Merck & Co. has shared the first results of a clinical trial of its experimental drug MK-0616, designed to lower low-density lipoprotein (LDL) cholesterol.
MK-0616 promises to be a blockbuster. First, it is safe. Second, the drug is made in an oral formulation. Third, MK-0616 lowers “bad” cholesterol levels significantly more than any other drug on the market.
The demand for the MK-0616 is expected to be huge due to the fact that the whole world really wants to defeat atherosclerosis as one of the most important causes of cardiovascular diseases, especially coronary artery disease.
Nevertheless, MK-0616 has yet to undergo an extensive clinical study in hundreds and thousands of patients to be finally convinced of its safety and effectiveness.
MK-0616: Mechanism of Action
Low-density lipoprotein (LDL) receptor is a mosaic protein that mediates endocytosis of cholesterol-rich LDL. LDL receptors are the primary receptors for the transport of LDL from the systemic bloodstream into cells, each carries 3000–6000 molecules of fat (including cholesterol).
In other words, LDL receptors maintain plasma LDL levels. At the same time, the liver is responsible for eliminating approximately 70% of circulating LDL. The more extensive the available pool of LDL receptors, the more efficient is the transport of cholesterol and the lower is its concentration in plasma.
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is one of the most important regulators of LDL cholesterol metabolism. This enzyme binds to LDL receptors on the surface of hepatocytes. As a result, instead of following their physiological pathway of recycling back to the hepatocyte membrane, they are redirected to lysosomal destruction in the liver. As the pool of free LDL receptors is reduced, plasma levels of LDL cholesterol increase. PCSK9 also inhibits intracellular degradation of apolipoprotein B (ApoB), a protein that is part of LDL particles and very-low-density lipoproteins (VLDLs).
Oral MK-0616 is a synthetic cyclic peptide that inhibits PCSK9. The result is an increase in the number of LDL receptors that contribute to the clearance of LDL cholesterol from the plasma. The gastrointestinal absorption of MK-0616 has been improved through the use of a permeability enhancer (sodium caprate).
MK-0616: Details of Early Clinical Evaluation
The first clinical trial included 60 healthy men randomized to receive MK-0616 daily at doses ranging from 10 to 300 mg or placebo. Administration of the experimental drug resulted in a reduction in PCSK9 levels of more than 90% from baseline, and regardless of MK-0616 dose.
The second clinical trial involved 40 men and women with high LDL cholesterol levels who were already on statin therapy. Participants were given MK-0616 daily at a dose of 10 mg or 20 mg or placebo. MK-0616 provided a 65% reduction in LDL cholesterol from baseline after 14 days of treatment. In the placebo group, the reduction was less than 5%.
The safety profile of MK-0616 is favorable, daily doses of the drug up to 300 mg did not result in any serious adverse reactions.
MK-0616 and Competitive Environment
The class of drugs targeting PCSK9 has been around for a long time. Its first representatives were Praluent (alirocumab) and Repatha (evolocumab), proposed by Sanofi/Regeneron Pharmaceuticals and Amgen in summer 2015.
Praluent and Repatha, which are prescribed once or twice a month, are able to lower LDL cholesterol by about 58% and 55%, respectively. However, they are not in great demand due to their exorbitant cost. For example, if American patients a year of treatment with statins costs about $600, then for these drugs will have to pay $5850.
In late December 2020, Novartis released Leqvio (inclisiran). The key feature of inclisiran is its dosing regimen: it is used once every 6 months in a maintenance regimen. The therapeutic efficacy of Leqvio is in the range of 50–52% decrease in LDL cholesterol.
The mechanistic difference between these three drugs is that alirocumab and evolocumab block circulating PCSK9, while inclisiran directly inhibits PCSK9 synthesis.
The main advantage of MK-0616 is its oral form — Praluent, Repatha, and Leqvio are administered by subcutaneous injection.
Merck & Co. allegedly understands that the only way to attract the attention of the patient and physician community to MK-0616 is through its price affordability.