Dr. Michael Coren
Credit: First Coast Cardiovascular Center

The use of an initial implementation strategy of inclisiran (Leqvio) in patients with atherosclerotic cardiovascular disease and LDL-C ≥70 can be used without raising safety concerns or limiting statin use, compared to usual treatment. It was associated with a significant reduction in LDL-C compared to Research presented at the American College of Cardiology 2024 (ACC.24) Annual Scientific Sessions.

Results from the VICTORION-INITIATE trial showed that use of an inclisiran-first strategy was associated with more than three times the non-inferior rate of LDL-C goal achievement and statin discontinuation compared with patients receiving usual care. It shows that¹

“V-INITIATE is an important step in the clinical practice of far too many patients with ASCVD, for whom statins alone do not achieve guideline-recommended LDL-C targets and where effective treatments other than statins are severely underutilized.” “We evaluated the solution to the problem,” said lead researcher Michael Koren. Physician, Medical Director and CEO of Jacksonville Clinical Research Center.² “Given the urgent need to manage LDL-C more aggressively, the results of V-INITIATE demonstrate that when added early in the treatment continuation, effective non-statin drugs like Leqvio We show that the therapy, when used systematically, can significantly lower LDL-C in patients with ASCVD who are struggling to reach or maintain their LDL-C goals. ”

Inclisiran is the first and only small interfering RNA (siRNA) therapy approved by the FDA to lower LDL-C with an initial dose and 3-month follow-up, followed by maintenance dosing twice a year. Ta. Dietary and maximum-tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL-C lowering. approved as a supplement. This approval is based on ORION-9, -10, and ORION-9. -11 clinical trials. In 2023, the FDA approved expanded indications for siRNA therapy to include treatment of adults with elevated LDL-C and high risk for heart disease.^3,4

At the time of approval, inclisiran’s twice-yearly dosing interval offered the prospect of reducing patient burden without compromising the LDL-C-lowering effects achieved with other PCSK9 inhibitors. The VICTORION-INITIATE study, a phase 3b trial, is a “inclisiran first” trial that immediately adds inclisiran to patients who have not achieved their LDL-C goal of less than 70 mg/dL despite maximally tolerated statin therapy. ” was launched with the purpose of evaluating whether the strategy was effective.^{1, 2}

With this in mind, this study utilized a prospective, randomized, parallel-group, open-label design to randomize 450 patients in a 1:1 ratio from 45 sites across the United States to receive initial treatment with inclisiran. strategy or usual care. To participate in the study, patients must be at least 18 years old, have a history of coronary heart disease, cerebrovascular disease, or peripheral artery disease, and have an LDL-C ≥70 mg/dL or non-HDL. Ta. -C >100 mg/dL and fasting triglycerides <500 mg/dL.¹

The median age of the 450 patient cohort was 67.0 years (27, 89 years), 30.9% were female, 12.4% were black, and 15.3% were Hispanic or Latino. Investigators noted that 97.1% had health insurance at baseline, and 58.4% reported an annual income of $50,000 or less. The mean baseline LDL-C in this cohort was 97.4 mg/dL, and 91.8% reported previous or current coronary heart disease. The researchers also noted that 25.8% were considered statin intolerant and 90.0% of the entire cohort were taking statins at baseline.¹

The study utilized co-primary endpoints of percent change in LDL-C from baseline to day 330 and discontinuation of statin treatment. For purposes of analysis, statin discontinuation was defined as he not using a statin for more than 30 days before the end-of-study visit.¹

Analysis showed that the mean change in LDL-C from baseline to day 330 was -60.0% (97.5% CI, -64.7 to -55.2) with inclisiran first strategy and -7.0% with inclisiran first strategy. (97.5% CI, -12.0 to -55.2). With usual care, the difference between groups was -53.0 percentage points (97.5% CI, -60.0 to -46.0; -60.0 to -46.0). P < .001). Discontinuation of statin therapy was observed in 6.0% of patients in the inclisiran initial treatment group versus 16.7% of patients in the usual care group.¹

Further analysis showed that a greater proportion of patients in the first inclisiran group achieved LDL-C below 70 mg/dL compared to placebo therapy (81.8% vs. 22.2%; P < .001). This trend was also observed when assessing the proportion of patients achieving LDL-C <55 mg/dL (71.6% vs. 8.9%; P < .001).¹

When assessing safety, researchers found that patients randomized to an initial strategy of inclisiran had similar rates of treatment-emergent adverse events compared to usual care. (62.8% vs. 53.7%). Additionally, a similar trend was observed for serious adverse events occurring during treatment (11.5% vs. 13.4%, respectively).¹

“The V-INITIATE data show that early initiation of innovative non-statin therapies like Leqvio represents a real opportunity for ASCVD patients to better treat them and improve the way we approach LDL-C lowering. “We’re showing that there’s promise,” said Global’s David Soergel, MD. Head of Cardiovascular, Renal and Metabolic Medicines Development at Novartis.² “This study adds real-world data to the growing body of evidence on Leqvio generated through our robust VictORION program and further strengthens the clinical value of this twice-yearly HCP treatment.”

References:

1. Collen MJ, Rodriguez F, East C et al. Initial strategy and usual care for Inclisiran in patients with atherosclerosis. Presentation location: American College of Cardiology (ACC.24) Annual Scientific Sessions. April 6-8, 2024, Atlanta, Georgia.
2. Novartis. New data from Novartis shows that early addition of Leqvio® (inclisiran) twice a year after maximally tolerated statin therapy significantly reduces LDL-C in real-world ASCVD patients. April 6, 2024. Accessed April 6, 2024.
3. Novartis. The FDA has approved Novartis Leqvio® (Inclisiran), a first-in-class Sirna that lowers cholesterol and keeps it low in twice-yearly doses. Novartis. December 22, 2021. Accessed April 6, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-leqvio-inclisiran-first-class-sirna-lower-cholesterol-and-keep-it-lower-two-dose-years.
4. Novartis. The US FDA has approved an expanded indication for Novartis Leqvio® (Inclisiran) to include the treatment of adults with elevated LDL-C and increased risk of heart disease. Novartis. July 10, 2023. Accessed April 6, 2024. https://www.novartis.com/us-en/news/media-releases/us-fda-approves-expanded-indication-novartis-leqvio-inclisiran-include-treatment – High LDLC and risk of heart disease in adults people who are increasing