First Oral PCSK9 Inhibitor Achieves Significant LDL Cholesterol Reduction

An innovative oral medication targeting PCSK9 has demonstrated a remarkable reduction in LDL cholesterol levels among high-risk cardiovascular patients, according to recent clinical research. This advancement could mark a significant shift in the management of cholesterol, offering a convenient alternative to current injectable therapies.

PCSK9, or proprotein convertase subtilisin/kexin type 9, is a protein that binds to LDL receptors on liver cells, promoting their internalization and degradation. This process reduces the number of available LDL receptors, limiting the liver's ability to remove LDL cholesterol--commonly known as 'bad' cholesterol--from the bloodstream. Inhibiting PCSK9 allows more LDL receptors to remain active on liver cell surfaces, thereby enhancing the clearance of LDL cholesterol and lowering its levels in the blood.

The investigational compound, Enlicitid decanoate, is a macrocyclic peptide developed by MSD and belongs to the class of PCSK9 inhibitors. Unlike existing therapies such as Alirocumab and Evolocumab--which require subcutaneous injections--Enlicitid decanoate can be administered orally, presenting a more patient-friendly option.

The CORALreef Lipids phase III randomized clinical trial evaluated the efficacy and safety of this oral drug. The study enrolled approximately 2,900 participants who had either experienced a heart attack or stroke or were identified as having a high risk for such cardiovascular events. All participants were already receiving stable statin therapy, with some also on Ezetimibe, yet their LDL cholesterol levels remained above target thresholds.

Participants were assigned to receive either 20 mg of Enlicitid decanoate or placebo once daily over a 24-week period. The primary endpoint focused on the percentage change in LDL cholesterol levels from baseline.

The trial results revealed that those treated with Enlicitid decanoate experienced up to a 60 percent reduction in LDL cholesterol compared to the control group. Additional benefits included a 53 percent decrease in non-HDL cholesterol, a 50 percent reduction in apolipoprotein B, and a 28 percent drop in lipoprotein(a) levels. Notably, more than two-thirds of patients receiving the active drug achieved both a minimum 50 percent reduction in LDL cholesterol and an absolute LDL value below 55 mg/dL.

In terms of safety, the incidence of adverse events leading to study discontinuation was comparable between the treatment and placebo groups, at 3 percent versus 4 percent respectively. This suggests that the new oral PCSK9 inhibitor is generally well tolerated.

Importantly, the magnitude of LDL cholesterol reduction achieved with Enlicitid decanoate was similar to that observed with current monoclonal antibody PCSK9 inhibitors. Furthermore, preliminary comparisons suggest that this new agent may offer greater numeric benefits than Inclisiran, an siRNA-based therapy that inhibits hepatic PCSK9 synthesis and is administered via infrequent injections.

Despite these promising findings, a critical question remains: will the substantial decrease in LDL cholesterol observed with Enlicitid decanoate translate into a meaningful reduction in cardiovascular events such as heart attacks and strokes? A dedicated outcomes trial is currently underway to address this issue, aiming to confirm whether lowering LDL cholesterol with this novel oral agent leads to improved long-term clinical outcomes.

The development of an effective oral PCSK9 inhibitor could represent a major step forward in cardiovascular disease prevention, especially for patients who are unable or reluctant to use injectable medications. Should ongoing studies confirm its impact on major adverse cardiovascular events, Enlicitid decanoate may soon become a valuable addition to the therapeutic arsenal for lipid management.