The US Food and Drug Administration has approved a significant label update for Novartis' Leqvio (inclisiran), enabling the twice-yearly injectable cholesterol-lowering therapy to be used as first-line monotherapy alongside diet and exercise for adults with hypercholesterolemia. The approval removes the previous requirement for Leqvio to be used in combination with statin therapy, marking a major expansion in treatment options for patients struggling to manage elevated LDL cholesterol levels.
Addressing Critical Treatment Gaps
The FDA's proactive label update comes as healthcare providers face mounting challenges in cholesterol management. Up to 80% of atherosclerotic cardiovascular disease (ASCVD) patients in the US struggle to reach the guideline-recommended LDL cholesterol target of less than 70 mg/dL. This treatment gap has become increasingly urgent following the latest 2025 ACC/AHA Joint Committee Clinical Practice Guideline for the Management of Patients with Acute Coronary Syndromes, which recommends more aggressive treatment approaches.
"This first-line label update reinforces Leqvio's proven ability to effectively lower LDL-C, a critical risk factor for heart disease," said Victor Bultó, President, US, Novartis. "With this new indication enabling Leqvio's use as monotherapy along with diet and exercise, we now have the potential to help even more patients achieve their LDL-C lowering goals earlier in their treatment journey."
Real-World Evidence Supports Early Intervention
Supporting data for the expanded indication comes from the V-INITIATE trial, which demonstrated the clinical value of early Leqvio intervention in real-world settings. The 12-month Phase IIIb study evaluated 450 ASCVD patients who failed to reach LDL cholesterol goals on maximally tolerated statin therapy alone.
Results showed that patients receiving Leqvio experienced significant LDL cholesterol reductions compared to usual care (60% vs. 7%, respectively; p<0.001). Notably, four in five patients receiving Leqvio achieved the guideline-recommended LDL cholesterol goal of less than 70 mg/dL compared to just one in five patients receiving usual care (81.8% vs. 22.2%, respectively; p<0.001).
"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 Michael Koren, M.D., Medical Director and CEO of Jacksonville Center for Clinical Research, and the primary investigator of the study.
Unique Dosing Advantage
Leqvio's twice-yearly, healthcare provider-administered dosing schedule distinguishes it from daily oral therapies. After an initial dose and another at three months, patients receive injections every six months. This approach may help address treatment adherence challenges that commonly plague cholesterol management.
The V-INITIATE study reinforced this advantage, showing that patients receiving healthcare provider-administered Leqvio maintained adherence to existing lipid-lowering therapy. The discontinuation rate of background statin therapy did not differ significantly between the Leqvio and usual care arms (5.8% vs. 16.7%, respectively).
Safety Profile Remains Consistent
The safety results from V-INITIATE aligned with findings from pivotal Phase III clinical trials and long-term open-label extension trials ORION-3 and ORION-8, which demonstrated sustained safety for up to six years of treatment. The most common side effects include injection site reactions (including pain, redness, and rash), arthralgia (joint pain), and bronchitis.
Expanding Treatment Paradigm
The label update also includes terminology refinements, replacing "primary hyperlipidemia" with the more specific term "hypercholesterolemia" throughout the prescribing information to more accurately focus on LDL cholesterol reduction.
"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, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis.
Leqvio represents the first and only small interfering RNA (siRNA) therapy approved to lower LDL cholesterol and is currently approved in over 90 countries, including the US, EU, Japan, and China. The therapy was developed under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics.
The V-INITIATE trial forms part of VictORION, Novartis' comprehensive clinical program for Leqvio comprising more than 30 trials enrolling over 60,000 patients across more than 50 countries worldwide, designed to establish the therapy's benefits across diverse patient populations and clinical scenarios.
