Risk factors

Oral PCSK9 inhibitor shows robust LDL-C lowering effects in Phase 1 studies


An oral PCSK9 inhibitor has been shown to have robust LDL-cholesterol lowering efficacy on top of statins in the first human trial results presented at AHA 2021.

Unlike currently available PCSK9 inhibitors which are given by injection every two to four weeks, Merck’s MK-0616 has been developed specifically as an orally-available medication that has GI absorption, said Dr Douglas Johns (PhD), clinical director of translational medicine/clinical pharmacology at Merck Research Laboratories.

Speaking at AHA 2021 virtual meeting,  he said the search for an oral drug had focused on cyclic peptides which  “bind to the flat PCSK9:LDL-R interface with mAb-like affinity.”

While most cyclic peptides had poor oral absorption, the molecule MK-0616 appeared to be chemically stable and resistant to GI degradation, he noted.

This had been confirmed in a single dose study involving 60 men, in whom oral doses of up to 300mg of MK-0616 reduced blood levels of free PCSK9 protein by more than 90% from baseline, regardless of dose. There were also no lab or ECG side effects.

A second study of multiple once a day dosing for 14 days in men (27) and women (13) who were already taking statins showed that MK-0616 decreased LDL-C by around 65% over and above the effects of the statin.

Dr Johns said he believed this was the first report of successful oral absorption of a synthesized cyclic peptide like MK-0616 in humans.

“We were pleased that it appeared to be consistently absorbed and concentrated in patients’ blood, and that it reduced cholesterol levels so effectively,” he told the meeting.

“The initial results are encouraging; however, more clinical studies are needed to confirm these findings, given limited clinical experience with the molecule MK-0616,” he added.

In a AHA 2021 discussion, Professor Anne Goldberg an endocrinologist and lipid researcher at Washington University School of Medicine, St Louis, said an oral PCSK9 inhibitor would have advantages over injection of being easier and more acceptable for patients to take, with the potential for use earlier in the course of lipid abnormalities.

However she said there are many additional questions to be addressed for an oral oral PCSK9 inhibitor such as the its metabolism, excretion, and drug interactions, which would —more of an issue than with the injectables.

And even if an oral PCSK9 inhibitor achieved 50% additional LDL reduction in addition to statin there was a question of whether this was likely to decrease cardiovascular risk, she added.

Also contributing to the discussion at AHA 21, Associate Professor Erin Michos, a cardiologist at Johns Hopkins Medicine, Baltimore said the oral agent appeared to have robust LDL lowering of 65% on top of that therapy.

“That is much greater than the other non-statin oral agents that are available such as eztimibibe, which lower LDL in the range of 18%,” she said.

“This is important because registry data shows that up to two thirds of high risk patients are not meeting their LDL goals and only 5% are taking a PCSK9 inhibitor.

“So having phase 1 data for a potential oral agent that is highly effective is really exciting, but of course we need evaluation in larger numbers of patients,” she added

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