Merck & Co. has developed MK-0616, a new drug for lowering low-density lipoprotein (LDL) cholesterol.
The 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 all other pills on the market, including bile acid sequestrants, statins, ezetimibe and bempedoic acid. Fourth, MK-0616 is as effective as powerful and expensive injectable LDL cholesterol–lowering drugs such as Praluent (alirocumab), Repatha (evolocumab), and Leqvio (inclisiran).
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 (CAD).
MK-0616 has yet to undergo an extensive clinical study in hundreds and thousands of patients to be finally convinced of its safety and efficacy.
A pivotal clinical trial of MK-0616 is scheduled for launch in the second half of 2023. If all goes well, the finished drug will be on the market tentatively in 2026.
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 tricyclic peptide that binds to the flat interface between PCSK9 and the LDL receptor with affinity similar to that of monoclonal antibodies, thereby preventing their interaction. MK-0616 results in an increase in the number of LDL receptors that contribute to the clearance of LDL cholesterol from plasma. Gastrointestinal absorption of MK-0616 is improved by the use of permeation enhancer (sodium caprate).
MK-0616: Details of Clinical Evaluation
The first clinical trial included healthy men (n=60) randomized to receive MK-0616 daily at doses ranging from 10 mg 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 men and women (n=40) 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.
The NCT05261126 phase 2b (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial invited adult patients (n=380) with hypercholesterolemia.
Among the main patient characteristics: median age 62 years, 49% female; mean low-density lipoprotein (LDL) cholesterol level was 119.5 mg/dL; 39% had atherosclerotic cardiovascular disease (ASCVD) in clinical form, 56% had intermediate or high risk ASCVD, and 5% had borderline risk ASCVD.
Participants were given MK-0616 (at a dose of 6 mg, 12 mg, 18 mg, or 30 mg) or placebo daily.
The primary efficacy endpoint of treatment was the percentage change in LDL cholesterol levels.
After 8 weeks, the 6-mg, 12-mg, 18-mg, and 30-mg MK-0616 subgroups recorded decreases in LDL cholesterol levels of 40%, 55%, 58%, and 60% — versus increases of 1.2% in the placebo group.
The corresponding difference, adjusted for placebo, was statistically significant (p<0.001) and was −41%, −56%, −59% and −61%.
The target LDL cholesterol levels, calculated according to the risk of ASCVD, were reached by 81%, 86%, 91%, and 81% of patients — vs. 9% in the control group.
Among other beneficial effects of MK-0616 in the treatment of hypercholesterolemia and pronounced changes in the levels of other metabolic parameters acting as important predictors of atherogenic risk relative to placebo:
- apolipoprotein B (ApoB): −33%, −46%, −49%, −52%
- non-high-density lipoprotein (non-HDL) cholesterol: −36%, −51%, −53%, −56%
- lipoprotein (a) [Lp(a)]: −12%, −21%, −22%, −24%
- high-density lipoprotein (HDL) cholesterol: −2%, +2%, +4%, −1%
- total cholesterol: −27%, −37%, −39%, −42%
- triglycerides: −8%, −14%, −16%, −16%
- very-low-density lipoprotein (VLDL) cholesterol: −6%, −14%, −14%, −13%.
The use of MK-0616 was well tolerated. Because of adverse events (AEs), 2% of patients discontinued MK-0616 — versus 1% in the placebo group. The incidence of AEs was identical in the drug and control subgroups: 40%–43% vs. 44%. Among the most common AEs were COVID-19, diarrhea, and dyspepsia. The latter were of mild severity. There were no reported AEs that occurred in a dose-dependent manner as a result of treatment.
Oral statin therapy has long been the gold standard in the treatment of hypercholesterolemia  . However, despite the guidelines, which focus on the use of high-intensity statin therapy, their use in clinical practice remains challenging, which may be partly due to adverse events and statin intolerance. In addition, even when successfully introduced, statins in high doses often do not contribute to treatment goals, especially in high-risk patients   .
Adding nonstatin drugs with alternative mechanisms of action is a recommended strategy, but many patients still remain under-treated     . The effectiveness of lowering low-density lipoprotein (LDL) cholesterol levels with additional oral medications is relatively modest. For example, bile acid sequestrants add approximately 12%–18% to the reduction of LDL cholesterol, ezetemibe 20%–25%, bempedoic acid 18%   .
MK-0616, in contrast to the aforementioned oral drugs, provided a significantly deeper reduction in LDL cholesterol levels — by 41%–61%, adjusted for placebo.
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 are able to reduce LDL cholesterol by about 58% and 55%, respectively. Despite infrequent dosing realized by subcutaneous injections once or twice a month, alirocumab and evolocumab are not in great demand due to their high cost, which health insurance providers are not particularly eager to cover. While an annual course of treatment with statins, which became generic ten years ago, costs pennies to American patients without proper health insurance, an annual course of treatment with Praluent or Repata will cost about $6,500 and $7,500 out of their own pockets. Moreover, at the very beginning, the manufacturers were asking a lot more for these drugs: $14,000 per year, but after a while, when they recognized that demand was catastrophically low, the price tag had to be drastically lowered.
In late December 2020, Novartis launched Leqvio (inclisiran) at a U.S. price of $7.0 thousand per year. A key feature of inclisiran, which is based on RNA interference, is its dosing regimen: It is administered subcutaneously once every 6 months in a maintenance regimen. The therapeutic efficacy of Leqvio is in the range of 51%–52% reduction in LDL cholesterol.
Two injections of inclisiran a year and you can forget about high cholesterol. Novartis doesn’t lie.
The mechanistic difference between these three drugs is that alirocumab and evolocumab block circulating PCSK9, while inclisiran directly inhibits PCSK9 synthesis.
Taking into account highly competitive environment of PCSK9 inhibitors market, there is no doubt that only one thing can attract attention of patient, physician, and insurance community to MK-0616 — its affordability.
The injectable nature of the three existing anti-PCSK9 medications against ‘bad’ cholesterol, even if administered not intravenously, but subcutaneously at home, still does not add to their appeal from the point of view of patients. It is much easier to take an oral statin and think, even if completely erroneously, that everything is fine.
The promising therapeutic efficacy of MK-0616 along with its safety and convenience of oral administration should be supported by long-term clinical trials. An 8-week trial is by no means enough to provide robust evidence, especially among diverse patient populations.
A phase 3 pivotal clinical trial of MK-0616 is scheduled to start in the second half of 2023. At that time, there will be a trial to test the suitability of the drug to reduce cardiovascular risks. The goal is to study both primary prevention and secondary prevention.
If MK-0616 is approved, which could happen closer to 2026, the fight against atherosclerosis, which affects half the adults in the world, will take on a whole new level. It is safe to say that there is no way that MK-0616 will become affordable to everyone, as is the case with cheap statins. We should expect that the price of MK-0616 will not be lower than that of bempedoic acid. It all depends on Merck & Co., which could easily go after the greed of its shareholders by asking a lot of money for MK-0616, thereby essentially driving the business prospects of this drug to the grave.
According to industry forecasts, MK-0616 has the potential to reach $5 billion at peak sales. And that’s pretty optimistic, considering that the entire PCSK9 inhibitor class made about $2 billion in 2022.
Pipeline of PCSK9 Inhibitors
Meanwhile, only AstraZeneca is developing the similar oral PCSK9 inhibitor AZD0780 for the prevention of cardiovascular complications in dyslipidemia. Results from the first phase 1 clinical trial of NCT05384262 in healthy volunteers will be collected in August 2023.
Novo Nordisk had previously done the same, but the oral PCSK9 inhibitor NN6435 (NNC0385-0434) is no longer mentioned in the 2022 closure report.
In September 2022, AstraZeneca withdrew ION449 (AZD8233), a joint with Ionis Pharmaceuticals anti-PCSK9 antisense oligonucleotide that, when administered by subcutaneous injections once a month to patients with hypercholesterolemia, provided a 62% reduction in LDL cholesterol levels. The scaling down of the program is probably due to the competitive environment. First, there are already monoclonal antibodies, which by analogy are administered subcutaneously once a month and which provide decent efficacy. Second, the emergence of oral MK-0616 is imminent.
It is possible that in the long term, the PCSK9 inhibitor sector will change dramatically when a single-treatment therapeutic modality becomes available. For example, VERVE-101 by Verve Therapeutics is an in vivo gene editing where mRNA instructions delivered into hepatocytes and, by appealing to CRISPR technology, change one DNA base pair of the gene encoding PCSK9, thereby disrupting production of the corresponding protein.
In a study in non-human primates, an intravenous infusion of the experimental VERVE-101 edited the PCSK9 gene with 70% efficiency, which was reflected by an 89% reduction in PCSK9 protein levels in the blood and a 69% reduction in LDL cholesterol levels. The results were maintained throughout the 1.3-year follow-up period. Importantly, no prerequisites for transmission of the edited PCSK9 gene to offspring were found.
The NCT05398029 phase 1b clinical trial testing the PCSK9 gene knockdown among patients with heterozygous familial hypercholesterolemia with advanced atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia is ongoing.
Precision Biosciences confirmed that the targeted LDL cholesterol-lowering effect accomplished in nonhuman primates by in vivo gene intervention in the PCSK9 gene structure persisted through 3 years of follow-up.
Gene editing by Precision is implemented through a proprietary ARCUS platform using I-CreI, a naturally occurring genome editing enzyme found in the alga Chlamydomonas reinhardtii and designed for highly specific cuts and insertions into cellular DNA. I-CreI belongs to a larger class of enzymes called homing endonucleases or meganucleases.
However, in January 2023, Precision paused the corresponding PBGENE-PCSK9 anti-PCSK9 program due to difficulties in obtaining FDA approval for clinical trials.
United Biomedical’s Vaxxinity expertise is built around synthetic peptide vaccines that stimulate the production of endogenous antibodies against specific targets. The optimal combination of proprietary synthetic T-helper peptides UBITh linked to target epitopes determines selective activation of the immune system, overcomes immune tolerance to endogenous proteins to induce a targeted humoral B-cell response, minimizes risks of immune evasion and T-cell mediated cytotoxicity.
Preclinical study of VXX-401 demonstrated sustained suppression of PCSK9, reflected by a 30%–50% reduction in LDL cholesterol. Immunization was well tolerated and confirmed that immune tolerance was overcome. The first clinical trial of VXX-401 is scheduled to begin in the first half of 2023.