A phase 3 trial has found that adding Esperion’s bempedoic acid to Zetia lowers LDL cholesterol by more than Merck & Co.'s cholesterol-fighter alone. The result sets Esperion to file for approval in the U.S. early next year, although a delay to its closely watched safety trial means doubts about its prospects will linger until October.

Bempedoic acid blocks cholesterol biosynthesis in the liver, leading Esperion to pitch it as a way to help patients who need something stronger than a statin. That pitch has taken some big hits as the drug has advanced through the clinic, most notably when an earlier clinical trial reported a higher death rate in the bempedoic acid arm. The safety scare wiped a chunk off Esperion’s share price and put safety front and center for all future readouts.

The top-line data from the phase 3 are free from safety red flags. The rate of serious adverse events was comparable among cohorts of patients who received bempedoic acid and Zetia in combination or as monotherapies, although the cocktail was associated with a higher rate of urinary tract infections. None of the serious events were linked to the study medication.

Esperion cleared the efficacy bar, too. LDL-C fell 35% in patients who received the combination, as compared to 24% among the subjects who took the active ingredient in Merck’s Zetia alone. Figures from the intent-to-treat analysis were a few percentage points lower across the board, resulting in the experimental drug statistically outperforming Zetia with a p value of less than 0.001.

The study also linked the combination to a reduction in high-sensitivity C-reactive protein. The presence of the protein is associated with inflammation and a higher risk of developing cardiovascular disease.

Those findings suggest bempedoic acid may safely improve the health of patients with elevated cholesterol levels, but a piece of the data jigsaw is missing. The data will come from a safety study that was due to readout by the end of September. The readout has now slipped to October, although Esperion is still on course to file for FDA approval in the first quarter of next year.

Doubts about the prospects of bempedoic acid will persist until the safety data are in. But Esperion has seen enough in the clinical data delivered to date to tout its drug as a good option for patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH).

"We know that 35% LDL-C lowering could help more than 6 million ASCVD and/or HeFH patients on maximally tolerated statins achieve LDL-C levels of 70mg/dL or less, an elusive LDL-C target for most patients today," Esperion CEO Tim Mayleben said in a statement.

If Esperion guides bempedoic acid past the safety readout and onto the market, attention will turn to whether this pitch resonates with payers. Today, patients whose cholesterol isn’t controlled by generic statins may progress onto PCSK9 inhibitors. These biologics carry a high, but falling, price tag. Esperion thinks that creates an opportunity for bempedoic acid to slot into the treatment pathway between statins and PCSK9 inhibitors.

Editor's Note: A previous version of the story mistakenly referred to Zetia as a statin. It actually lowers plasma cholesterol levels rather than suppressing its production in the liver.

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