LDL cholesterol levels reduced by oral PCSK9 inhibitor in phase 2 trial

MK-0616, an experimental oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, met its primary endpoint and substantially reduced levels of low-density lipoprotein (LDL) cholesterol in people with high cholesterol and/or heart disease related to clogged arteries, in a study being presented at the American College of Cardiology's Annual Scientific Session Together With the World Congress of Cardiology.

The experimental pill, MK-0616, is one of the first oral PCSK9 inhibitors to be tested in clinical trials. All currently available PCSK9 inhibitors must be administered through an injection under the skin. Like other PCSK9 inhibitors, MK-0616 is designed to reduce levels of LDL cholesterol in people who have too much of it, thereby lowering their risk of heart disease. PCSK9 inhibitors are usually taken alongside statins—the standard first-line therapy for treating high cholesterol—and can be used alone in people who cannot take statins.

Results from the phase 2 trial showed MK-0616 reduced LDL cholesterol by around 60% among people taking 30 mg or 18 mg daily, compared to those taking a placebo.

This is a highly effective compound that was well tolerated. MK-0616 could offer another potential option. Between this and statins and the other therapies we have, we should be able to basically treat almost everybody in terms of LDL cholesterol."

Christie M. Ballantyne, MD, director of the Center for Metabolic Disease Prevention at Baylor College of Medicine in Houston and the study's lead author

For the study, researchers enrolled 381 adults who had either a history of heart disease or risk factors for heart disease with elevated levels of LDL cholesterol. About 60% of the participants were taking statins at the start of the study, with about one-quarter receiving high-intensity statin therapy.

Participants were randomly assigned to one of five groups; one group received a placebo while the other groups received MK-0616 at one of four doses (6 mg, 12 mg, 18 mg or 30 mg per day). Participants continued taking the placebo or study drug for eight weeks and then discontinued their assigned regimen. Researchers assessed the change in LDL cholesterol between baseline and week eight (the study's primary endpoint) and tracked adverse events through week 16.

At eight weeks, MK-0616 doses demonstrated significant reductions in LDL cholesterol compared with placebo, showing drops of over 60% in those receiving 30 mg; 59% in those receiving 18 mg; more than 55% in those receiving 12 mg; and 41% in those receiving 6 mg daily. Participants also experienced large reductions in non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B (ApoB). These tests measure total "bad" cholesterol and particles that carry cholesterol in the blood, which can indicate a buildup of plaques in the arteries.

MK-0616 is designed to work via the same biological mechanism that available injectable PCSK9 inhibitors do, by helping the body clear LDL cholesterol more effectively. If further studies confirm the oral drug has a similar level of efficacy and safety as the injectable forms, researchers said having a PCSK9 inhibitor in a pill form could help lower costs, increase convenience and expand access to this cholesterol-lowering agent to more patients.

"I was told early on that developing an oral PCSK9 inhibitor is impossible," Ballantyne said. "But the technology keeps advancing. It's very exciting to see the tremendous advances in understanding the pathways and finding ways to make a challenging target like PCSK9 treatable with a once daily pill."

Researchers said the study found no evidence of serious side effects and no evidence that side effects increased with higher doses of MK-0616. However, longer studies involving more participants are needed to assess potential side effects more definitively.

As a phase 2 study, the trial was limited by a relatively short duration and small sample size. Researchers will continue to study how the drug behaves within the body to determine the efficacy and safety of this therapy in a phase 3 clinical trial program being planned.

The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., developer of MK-0616.

It was simultaneously published online in the Journal of the American College of Cardiology at the time of presentation.