would really be beneficial; people who genetically have higher HDLs don't seem to get a benefit. But, ironically, similar genetic studies seem to hint that there might be a benefit for people with lower levels of CETP, perhaps because they have lower levels of LDL, the bad cholesterol, or of other types of blood fat that might be bad for the arteries. It's even been proposed as a longevity gene. Could another CETP inhibitor work?

Two are in development. One from Merck, with results due in the first half of 2015; it has the unfortunate handicap that the molecule can stay in the bloodstream for years; and another from Eli Lilly, which could have results by 2017. Wall Street analysts don't expect much from either medicine. It's at least worth thinking about what happens if these drugs really do work.