Lerodalcibep in Atherosclerosis: Addressing Low-density Lipoprotein Cholesterol Reduction and Statin Intolerance

Dear Sir/Madam, The prevalence of atherosclerotic cardiovascular disease (ASCVD) has more than doubled since the late 20th century to reach 500 million in 2019, causing significant morbidity and mortality.[1] The proportion of deaths attributable to cardiovascular disease in the period mentioned above has also risen more than 50% reaching 19 million.[1] It is projected to cause more than 20 million deaths annually in the next decade.[1] It is also estimated to have led to nearly 200 million disease-adjusted life years since 1990.[1] The risk factors for ASCVD include modifiable and nonmodifiable factors. The former include dyslipidemia, smoking hypertension, obesity, diabetes mellitus, and sedentary lifestyle among others. “Bad cholesterol,” also known as low-density lipoprotein cholesterol (LDL-C) is a well-established and strategically targeted modifiable risk factor for the primary and secondary prevention of ASCVD. Currently, for patients at high or very high risk, the consensus recommendation initially suggests the highest tolerated dose of statins.[2] While statins are the cornerstone of LDL-C lowering therapy, nearly one in ten patients at high or very high risk for ASCVD is intolerant to it.[3] Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a category of drugs that function primarily by obstructing the activity of PCSK9. PCSK9 inhibitors are a category of drugs that function primarily by obstructing the activity of PCSK9. The binding of LDL receptors to PCSK9, thereby allowing for a greater number of these receptors to recycle to the cell surface for the further removal of blood LDL-C.[4] PCSK9 inhibitors, when used in supplementation to statins, have reduced LDL-C levels by two-thirds from the baseline.[4] However, more frequent dosing and the requirement of constant refrigeration limit their use in a wider population. Lerodalcibep is a novel recombinant fusion protein comprising the binding domain of the PCSK9 gene and human serum albumin.[5] In a recent placebo controlled 52-week study, the mean reduction in LDL-C at the primary efficacy endpoint was 56% (mean change −56.1, confidence interval: −60.48 to −51.9) with once-a-month dosage.[5] It also significantly reduced nonhigh-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. These large reductions occurred in patients at high and very high risk despite maximally tolerated statins and other drugs. Lerodalcibep also demonstrated a good safety profile, exhibiting only a slightly higher incidence of mild-to-moderate injection site reaction versus placebo. However, these did not lead to more frequent discontinuations compared to placebo.[5] Lerodalcibep represents a promising advancement in managing ASCVD. It offers substantial LDL-C reduction in high-risk patients despite statin intolerance and resistance. With its manageable safety profile and convenient dosing schedule, Lerodalcibep holds the potential to address the significant unmet needs in cardiovascular care. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.