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Merck readies oral, macrocyclic PCSK9 inhibitor for phase II test
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Nov 18 2021
PCSK9 remains a fertile testing ground for new therapeutic approaches, as Merck & Co. prepares to advance its oral tricyclic macrocycle MK-0616 into phase II trials. The company disclosed the compound's origins in The Journal of Medicinal Chemistry in October, and showcased phase I data at an American Heart Association meeting in November. It joins the growing LDL-cholesterol-lowering pipeline.
"PCSK9 is our flagship, representing what we think we can do with cyclic peptides in the future," says Rob Garbaccio, Head of Discovery Chemistry at Merck. "There are lots of really interesting, long-standing problems in biology that we believe this technology can address," he adds.
PCSK9 is a secreted protease that degrades the LDL receptor, and a poster child for genetically validated targets. Gain-of-function mutations lead to increased cholesterol levels, and loss-of-function mutations lower LDL-cholesterol and reduce the risk of heart disease. This biology and cardiovascular opportunity have prompted drug developers to test multiple modalities against PCSK9.
The FDA approved two PCSK9-targeted antibodies - Amgen's alirocumab and Regeneron's evolocumab - in 2015. But sales of these remain lacklustre, slowed by the cost and subcutaneous delivery of these drugs. Merck expects an oral drug to fare better.
MK-0616 originated from collaboration with Ra Pharmaceuticals, a company that built a library of diverse cyclic peptides. Merck's medicinal chemists worked to stabilize and optimize these, resulting in tricyclic peptides with picomolar potency against PCSK9. Formulation scientists used permeation enhancers to enable oral delivery.
"This is a chemist's dream, to be able to work in a very structure-based-design way on a molecule with such great complexity," says Garbaccio. This work shows that small molecules and peptides span a single modality continuum, he adds.
The drug was safe and lowered LDL-cholesterol in a 60-patient phase I trial, Merck's data show. Merck plans to start a phase II trial in 2022.
Novartis and Alnylam hope to soon secure approval for their subcutaneous PCSK9-directed siRNA drug inclisiran. Novo Nordisk's oral PCSK9 inhibitor NNC0385-0434 is in phase II. Verve plans to move a CRISPR-based candidate into the clinic in 2022. AstraZeneca acquired a small-molecule contender from Dogma Therapeutics in 2020.
Nature Reviews Drug Discovery 21, 9 (2022)
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American Heart Association Scientific Sessions 2021, LBS.06
Research Highlights:
• Two studies report the safety and effectiveness of MK-0616, a new cholesterol-lowering medicine in a class of drugs called PCSK9 inhibitors. MK-0616 is taken by mouth, as opposed to injection like currently available PCSK9 inhibitors.
• Men who received once-daily doses of up to 300 milligrams of MK-0616 did not experience serious side effects.
• MK-0616 reduced blood levels of free PCSK9 protein by more than 90% from baseline when administered to healthy men as a single dose of between 10 and 300 milligrams, regardless of the dose.
• A second study found that LDL-cholesterol decreased by about 65% from baseline levels in men and women with high cholesterol when oral MK-0616 was added to their current statin therapy for 14 days.
Monday, Nov. 15, 2021
DALLAS, Nov. 15, 2021 - Results from two early clinical studies show the first version of an oral PCSK9-inhibitor cholesterol-lowering medicine was well tolerated and highly effective at reducing high levels of LDL cholesterol, according to late-breaking research presented today at the American Heart Association's Scientific Sessions 2021. The meeting is fully virtual, Saturday, November 13-Monday, November 15, 2021, and is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care worldwide.
PCSK9 inhibitor medicines work by blocking a liver protein that helps to destroy LDL cholesterol receptors on the surface of cells. Those receptors are responsible for taking cholesterol out of the blood stream. With more receptors active, more LDL can be removed from the blood stream. Currently, PCSK9 inhibitors are only available by injection. This study is the first human data on the new medication called MK-0616, which is an oral version of a PCSK9 inhibitor.
"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," said lead study author Douglas Johns, Ph.D., FAHA, clinical director of translational medicine/clinical pharmacology at Merck Research Laboratories. "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."
MK-0616 reduced LDL cholesterol without causing serious side effects or death when taken as once daily oral doses of up to 300 milligrams alone in healthy men, or in combination with statins among men and women with high cholesterol.
"I believe this is the first report of successful oral absorption of a synthesized cyclic peptide like MK-0616 in people," said Johns. "We were pleased that it appeared to be consistently absorbed and concentrated in patients' blood, and that it reduced cholesterol levels so effectively."
The first study of MK-0616 included 60 healthy male volunteers, ages 18-50. Fifty-one participants in the randomized study received single oral doses of MK-0616, ranging from 10 to 300 milligrams, while 23 received at least one dose of a placebo. The study was a "cross-over" design, so some participants received MK-0616 during one period, then "crossed over" to placebo during another period. In each period, 75% of participants received MK-0616 and 25% received a placebo. Researchers found that MK-0616 reduced levels of PCSK9 that contribute to high LDL cholesterol by more than 90% from baseline at all single-dose levels tested.
The second study of MK-0616 included 40 male and female volunteers, ages 18-65, who had already been taking statin medications to control their cholesterol levels for at least three months. In this study, 75% (31) participants received a once-daily oral dose of 10 milligrams or 20 milligrams of MK-0616, while 25% (9) received a placebo – both groups receiving them in addition to their current statin therapy. MK-0616 lowered participants' blood cholesterol by approximately 65% from baseline levels after 14 days of treatment. Patients treated with the placebo had less than 5% reduction in cholesterol measures compared to baseline.
"The initial results are encouraging; however, more clinical studies are needed to confirm these findings, given limited clinical experience with the molecule MK-0616," said Johns.
Co-authors are Yuddy Almonte, B.E.; Puja Banka, M.D.; An Bautmans, D.V.M.; Louis-Charles Campeau, Ph.D.; Mark T Cancilla, Ph.D.; Justin Chapman, B.Sc.; Inne Crevecoeur, Ph.D.; Erik D. Guetschow, Ph.D.; Eunkyung A. Kauh, M.D.; Eseng Lai, M.D.; Christine L. Lanning, Ph.D.; Anita Y.H. Lee, M.S.; Li Li, Ph.D; Yale B. Mitchel, M.D.; S. Aubrey Stoch, M.D.; Kristien Van Dyck, Ph.D.; Frederic P. Vanhoutte, M.D.; Bram Volckaert, M.D.; Dennis G. Wolford, M.S.; Harold B. Wood, Ph.D.; Andy Xu, Pharm.D.; Tian Zhao, Ph.D. and Susan Zhou PhD. Authors' disclosures are listed in the abstract.
The study was funded by Merck & Co., Inc.
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