A possible shift in policy at the FDA means that the much-heralded novel cholesterol drug bempedoic acid could be substantially delayed.
Esperion Therapeutics' agent, formerly known as ETC-1002, had previously been thought to be eligible for approval within a few years. But earlier this week, the company announced that, after discussions with the FDA, it now appears that bempedoic acid won't be eligible for FDA approval until the completion of a large cardiovascular outcomes trial.
Bempedoic acid is being developed by Esperion for lowering LDL cholesterol in statin-intolerant patients. The company had previously said that it believed approval could be based on phase III studies demonstrating that it was safe and effective in lowering LDL cholesterol as a surrogate endpoint in statin-intolerant patients with hypercholesterolemia.
But this week, the company said that the FDA "indicated its position regarding an LDL-cholesterol lowering indication could be impacted by potential future changes in their view of LDL-cholesterol lowering as a surrogate endpoint or the possibility of a shift in the future standard-of-care for statin intolerant patients with elevated LDL-cholesterol levels." Without the surrogate endpoint of LDL lowering, the approval would be pushed back to 2022 when the company expects to complete the hard outcomes trial.
The company also announced this week that it began LDL-lowering phase III trials in January of this year. The company anticipates European approval of bempedoic acid by 2019 on the basis of these trials. Esperion also announced that the cardiovascular outcomes trial, which will be known as Cholesterol Lowering via Bempedoic Acid, an ACL-inhibiting Regimen (CLEAR) Outcomes, will be chaired by Steve Nissen, MD, of the Cleveland Clinic, and will enroll 12,600 statin-intolerant patients with or at high risk for cardiovascular disease. The company said the trial will be initiated in the fourth quarter of 2016.
For many years, Esperion had made repeated assurances that it could gain approval based on the LDL surrogate. But, as Matthew Herper wrote in Forbes this week, "It should have always been obvious that the FDA might ask for a study that looks at hard endpoints like heart attacks and strokes, not just blood test results. The FDA was hurt by years of controversy over its approval of a Merck drug, Zetia [ezetimibe], that lowered cholesterol and now looks set to require such big trials regardless."
Another issue raised by Herper is the size of the statin-intolerant population. Are there enough potential patients to make the drug profitable? Given the modest success of the PCSK9 inhibitors so far, does it even matter that the company won't get an early approval, since it now appears that only a positive cardiovascular outcomes trial will drive usage?
Another issue may be worth raising: In its early days, Esperion said the drug had all kinds of potential benefits. In addition to lowering LDL cholesterol, early studies suggested beneficial effects on inflammation, glucose metabolism, blood pressure, and weight control. It may now be reasonable to wonder why the company focused so exclusively on LDL cholesterol, especially given that it was years behind the PCSK9 inhibitors in development.
Esperion said that it has enough money to complete the phase III trials, but by all accounts it will need extra funds to finish the cardiovascular outcomes trials. This means the company will need to find a partner or raise cash to complete the trial. But the once high-flying company has lost much of its stellar reputation. The stock price has plummeted from nearly $100 last summer to under $10 this week. The company long wanted to bring bempedoic acid to market on its own. Now it may be forced to partner -- if it can find one.