Inclisiran First Strategy Safe, Effective for LDL-C Control in ASCVD Patients

Michael Koren, MD
Credit: First Coast Heart & Vascular Center

Use of an inclisiran (Leqvio) first implementation strategy among patients with atherosclerotic cardiovascular disease and an LDL-C at 70 or greater was associated with a significant reduction in LDL-C relative to usual care, without incurring safety concerns or limiting statin use, according to a study presented at the American College of Cardiology 2024 (ACC.24) Annual Scientific Sessions.

Results of the VICTORION-INITIATE trial indicate use of an inclisiran first strategy was associated with a more than tripling in the rate of patients achieving their LDL-C target goal and noninferior statin discontinuation rates relative to their counterparts receiving usual care.¹

“V-INITIATE evaluated a solution to the important challenge seen in clinical practice of too many patients with ASCVD not achieving guideline-recommended LDL-C goal on statins alone and effective non-statin therapies being markedly underutilized,” said lead investigator Michael Koren, MD, medical director and chief executive officer of Jacksonville Center for Clinical Research.² “Given the urgent need to more aggressively manage LDL-C, the results from V-INITIATE show that when added earlier in the treatment continuum, the structured use of effective non-statin therapies like Leqvio can significantly reduce LDL-C for ASCVD patients who are struggling to reach or maintain their LDL-C goal.”

Inclisiran became the first and only small interfering RNA (siRNA) therapy approved by the FDA to lower LDL-C with 2 maintenance doses a year after receiving the initial and 3-month follow-up dosing. Approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL-C lowering, the approval was based on the ORION-9, -10, and -11 clinical trials. In 2023, the FDA approved a label expansion for the siRNA therapy to include treatment of adults with elevated LDL-C and at increased risk of heart disease.^3,4

At the time of approval, the twice-yearly dosing interval of inclisiran offered the prospect of decreased patient burden without compromising on the LDL-C lowering effect achieved with other PCSK9 inhibiting agents. A phase 3b trial, the VICTORION-INITIATE study was launched with the intent of assessing whether an “inclisiran first” strategy of immediately adding inclisiran upon failure to reach an LDL-C target of less than 70 mg/dL despite maximally tolerated statin therapy.^1,2

With this in mind, the trial leveraged a prospective, randomized, parallel-group, open-label design and randomized 450 patients from 45 sites across the US in a 1:1 ratio to an inclisiran first strategy or usual care. For inclusion in the trial, patients needed to be at least 18 years of age and have a history of coronary heart disease, cerebrovascular disease, or peripheral artery disease, with an LDL-C of 70 mg/dL or greater or a non-HDL-C of 100 mg/dL or greater, and fasting triglycerides less than 500 mg/dL.¹

The cohort of 450 patients had a median age of 67.0 years (27, 89), 30.9% were female, 12.4% were Black, and 15.3% were Hispanic or Latino. Investigators pointed out 97.1% had health insurance at baseline and 58.4% reported an annual income of $50,000 or less. The cohort had a mean baseline LDL-C of 97.4 mg/dL and 91.8% reported prior or current coronary heart disease. Investigators also pointed out 25.8% were considered statin intolerant and 90.0% of the overall cohort took statins at baseline.¹

The trial leveraged co-primary endpoints, which were the percentage change in LDL-C from baseline to Day 330 and discontinuation of statin therapy. For the purpose of analysis, statin discontinuation was defined as no statin use for 30 days or more before the end-of-study visit.¹

Upon analysis, results indicated the mean percentage change from baseline to day 330 in LDL-C was −60.0% (97.5% CI, −64.7 to −55.2) with the inclisiran first strategy and −7.0% (97.5% CI, −12.0 to −1.9) with usual care, which yielded a between-group difference of −53.0 percentage points (97.5% CI, −60.0 to −46.0; P < .001). Discontinuation of statin therapy was observed among 6.0% of the inclisiran first arm compared to 16.7% of the usual care arm.¹

Further analysis indicated a greater proportion of patients in the inclisiran first arm achieved an LDL-C of less than 70 mg/dL relative to placebo therapy (81.8% vs 22.2%; P < .001). This trend was also observed when assessing the proportion of patients who achieved an LDL-C of less than 55 mg/dL (71.6% vs 8.9%; P < .001).¹

When assessing safety, investigators found treatment-emergent adverse events occurred at a similar rate for those randomized to an inclisiran first strategy relative to usual care (62.8% vs 53.7%). Additionally, a similar trend was observed for serious treatment-emergent adverse events (11.5% vs 13.4%, respectively).¹

“The data from V-INITIATE illustrate that earlier initiation of innovative non-statin therapies, like Leqvio, presents a real opportunity to do better for ASCVD patients and improve the way we approach LDL-C lowering,” said David Soergel, MD, global head of Cardiovascular, Renal and Metabolic Drug Development at Novartis.² “This study adds data from a real-world setting to the growing body of evidence for Leqvio being generated through our robust VictORION program, and further reinforces the clinical value of this twice-yearly HCP-administered therapy.”

References:

1. Koren MJ, Rodriguez F, East C, et al. An Inclisiran First Strategy vs Usual Care in Patients with Atherosclerosis. Presented at: American College of Cardiology (ACC.24) Annual Scientific Session. April 6 – 8, 2024. Atlanta, GA.
2. Novartis. New Novartis data show early addition of twice-yearly* Leqvio® (inclisiran) following maximally tolerated statin therapy significantly reduces LDL-C in ASCVD patients in real-world setting. April 6, 2024. Accessed April 6, 2024.
3. Novartis. FDA approves Novartis Leqvio® (Inclisiran), first-in-class Sirna to lower cholesterol and keep it low with two doses a year. 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-low-two-doses-year.
4. Novartis. US FDA approves expanded indication for Novartis Leqvio® (Inclisiran) to include treatment of adults with high LDL-C and who are at 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-adults-high-ldl-c-and-who-are-increased-risk-heart-disease