Daily Oral PCSK9 Inhibitor Encouraging in
Phase 1 Trials

November 23, 2021

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a "me-too" drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

In fact, it would be something of a breakthrough. The new agent under study — now called MK-0616 — comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase-1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, "MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams," the maximum tested in the studies, reported Douglas G. Johns, PhD, at the virtual American Heart Association (AHA) Scientific Sessions 2021.

The collective results from the oral agent's earliest human experience are "definitely encouraging" and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Johns, clinical director of translational medicine for Merck in Kenilworth, New Jersey.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), FDA-approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Johns said MK-0616 is a cyclic peptide that is "about one-hundredth the size of a monoclonal antibody, but we're able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint."

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents "also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval," observed Anne C. Goldberg, MD, as invited discussant after the Johns presentation.

Also, "They require every 2- to 4-week injections. They're generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia," said Goldberg, from Washington University School of Medicine, St. Louis, Missouri. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

"Certainly, an oral form would be easier to use," she said. "This would be particularly helpful in patients averse to injections," especially, perhaps, in kids. "Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection." That would be good reason to emphasize the enrollment of children in the drug's upcoming clinical trials, Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. "If it's priced too high, then are you really going to see the increased use?" she posed. "Certainly, there's a high bar for therapies that are add-on to statins in terms of cost effectiveness."

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, 3 participants took the drug for every 1 who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by "about 50% to 60%" when dosing was preceded by food intake within the previous 30 minutes. "However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible."

These preliminary results show the drug is "orally bioavailable and exerts a clinically meaningful effect," Johns said. "However, there's definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year."

The research was funded by Merck. Johns disclosed employment with and equity ownership in Merck, as did all the study's coauthors. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

American Heart Association Scientific Sessions 2021. Session LBS.06 The Clinical Safety, Pharmacokinetics, and LDL-Cholesterol Lowering Efficacy of MK-0616, an Oral PCSK9 Inhibitor. Presented November 15, 2021.

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