Over 600,000 Americans die every year because of heart disease, and those deaths are often due to patients failing to achieve their bad cholesterol target despite taking statins. In a bid to change that, Esperion Therapeutics (ESPR -1.29%) is developing bempedoic acid, a drug that lowers cholesterol in an entirely new way.

So far, bempedoic acid's trials show it effectively reduces bad cholesterol levels, but Esperion Therapeutics' stock price has been waylaid by safety concerns. Can Esperion Therapeutics overcome worry over its safety and reshape the heart disease prevention market?

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What's at stake

Over one-fifth of Americans between ages 40 to 75 take statins to lower their bad cholesterol, but millions of patients discontinue using these drugs because of side effects, or they fail to see their cholesterol levels drop to desirable levels.

Because statins are so widely used, they're the most prescribed medicines in the world, and that's been a bonanza for companies like Pfizer (PFE -0.85%), which developed top-selling cholesterol drug Lipitor, and Merck & Co. (MRK -0.90%), which created cholesterol-lowering add-on therapy Zetia.

At their peaks, Lipitor was hauling in nearly $14 billion in annual sales and Zetia was generating more than $2.5 billion in annual revenue. Both of these drugs have lost patent protection since then, yet they remain commonly prescribed staples in the battle against bad cholesterol, a fatty substance that can build up in arteries, leading to a heart attack or stroke.

Current treatment falls short

Up to 45% of patients who are prescribed statins discontinue taking them within six months, according to a study published in the Annals of Internal Medicine.

That's frustrating given that studies have proven statins' cholesterol-lowering ability translates into a reduced risk of cardiovascular events, like a heart attack, that can result in death. 

Side effects occur in up to one-third of statin patients, and confusion, memory loss, and muscle weakness are often cited as the reason for discontinuing treatment. The decision to stop taking statins can be deadly, though. In one 28,000-person study, 8.5% of patients who ditched their statins suffered a major cardiovascular event within four years compared to just 7.6% of patients who continued taking their statins.

New treatment options

Statins work by reducing cholesterol production in the liver, but in 2015, the FDA approved two new drugs that reduce cholesterol by boosting the number of cholesterol receptors in a patient's liver. These drugs inhibit a protein called PCSK9, and in trials, they reduced bad cholesterol levels by as much as 60% when used on top of statins.

One of these two drugs is Amgen's (AMGN 0.05%) Repatha, and the other is Praluent, which was co-developed by Sanofi SA (SNY -0.95%) and Regeneron Pharmaceuticals (REGN -0.49%). Both drugs launched to billion-dollar blockbuster expectations, but because they're complex biologics that are expensive to make, they cost about $14,000 per year. Their high cost, plus the fact that they're injected rather than taken orally, may make them best suited for patients with stubbornly high cholesterol who are at the greatest risk of heart disease.

For the millions of patients who are close to achieving their bad cholesterol target, Esperion Therapeutics' bempedoic acid may be a better option. Like statins, bempedoic acid reduces cholesterol production; however, it does so upstream of statins, so it can be dosed alongside them, or in place of them in patients who can't tolerate statins.

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Effective, but investors are antsy

In trials, bempedoic acid has shown that it lowers bad cholesterol when used in addition to Lipitor, Zetia, and PCSK9 inhibitors.

In phase 2 trials, combining bempedoic acid with statins reduced bad cholesterol levels by an additional 20%, and in early March, Esperion Therapeutics reported results from a phase 3 study showing that combining bempedoic acid and Zetia lowered bad cholesterol by an additional 23%. The company also reported phase 2 data in March showing that bempedoic acid's use alongside PCSK9 therapy reduced bad cholesterol by an extra 27%, and this week, it reported phase 3 data from a 2,230 patient study confirming that using it alongside statins lowered bad cholesterol by an additional 18%.

The ability to reduce bad cholesterol by an additional 20% could allow millions of patients to reach their bad cholesterol targets, yet investors reacted to Esperion Therapeutics' news by pressing the sell button.

After reporting data from its combination trial with Zetia, Esperion Therapeutics tumbled because of concerns regarding elevated liver enzymes, and then, shares fell again this week because more people died in the statin study than died in the placebo group.

In the Zetia combination study, two patients, or 1.1% of participants, had liver enzymes levels in their blood that were greater than three times the upper limit of normal. That's not good news, but it should be taken in context. If you include the results from the Zetia study with results from all of the studies presented so far, the rate of patients above three times the upper limit of normal falls to 0.58%, which compares favorably to large-scale Lipitor studies showing elevated liver function above 3 times the upper limit of normal occurs in 0.7% of patients.

In the statins study, 0.9% of patients taking bempedoic acid died compared to just 0.3% of patients taking a placebo. Although that discrepancy raises eyebrows, independent monitors say bempedoic acid wasn't to blame for the deaths. Instead, it appears the deaths were due to chance.

According to Esperion Therapeutics, five of the 13 deaths in the bempedoic acid arm of this study were related to cardiovascular disease, and five more were caused by cancer. Of the remaining deaths, gastrointestinal problems, including pancreatitis, caused two deaths, and one death was due to a neurological problem that may have been a stroke.

What now

Esperion Therapeutics says it's on track to file bempedoic acid for approval in 2019, but first, data from the drug's remaining trials will need to continue demonstrating its efficacy and mitigate lingering safety concerns. Results from three phase 3 trials are still anticipated, including:

  • One pivotal study in patients with atherosclerotic cardiovascular disease (ASCVD) on maximally tolerated statin therapy, with top-line results expected in September 2018.
  • One pivotal study (study 3) in statin-intolerant patients with ASCVD, or at a high risk for ASCVD, with top-line results expected in May 2018.
  • One pivotal study evaluating a bempedoic acid/Zetia combination pill in 350 patients with ASCVD, or at high risk for ASCVD, on maximally tolerated statin therapy, with top-line results expected in August 2018.

If these trials don't raise any new concerns, then an argument can be made that bempedoic acid will clear the FDA's review sometime in late 2019 or early 2020. If so, then single-dose combination pills including it, Lipitor, and Zetia could eventually become the standard of care in second-line treatment, and that would represent a blockbuster market opportunity that investors shouldn't ignore.