Oral PCSK9 Inhibitor Slashed Cholesterol

People with high LDL cholesterol already on statin therapy were able to reduce their levels by as much as 65% with MK-0616, an investigative oral PCSK9 inhibitor, a researcher reported at the American Heart Association (AHA) virtual meeting.

In two phase I trials, MK-0616 was effective in reducing cholesterol within 14 days, reported Douglas Johns, PhD, of Merck Research Laboratories in Kenilworth, New Jersey.

In the first study, involving 60 healthy male volunteers, use of MK-0616 reduced blood levels of free PCSK9 protein by more than 90% from baseline at all single-dose levels tested (10 mg to 300 mg), Johns said. The protein is known to contribute to high LDL levels.

In the second study, 51 men and women being treated for hypercholesterolemia participated in a randomized crossover-design trial of single oral doses of MK-0616 ranging from 10 mg to 20 mg, with 23 receiving at least one dose of placebo. In each crossover period, 75% of participants received MK-0616 and 25% received a placebo.

LDL levels decreased by about 65% from baseline in participants receiving MK-0616, compared with about 5% for those who received placebo.

Johns noted that delivering the oral agent with meals attenuated the effect on reducing cholesterol.

“I believe this is the first report of successful oral absorption of a synthesized cyclic peptide like MK-0616 in people,” Johns said at an AHA press conference. “We were pleased that it appeared to be consistently absorbed and concentrated in patients’ blood, and that it reduced cholesterol levels so effectively.”

Currently approved PCSK9 inhibitors are injected agents, and there had been speculation that making an oral PCSK9 inhibitor might not be feasible.

“In spite of how difficult it has been historically to identify and develop oral PCSK9 inhibitors, our goal is to deliver a simple oral medication to help patients lower their bad cholesterol,” Johns said. “We used novel technology and medicinal chemistry to identify a molecule — MK-0616 — that can be administered orally to block the PCSK9 protein, subsequently helping lower ‘bad’ LDL cholesterol that can build up in arteries.”

“There are still an unacceptably high number of people worldwide who are still trying to control their cholesterol, despite the existence of numerous therapies,” he added.

Adverse effects appeared to be manageable: “MK-0616 was well tolerated at doses up to 300 mg with no deaths, serious adverse events, or clinically meaningful trends in laboratory safety tests, vital signs, or electrocardiographs as a function of [the] study intervention,” Johns and his colleagues reported in their abstract.

AHA’s designated press briefing discussant, Erin Michos, MD, MHS, director of Women’s Cardiovascular Health at Johns Hopkins Medicine in Baltimore, said: “I was very excited about this study. The agent is well absorbed and concentrated in patients’ blood, and it inhibited the target it is supposed to inhibit.”

“But more importantly, it reduced what we care about, as there was a 65% lowering of LDL cholesterol,” she continued. “We think that LDL is causally related to the development of atherosclerotic cardiovascular disease, and it is the primary central target of all our interventions.”

“We now have PCSK9 monoclonal antibodies that are administered twice a month, which lower LDL in the range of 50-60%; now we see that MK-0516 lowers LDL by 65% on top of statins,” Michos said. “This is important because registries show us that two-thirds of at-risk patients remain above goal for LDL cholesterol. I am very excited at the potential to have another oral agent that is highly effective for LDL lowering. Of course, we need larger clinical trials.”