Data presented at the American Heart Association (AHA) Scientific Sessions 2024 highlight inclisiran's efficacy in reducing low-density lipoprotein cholesterol (LDL-C) and improving patient adherence due to its twice-yearly dosing schedule. This is particularly significant for patients with atherosclerotic cardiovascular disease (ASCVD), where achieving and maintaining LDL-C goals is critical.
Addressing Adherence Challenges in LDL-C Management
Many patients with ASCVD struggle to reach and maintain their LDL-C targets, leading to increased cardiovascular event risks. Data indicates that patients not meeting LDL-C goals face a nearly 50% higher risk of such events. Despite being on statin regimens, up to 80% of ASCVD patients still have LDL-C levels of 70 mg/dL or higher, and those who do achieve their goals often maintain them for only about six months. Discontinuation rates are also high, with 25% to 50% of patients stopping statins within 6 to 12 months due to factors like adverse effects, dosing burden, and cost.
According to Dr. Kwon, clinicians and patients seek treatments with high efficacy and fewer burdens, such as reduced dosing frequency and greater affordability. Inclisiran (Leqvio; Novartis), a first-in-class small interfering RNA lipid-lowering therapy, addresses these challenges with its proven efficacy and twice-yearly dosing.
Inclisiran's Mechanism and Clinical Trial Results
Inclisiran leverages RNA interference to selectively target the liver, where LDL-C uptake occurs. It prevents the formation of PCSK9 protein, leading to undetectable levels in circulation within 24 to 48 hours. Its slow release into hepatocyte cytoplasm ensures a prolonged duration of action, enabling the twice-yearly dosing schedule.
Two phase 3 trials, ORION-10 and ORION-11, demonstrated inclisiran's efficacy in patients with primary hyperlipidemia. ORION-10, an 18-month trial with 1561 patients on maximally tolerated statins, showed significant LDL-C reduction, with 84% of patients achieving LDL-C levels below 70 mg/dL, compared to 18% on placebo. ORION-11, involving 1617 patients with or at increased risk for ASCVD, yielded similar results. LDL-C reduction was evident within 14 days of the initial dose.
The ORION-8 study further examined the long-term efficacy and safety of inclisiran, including patients from previous ORION trials. Results showed that 78% of participants achieved their target LDL-C, with an approximate 50% LDL-C reduction at the study's end (-49% mean change in LDL-C, 95% CI: -50%, -48%).
Real-World Evidence and Adherence Rates
The V-INITIATE trial, a 12-month, randomized, open-label study, assessed inclisiran's effectiveness in real-world clinical practice. Initiated immediately upon failure to achieve the 70 mg/dL LDL-C threshold, inclisiran was compared with usual care. The study demonstrated a 53% difference in LDL-C reduction between the inclisiran and usual care arms, with 82% of inclisiran participants achieving their target LDL-C level, compared to 22% in the usual care arm.
US claims database data also highlight inclisiran's superior adherence rates compared to PCSK9 monoclonal antibodies. At 12 months, 79% of patients receiving inclisiran were fully adherent, versus 56% of those receiving evolocumab (Repatha; Amgen) or alirocumab (Praluent; Regeneron). This higher adherence is attributed to inclisiran's administration by healthcare professionals, ensuring the injection is received, unlike self-administered alternatives.
Practical Considerations and Cost Management
Inclisiran is administered subcutaneously in the abdomen, arm, or thigh, with no refrigeration required and a three-year shelf life. Maisha Rudison-Bryant from Novartis emphasized that inclisiran is broadly covered and affordable, with most commercial insurance plans not requiring a step-up from other injectable medications. The Leqvio copay program further reduces costs, with 94% of patients paying as little as $0. For traditional Medicare plans, no prior authorization is needed, accelerating treatment access.
With strong efficacy data, improved adherence, and wide availability, inclisiran offers a promising new approach to controlling LDL-C and reducing cardiovascular event risks.
