Esperion unveiled top-line results from a yearlong phase 3 trial of bempedoic acid, showing it can lower LDL cholesterol levels by an additional 20% over 12 weeks in high-risk patients taking statins. However, the study also reported 13 fatalities in its treatment arm, a rate of 0.9%, about three times that seen with placebo.
Shares tumbled by more than 20% before the market opened. The company’s initial press release categorized the adverse events as unrelated to the treatment, with deaths listed in a separate chart (much to the chagrin of Bio-Twitter), but did not offer an immediate explanation.
On a later conference call with investors, Esperion’s senior vice president for clinical research, Bill Sasiela, said the deaths stemmed from an older, less-healthy study population, two-thirds of which were current or former smokers.
Five of the deaths in the treatment arm were related to lung cancer, with most seeing tumors discovered within the first three months of the study. The short timeline made it highly unlikely that those events were caused by bempedoic acid, Sasiela said. In addition, between 12% and 14% of the overall participants had a history of cancer.
Another five deaths were cardiovascular-related, with most events occurring within the first 60 days. Esperion CEO Tim Mayleben described the study’s population as more rigorous than the intent-to-treat population, with maximally tolerated statins and advanced disease, with about 80% diagnosed with hypertension and 28% with diabetes.
The study, the company’s largest in bempedoic acid, enrolled 2,230 patients at high risk for cardiovascular events, requiring diagnoses of heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease.
Participants were randomized 2:1 versus placebo, which saw two total deaths, or 0.3%, with one being labeled as CV-related following adjudication by an independent committee.
Though the trial excluded patients who had had a significant cardiovascular event within three months of enrolling, the company said the safety results were as expected—and that previous trials covering that early timeline did not produce cause for alarm.
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The phase 3 trial met its endpoints in safety and efficacy, including a 22% reduction in high-sensitivity C-reactive protein, and Esperion expects to submit applications to the FDA in the first quarter of 2019, and in Europe by the second quarter.
With daily, oral bempedoic acid, Esperion hopes to offer a cheaper alternative, at about $4,000 annually, to lowering LDL in combination with a statin, compared to PCSK9 inhibitor infusions from Amgen and Regeneron with list prices that can reach $14,000 a year.
The company expects results from three more phase 3 studies in the coming months, examining bempedoic acid alone and in combination with ezetimibe, also known as Merck’s Zetia.
Pfizer's former R&D executive and Forbes columnist John LaMattina said on Twitter this morning: "My guess is that the FDA will require the results of Esperion's CV outcomes study before approval. In addition, the price that Esperion plans to charge for bempedoic acid is not much lower than the price that Express Scripts apparently is getting from Regeneron for Praluent. There's also the issue that more patients died on bempedoic acid compared to placebo in this trial. Given that the bempedoic acid mechanism isn't locked down, the FDA will be uncomfortable approving without the CVOT."