Long-term treatment with inclisiran was well-tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia, according to a new post hoc analysis of data from seven clinical trials. The analysis, published online Monday and in the Dec. 12 issue of the Journal of the American College of Cardiology, noted that extensive evidence has shown that lowering low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of cardiovascular (CV) events, whereby the risk decreases in correspondence to the duration of treatment with lipid-lowering therapy (LLT). Indeed, led by R. Scott Wright, MD, from the Mayo Clinic, Rochester, Minnesota, the authors noted that guidelines recommend specific target levels to lower LDL-C related to CV risk and recommend maintaining those levels indefinitely. “However, a considerable proportion of patients do not achieve or maintain the recommended treatment goals with existing therapies, resulting in a diminished effectiveness in mitigating CV risk,” they said. “Therefore, new approaches to LLT are needed to improve attainment and maintain treatment goals.” The team noted that multiple studies, including a 4-year open-label extension (OLE) trial, ORION-3, have demonstrated that twice-yearly dosing with inclisiran, a first-in-class small interfering RNA, reduces LDL-C levels by approximately 50% in combination with maximally tolerated oral LLT in a range of patients. “This pooled analysis of data from 7 clinical trials investigating the safety and tolerability of inclisiran … provides the largest data set to date showing that twice-yearly inclisiran treatment is well tolerated in combination with statins and/or other oral LLT in patients with elevated LDL-C levels,” they said. Study details Wright and colleagues pooled data from seven clinical trials, including 3,576 patients treated with 300 mg-inclisiran sodium subcutaneous injections for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Among these patients, 43.3% were treated with inclisiran for more than 3 years, they said. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed, the researchers stated, noting that baseline characteristics were balanced between groups. “Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period,” said Wright and colleagues. They added that, numerically, fewer major cardiovascular events reported as TEAEs occurred with inclisiran (exposure-adjusted incidence rate [EAIR]: 3.79; 95% confidence interval [CI]: 3.41-4.20) than placebo (EAIR: 6.75; 95% CI: 5.79-7.83) per 100 patient-years. Furthermore, the analysis showed that treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%), and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs. “Long-term use of inclisiran is safe and generally well tolerated in a diverse population of patients with dyslipidemia treated for as long as 6 years,” concluded Wright and colleagues. “Taken together with the effective and consistent LDL-C–lowering ability of inclisiran, these data lend support to its long-term use in patients at high CV risk,” they said, noting that ongoing trials will provide additional data on the safety of inclisiran and its and effect on cardiovascular outcomes. Promising new therapy Writing in an accompanying editorial, Christie M. Ballantyne, MD, and Abdul Mannan Khan Minhas, MD, from the Baylor College of Medicine, Houston, alongside Carl E. Orringer, MD, from the NCH Rooney Heart Institute, Naples, Florida, noted that inclisiran has received U.S. Food and Drug Administration approval as an adjunct to diet and statin therapy for patients with clinical atherosclerotic cardiovascular disease (ASCVD), heterozygous familial hypercholesterolemia, or primary hypercholesterolemia with ASCVD-related comorbidities who require additional LDL-C lowering. “As a first-in-its-class product to be used with a goal of cardiovascular risk reduction, regulatory agencies and clinicians place a high premium on ensuring this drug’s sustained safety and efficacy,” they said. “Inclisiran is a promising new therapy with the advantages of less-frequent dosing, robust LDL-C reduction, good tolerability, and a favorable safety profile.” The editorialists added that an informed clinician–patient discussion about the initiation of inclisiran should include a disclaimer of uncertainty about cardiovascular outcomes and shorter follow-up for adverse effects as compared with the PCSK9 monoclonal antibodies. “Additionally, treatment decisions may be affected by insurance coverage, which for PCSK9 monoclonal antibodies is via pharmacy benefits, and for inclisiran is through medical benefits,” they said, adding that ongoing large trials will provide important information on the safety and efficacy of inclisiran. Sources: Wright RS, Koenig W, Landmesser U, et al. Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials J Am Coll Cardiol 2023;82:2251-2261. Ballantyne CM, Minhas AMK, Orringer CE. Where Are We on Safety, Efficacy, and Clinical Effectiveness of siRNA Therapies for Prevention? J Am Coll Cardiol 2023;82:2262-2264. Image Credit: LASZLO – stock.adobe.com