Merck Preps Potential First Oral PCSK9 Inhibitor for Phase III

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Pictured: Merck building/courtesy Michael Vi/Getty Images

Merck released Phase IIb data Monday showing that its hypercholesterolemia hopeful, MK-0616, met the primary endpoint of significantly decreasing low-density lipoprotein cholesterol (LDL-C).

The data were presented at the American College of Cardiology’s 72nd Annual Scientific Session. 

After eight weeks of treatment, all doses of MK-0616 led to substantial and significant reductions in LDL-C relative to baseline. The placebo-adjusted treatment effects ranged from 41.2% for the 6-mg dose to 60.9% for the 8-mg dose.

Across all of its dose groups, Merck’s candidate reached “near-complete efficacy” by week two, with the treatment effect persisting until the follow-up at eight weeks, according to the announcement.

MK-0616 also hit its secondary endpoints, leading to significant drops in apolipoprotein B and non-high-density lipoprotein cholesterol levels. The proportion of participants who reached the protocol-defined LDL-C goals were also higher in all MK-0616 groups than placebo.

There were no serious adverse events related to MK-0616. The candidate was generally well-tolerated and showed no clear trend in discontinuation rates across doses.

These findings suggest MK-0616 could become the first oral PCSK9 inhibitor on the market and potentially transform the treatment landscape for patients with hypercholesterolemia, Joerg Koglin, VP, global clinical development, Merck Research Laboratories, said in a prepared statement.

The company plans to advance MK-0616 into a Phase III study in the second half of 2023, Koglin added.

Designed to be taken once a day, MK-0616 is an orally available inhibitor of the PCSK9 enzyme, which helps in cholesterol homeostasis by regulating the levels of LDL receptors. By disrupting the activity of PCSK9, Merck’s candidate increases the number of LDL receptors in cells, allowing for better clearance of LDL-C from the blood.

Competition in Cholesterol Control

While MK-0616 could become the first oral drug against PCSK9, several other injectable inhibitors have already made it to the market.

These include Amgen’s Repatha (evolocumab), which was first approved in 2015 for the treatment of high cholesterol levels alongside dietary adjustments or other lipid-lowering treatments.

In 2022, Repatha made Amgen nearly $1.3 billion in earnings, up 16% from 2021. This was driven mainly by strong sales volume growth, which was only partly offset by the medicine’s lower selling price.

Also in the PCSK9 market are Regeneron and Sanofi, whose Praluent (alirocumab) was FDA-approved in 2015, just weeks ahead of Repatha. Last year, the injectable antibody earned some $467 million, up 11% from the previous year. Praluent bagged $130 million in U.S. sales alone in 2022.

Novartis is also in the hypercholesterolemia market with its small interfering RNA therapy, Leqvio (inclisiran). It received FDA approval in December 2021, becoming the first siRNA therapeutic for lowering LDL-C. Leqvio’s launch is ongoing and was one of the company’s key growth drivers in the fourth quarter of 2022.

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