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Oral PCSK9 inhibitor MK-0616 significantly lowers LDL cholesterol

MK-0616 is an oral PCSK9 inhibitor and in a Phase II trial significantly lowered LDL cholesterol in patients with hypercholesterolaemia

Drug manufacturer Merck, has reported in a press release that their investigational, oral and once daily, PCSK9 inhibitor, MK-0616, produced significant reductions in LDL cholesterol in adult patients with hypercholesterolaemia.

Increased levels of PCSK9 elevate plasma LDL cholesterol and conversely, lowering PCSK9 reduces LDL cholesterol. Consequently, inhibition of PCSK9 represents a therapeutic target and drugs such as evolocumab have been recommended in the treatment of primary hypercholesterolaemia or mixed dyslipidaemia and in patients with a high or very high risk of cardiovascular disease, where LDL cholesterol levels remain above 3.5 mmol/litre. To date however, all PCSK9 inhibitors are only available as an injectable form, whereas MK-0616 is an oral PCSK9 inhibitor.

In a study of healthy patients with hypercholesterolaemia, the use of once daily MK-0616 (dose 10 to 300 mg), exhibited a dose dependent increase in plasma exposure and a > 90% mean maximum reduction of free plasma PCSK9 levels from baseline at all dose levels studied. The current press release relates to the findings from a phase 2b clinical trial in which MK-0616 was given at varying doses (6, 12, 18 and 30mg) to adult patients with hypercholesterolaemia and who were divided into one of three categories, in which fasting LDL cholesterol levels ranged from > 1.81 to < 6.48 mmol/L. In addition, participants were either stable on one or more lipid lowering therapies or who had not received any such treatments for more than 30 days before screening. Individuals were then randomised 1:1:1:1:1 (i.e., each dose and placebo) and the treatment continued for 16 weeks and the primary objective of the study was to evaluate the percent change in LDL cholesterol from baseline to week 8.

MK-0616 and reduction in LDL cholesterol

A total of 380 participants with a median age of 62 years (49% female) with hypercholesterolaemia and a moderate to high risk of atherosclerotic cardiovascular disease were included.

At week 8, all four doses of MK-0616 significantly reduced LDL-C compared to placebo and the placebo-adjusted reduction from baseline ranged from 41.2% with the 6mg dose to 60.9% with the 30mg dose (p < 0.001 for each dose).

The drug was well tolerated and the proportion of participants experiencing greater than one adverse event was similar (ranging from 39.5% to 44.2%) between the different doses and placebo (44%).

The findings of the phase 2b study have been published in the Journal of the American College of Cardiology.

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