-Lowering LDL-C is known to reduce the risk of ASCVD
-In patients at very high risk for ASCVD or in those with intolerance to statins, PCSK-9 inhibitors are recommended, however, current PCSK-9 inhibitors are administered subcutaneously, limiting their use
-The findings of this Phase 2 trial suggest that MK-0616, an oral PCSK-9 inhibitor significantly reduced LDL-C at 8 weeks by as much as 60.3% compared to placebo
Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) and treatment focuses on lowering low density lipid cholesterol (LDL-C). While statins are the mainstay for treating hypercholesterolemia, there is a growing role for proprotein convertase subtilisin/kexin type (PCSK) 9 inhibitors. PCSK-9 inhibitors are especially useful in patients on maximally tolerated statin and very high ASCVD risk who require further LDL-C reduction and in those with intolerance to statins. One barrier to patients adopting the use of PCSK9 inhibitors is that they are injectable.
PCSK-9 inhibitors reduce cholesterol levels by preventing the degradation of LDL-C receptors on the surface of hepatocytes, thereby promoting clearance of LDL-C from plasma. The results of a trial (NCT05261126) evaluating a new, daily, oral PSCK-9 inhibitor in reducing LDL-C in subjects with hypercholesterolemia was presented by Dr. Christie Ballantyne (Baylor College of Medicine, Houston, TX) at ACC 2023 conference this afternoon.
A total of 381 participants with a wide range of ASCVD risk were enrolled in this randomized, double-blind, placebo-controlled trial. There were five treatment arms; four escalating doses (6mg, 12mg, 18mg, or 30mg) of the oral PSCK-9 inhibitor, MK-0616, and placebo. The primary outcome was LDL-C level change from baseline to 8 weeks. Eligible participants had a history of stable background statin therapy including no statin, clinical ASCVD or 10-year risk of event ≥ 5%. Subjects with a history of homozygous familial hypercholesterolemia, impaired renal function, or a major cardiovascular event within 3 months were excluded. The median age of the participant was 62 years, 49% female, 66% white, the average LDL-C was 119.5mg/dL, and 38.6% had clinical ASCVD.
All four doses of MK-0616 resulted in significant reductions in LDL-C, with the highest dose (30mg) resulting in a 60.9% placebo-adjusted reduction at eight weeks. Furthermore, at the highest dose, MK-0616 reduced ApoB by 51.8% and non-HDL-C by 55.8%, and 90.8% participants met their LDL-C goal (defined as a LDL-C <70 mg/dL in participants with ASCVD), compared to 9.3% with placebo. An exploratory endpoint, found that MK-0616 reduced Lipoprotein A by 23.7%. A similar proportion of adverse events occurred in the treatment and placebo group after 16 weeks.
When discussing the clinical implications of the study at ACC 23, Dr. Ballantyne stated: “we know LDL is important [and] we know that current injectable PSCK-9 inhibitors are effective [but] have had a poor uptake.” An oral PCSK-9 inhibitor may change that trend.
This phase 2 trial successfully demonstrated that an oral, daily, PCSK-9 inhibitor effectively and safely reduced LDL-C. With these encouraging results, clinicians will look forward to a larger phase 3 trial evaluating the effect of MK-0616 on major adverse cardiovascular events.