Cardiovascular disease (CVD) is the leading cause of death worldwide and is responsible for over 900,000 deaths in the U.S. annually—and hypercholesterolemia, or elevated blood cholesterol levels, is the most common form.
Hypercholesterolemia is made up of good (high-density lipoprotein or HDL) and bad (low-density-lipoprotein or LDL) cholesterol. An elevated LDL means a higher risk for heart disease, specifically coronary artery disease (CAD).
So, depending on the patient’s risk profile, the lower the LDL, the better.
There are several good options available on the market for lowering LDL—but more options are needed. Merck is investigating a promising oral pill that would lower bad cholesterol, which would be a welcome development for patients.
A brief history of CVD treatments
Since the late 1980s, HMG-CoA reductase inhibitors (statins) have been the focus of prevention and treatment of CVD as well as the first-line treatment of LDL cholesterol. However, despite the wide availability of statins, millions of patients still do not reach their LDL goals or have an intolerance to statin therapy. These patients are at higher risk for CVD creating a need for drugs that are both effective and well-tolerated.
In 2003, another option for lipid-lowering therapy was discovered and involved a protein on the surface of liver cells. The protein, proprotein convertase subtilisin/Kexin type 9 (PCSK9), was found to control the number of LDL receptors on the cell surface and plays a role in regulating blood cholesterol levels.
PCSK9 inhibitors work differently than statins but have demonstrated their lipid-lowering effects as well as their ability to prevent coronary artery plaque progression.
Over the next decade, the strategy for lipid management evolved and included human monoclonal antibodies directed against PCSK9 and small interfering RNA (SiRNA) therapy targeting PCSK9.
In 2015, the FDA approved the first PCSK9 inhibitor as an adjunct for patients already on maximum levels of statin therapy.
PCSK9 inhibitors on the market today—marketed by Novartis, Amgen, and Regeneron—are highly effective in lowering LDL.
In fact, a synthetic SiRNA, known as inclisiran, targets the production of PCSK9 in the liver and shows a 50% reduction in LDL sustained for at least 6 months.
Why we need additional LDL therapies
If there are effective medications available that lower LDL, why is another medication necessary? Joerg Koglin, M.D., Ph.D., VP, Global Clinical Development at Merck Research Laboratories and Global Therapeutic Area Head for Cardiovascular and Respiratory Clinical Research, explains.
“Available PCSK9 inhibitors … require an IV from a trained healthcare professional. Administration timing is variable and starts at 2 weeks with maintenance dosing between 2-4 weeks, or monthly. This adds a layer of complexity and patient compliance,” he says.
Additionally, he adds, “Drugs are expensive, and many require prior authorization. In these cases, the patient needs to have a high-risk profile, have had a prior [myocardial infarction or heart attack] or stroke, or have yet to reach their LDL goal despite trying other therapies.”
Merck has long been dedicated to the discovery and implementation of treatment for cardiovascular disease. As part of their mission to bring an oral PCSK9 inhibitor with the same mechanism and success as the injectable forms on the market, Koglin discusses the initiation of their Phase 3 clinical program, CORALreef.
MK-0616 is an investigational, oral PCSK9 inhibitor which is undergoing evaluation for the treatment of adults with hypercholesterolemia. According to Koglin, “The Phase 3 program follows the results of the Phase 2b clinical trial, which demonstrated MK-0616 was well-tolerated and contributed to a significant reduction in LDL cholesterol.”
“The outcome is not only comparable to injectable monoclonal antibodies in clinical outcome, but includes comparable safety profiles minus the injection site reactions,” he continues.
A significant advantage of MK-0616, explains Koglin, “is that it is a small, cyclic peptide that is one-hundredths the size of an antibody, and acts together with a permeation enhancer (sodium caprate). Absorption is believed to occur via opening of gap junctions through the permeation enhancer. Its size and permeability allow for safe, systemic exposure that is good enough to reduce PCSK9 by 90% and reduce LDL by 60%,” says Koglin.
What’s next for MK-0616?
On August 25, 2023, Merck announced the initiation of its next phase involving MK-0616. CORALreef is the first Phase 3 clinical program dedicated to an oral PCSK9 inhibitor. With a proposed plan of enrollment that includes approximately 17,000 participants, CORALreef encompasses three global studies: CORALreef Lipids, CORALreef HeFH, and CORALreef Outcomes.
According to Koglin, “Merck has reached an important milestone with the initiation of their Phase 3 clinical program,” which is setting the stage for a highly effective oral medication intended to assist patients in reaching their individual LDL goals.
Enrollment has begun in the Lipids and HeFH studies within CORALreef. The Lipids trial includes patients with a history of at least one major atherosclerotic cardiovascular disease event and those at intermediate to high risk for a first event.
Randomized study participants receive 20 mg of MK-0616 daily or a placebo for up to 52 weeks, along with their normal daily lipid-lowering therapy.
The primary endpoint is a mean percent change from baseline in LDL cholesterol at week 24.
The HeFH study involves patients with heterozygous familial hypercholesterolemia who are on stable lipid lowering therapies.
The anticipated completion dates for the first two studies are set for 2025, with a larger study set to run from the end of 2023 to 2029.
Koglin relays the excitement of Merck in their screening and recruitment numbers at this early stage of Phase 3. By introducing an oral alternative in the treatment of hypercholesterolemia that is accessible and affordable, Merck is well on its way to bringing more patients to their treatment goals and creating the public health impact they have been striving for all of these years.