Esperion Slumps on Lack of FDA Clarity for Cholesterol Drug

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  • Co. may need to wait 6 years before reaching the U.S. market
  • FDA may change the way it views treating bad cholesterol

Esperion Therapeutics Inc. slumped as much as 29 percent in late trading after saying its experimental drug may not win Food and Drug Administration approval based solely on its ability to cut cholesterol, raising concerns it may take six more years to reach the U.S. market.

Lowering bad cholesterol has been a requirement used to clear previous medicines, but the agency may change the way it views treating people with elevated levels. For Esperion, it could mean having to wait for the results of a trial that will determine if its bempedoic acid drug prevents heart attacks, strokes and death from cardiovascular disease, a trial that won’t be done until 2021.

The shares were down 27 percent to $11.78 at 7:05 p.m. New York time.

Esperion said in a statement Tuesday that it will start two sets of studies by the end of this year. The first, to be completed by 2019, will show whether the drug significantly lowers bad cholesterol, which until now has been the route to getting approval. The second will assess whether the pill reduces heart complications in high-risk patients who aren’t able to take statin medications, the gold standard of care. Esperion plans to submit the results to regulators by 2022.

No Clarity

The drugmaker said the FDA wouldn’t provide it with clarity on whether proof that the drug lowers bad cholesterol, known as low-density lipoprotein, or LDL, will be enough to get access to the U.S. market. While the agency granted limited approval to injected drugs from Sanofi, Regeneron Pharmaceuticals Inc. and Amgen Inc. based on their potent cholesterol-lowering abilities, definitive studies showing whether that translates into fewer heart attacks, strokes and deaths are still pending.

FDA officials “aren’t willing to give advice on whether an LDL lowering indication will be available years from now,” Esperion Chief Executive Officer Tim Mayleben said. “It’s not that the rules are different, but the FDA is saying that they don’t know if it will be different.”

Any time a drug’s benefit is measured by its effect on a surrogate marker, such as LDL cholesterol, its true ability to improve health remains somewhat uncertain, said Theresa Eisenman, an FDA spokeswoman. The agency approved the injected drugs for specific groups of patients because the benefit was expected to outweigh the risks, even before the final studies were complete, she said.

FDA Standards

For future decisions, a drug’s mechanism of action, magnitude of benefit, potential for side effects or other harm, and the target population could all affect the likelihood that the agency would approve a product that works in an entirely new way based on its cholesterol-lowering effects, she said.

European regulators told the company they will accept a filing based on cholesterol-lowering ability, which it plans to submit by 2019. An approval would provide Esperion with cash flow to continue the longer study. The company said it expects to have about $220 million in cash and investments on hand at the end of the year, enough to fund operations into the early part of 2019. 

“We have superior cash resources available to fund this program through those key inflection points,” Mayleben said. “We are not going to be asking investors for additional capital.”

Surrogate Markers

More than a dozen drugs have gotten FDA approval based on their ability to lower bad cholesterol over the past three decades. While the vast majority also found a reduction in cardiovascular complications, including death from heart disease, some recent results may have made the agency question whether LDL lowering is a good way to measure likely benefit.

Esperion’s cardiovascular outcomes trial will focus on about 12,600 patients who can’t tolerate statins, including medicines like Pfizer Inc.’s Lipitor and AstraZeneca Plc’s Crestor, now available in less expensive generic formulations. Many such patients may eventually turn to injected drugs like Amgen’s Repatha, or Praluent, from Sanofi and Regeneron, if long-term studies show a clear heart benefit.

Such a result would be a double-edged sword for Esperion. It could help the company get U.S. approval before obtaining proof that its drug lowers cardiac events. It may also make it difficult to find high-risk patients for its trial if drugs with proven benefits are available.

Clogged Arteries

Bad cholesterol contributes to plaque that can build up in the arteries, causing thick deposits can lead to heart attacks, strokes or death. Nearly 80 million Americans have elevated levels of bad cholesterol, with 3.5 million unable to take statins. Another 3.5 million Europeans and 1 million people in Japan are intolerant of the statin drugs. Many rely on Merck & Co.’s Zetia, which works by blocking the absorption of cholesterol in the stomach.

Esperion’s drug is a pill that reduces cholesterol production in the liver, similar to the way statins work. Unlike statins, the drug doesn’t seem to have an effect on muscles and is less likely to cause pain and weakness that limits their use, said Steve Nissen, chairman of cardiology at the Cleveland Clinic and chair of Esperion’s cardiovascular outcomes study. Esperion is developing its drug alone and in combination with ezetimibe, the active ingredient in Zetia.

“Esperion realized they needed to show the drug has an effect on the things that matter to patients,” Nissen said. “No one has ever done an outcomes study on statin-intolerant patients. These are very high risk patients and we could see an early benefit,” he said. “Stranger things have happened.”