A new oral pill reduces bad cholesterol levels by 60% at eight weeks

Low-density lipoprotein (LDL) cholesterol, also known as "bad cholesterol," is a severe health condition that develops in the walls of arteries and restricts blood flow, which increases the risk of heart disease and stroke.

Phase 2 trial of MK-0616, a new experimental drug, shows promise for addressing the high LDL cholesterol levels by reducing "bad" cholesterol levels by 60 percent in eight weeks.

Inhibiting the activity of PCSK9

The new pill inhibits the activity of a specific protein called PCSK9, which can decrease the amount of LDL cholesterol the liver breaks down. While PCSK9 inhibitors have been an effective strategy for reducing cholesterol, their administration typically involves subcutaneous injections and, in some cases, gene therapy, as observed in one study.

"This is a highly effective compound that was well tolerated," said Christie M. Ballantyne, MD, director of the Center for Metabolic Disease Prevention at Baylor College of Medicine in Houston and the study's lead author, in the press release.

"MK-0616 could offer another potential option. Between this and statins and the other therapies we have, we should be able to basically treat almost everybody in terms of LDL cholesterol."

The clinical trial included 381 adults with either a history of heart disease or risk factors for heart disease and high levels of LDL cholesterol. At the beginning of the study, around 60 percent of the participants were already on statins, while approximately 25 percent were being treated with high-intensity statin therapy.

The study subjects were randomly divided into five groups, wherein they were given a placebo or MK-0616 at four different dosages — 6 mg, 12 mg, 18 mg, or 30 mg. While they took continued the regimen for eight weeks before discontinuing it, the researchers examined their LDL cholesterol levels before and after the trial.

The trial resulted in promising results

Results of the trial have shown that participants taking any dosage of the drug showed a considerable decline in their LDL cholesterol levels compared to the placebo group. Those who received 30 mg of the medication observed drops of over 60 percent, while those given 18 mg, 12 mg, and 6 mg had decreases of 59 percent, 55 percent, and 41 percent, respectively. Additionally, other indicators of unhealthy cholesterol, such as non-HDL cholesterol and ApoB protein, were also lowered.

Crucially, no harmful side effects at any of the dosages were observed or reported by the research team who are seeking further trials to investigate MK-0616 in more detail.

"I was told early on that developing an oral PCSK9 inhibitor is impossible," Ballantyne said. "But the technology keeps advancing. It's very exciting to see the tremendous advances in understanding the pathways and finding ways to make a challenging target like PCSK9 treatable with a once daily pill.

The results of the study were published in the Journal of the American College of Cardiology.

Study abstract:

Background: MK-0616 is an oral PCSK9 macrocyclic peptide inhibitor in development for the treatment of hypercholesterolemia.

Objectives: This Phase 2b, randomized, double-blind, placebo-controlled, multi-center trial (NCT05261126) aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia.

Methods: This study planned to include 375 adult participants with a wide range of ASCVD risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg QD) or matching placebo. The primary endpoints included percent change from baseline in LDL-C at Week 8 and the proportion of participants with adverse events (AE) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the treatment period.

Results: Of the 381 participants randomized, 49% were female, and median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (p<0.001) differences in LS mean % change in LDL-C from baseline to Week 8 vs. placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group.

Conclusions: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated over 8 weeks of treatment and an additional 8 weeks of follow up.