U.S. Food and Drug Administration (FDA)-Approved Indications

Leqvio is indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C).

Inclisiran, available as Leqvio (Novartis Pharmaceuticals Corporation), is a double-stranded small interfering ribonucleic acid (siRNA) directed to PCSK9 (proprotein convertase subtilisin kexin type 9) messenger ribonucleic acid (mRNA). Inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases low-density lipoprotein cholesterol (LDL-C) receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation (Novartis, 2023).

Based on the mechanism of action, Leqvio may cause fetal harm when administered to pregnant patients. Per the prescribing information, Leqvio should be discontinued when pregnancy is recognized. There is no information on the presence of inclisiran in human milk, the effects on the breastfed infant, or the effects on milk production. In clinical trials involving rats, inclisiran was present in the milk of lactating rats in all dose groups.

The safety and effectiveness of Leqvio have not been established in pediatric patients.

The most common adverse reactions in clinical trials (3% or more) include injection site reaction, arthralgia, diarrhea, and bronchitis.

Clinical Atherosclerotic Cardiovascular Disease (ASCVD) and Heterozygous Familial Hypercholesterolemia (HeFH)

Clinical atherosclerotic cardiovascular disease (ASCVD) is a general term that includes conditions such as acute coronary syndrome, peripheral arterial disease, myocardial infarction and stroke. ASCVD is a heterogenous condition that is characterized by cholesterol plaque buildup in the arteries that leads to thickening and loss of elasticity in the arterial wall which increases the risk of morbidity and, if left untreated, mortality. Symptoms develop when growth or rupture of the plaque reduces or obstructs blood flow. Symptoms vary by the artery affected. It is estimated that 18.3 million American adults have ASCVD (FDA, 2021; Klimchak et al, 2020; Thanassoulis and Afshar, 2019).

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that that affects the body’s ability to manage cholesterol, typically resulting in very high levels of low-density lipoprotein cholesterol (LDL-C). There are two types of FH, homozygous (HoFH) and heterozygous (HeFH). Homozygous is rare and occurs as a result of inheriting the FH gene from both parents; whereas, heterozygous is more common and results from inheriting the FH gene from one parent. Persons with HeFH generally have cholesterol levels two to three times higher than normal. HeFH increases the risk of cardiovascular events, such as heart attack, stroke, and coronary artery disease. HeFH can be life-threatening. HeFH occurs in approximately 1 in 250 individuals globally. In the absence of aggressive lipid lowering therapy, life span is significantly shortened. In addition, for a given level of LDL-C, the prognosis is worse for persons with FH than those without FH (FDA, 2021; McGowan et al, 2019; Rosenson and Durrington, 2020).

On December 22, 2021, the FDA approved Leqvio (inclisiran) injection as a treatment to be used along with diet and maximally tolerated statin therapy for adults with HeFH or clinical ASCVD who require additional lowering of LDL-C. Leqvio works to reduce circulating levels of LDL-C. FDA approval was based on the efficacy results of inclisiran that was studied in three randomized, double-blind, placebo-controlled trials (ORION-10, NCT03399370; ORION-11, NCT03400800; and ORION-9, NCT03397121) (FDA, 2021).

ORION-10 enrolled 1,561 adults with ASCVD. At day 510, the Leqvio group had an average LDL-C decrease of 51% whereas the placebo group had an average LDL-C increase of 1% (FDA, 2021).

ORION-11 enrolled 1,414 adults with ASCVD. At day 510, the Leqvio group had an average LDL-C decrease of 46% whereas the placebo group had an average LDL-C increase of 4% (FDA, 2021).

Study inclusion criteria for both ORION-10 and ORION-11 required participants to be adults aged 18 years or older, have a history of ASCVD, serum LDL-C greater than or equal to 70 mg/dL, and that participants were receiving a maximally tolerated dose of statins or have documented evidence of intolerance to all doses of at least 2 different statins.

Ray et al (2020) state that inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9) and that previous studies suggest that it might also provide sustained reductions in LDL-C with infrequent dosing. Thus the investigators conducted a phase 3 trial which enrolled patients with ASCVD (ORION-10 trial) and patients with ASCD or an ASCD risk equivalent (ORION-11 trial) who had elevated LDL-C levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The co-primary end points in each trial were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 and up to day 540. "A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (p<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent." The investigators concluded that reductions in LDL-C levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months; however, more injection-site adverse events occurred with inclisiran than with placebo.

ORION-9 was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 482 patients with HeFH were randomized 1:1 to receive subcutaneous injections of either

Leqvio 284 mg (n = 242) or placebo (n = 240) on Day 1, Day 90, Day 270, and at Day 450. The primary efficacy outcome measure in Study 3 was the percent change from baseline to Day 510 in LDL-C (Novartis, 2021). At day 510, the Leqvio group had an average LDL-C decrease of 40% whereas the placebo group had an average LDL-C increase of 8% (FDA, 2021). Study inclusion criteria required participants to be adults aged 18 years or older; have a history of HeFH with a diagnosis of HeFH by genetic testing, and/or a documented history of untreated LDL-C of greater than 190 mg/dL, and a family history of FH, elevated cholesterol or early heart disease that may indicate FH; serum LDL-C greater than or equal to 100 mg/dL at screening, and that participants were receiving a maximally tolerated dose of statins or have documented evidence of intolerance to all doses of at least 2 different statins.

Raal et al (2020) state that monoclonal antibodies directed against PCSK9 have been shown to reduce LDL-C levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with HeFH. Thus, the investigators conducted a phase 3, double-blind trial, that randomly assigned, in a 1:1 ratio, 482 adults who had HeFH to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL-C level on day 510 and the time-adjusted percent change from baseline in the LDL-C level between day 90 and day 540. At day 510, the percent change in the LDL-C level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (p<0.001). The time-averaged percent change in the LDL-C level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (p<0.001). There were robust reductions in LDL-C levels in all genotypes of FH. Adverse events and serious adverse events were similar in the two groups. The investigators concluded that "among adults with HeFH, those who received inclisiran had significantly lower levels of LDL-C than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile".

Primary Hyperlipidemia

In July 2023, the FDA approved a label update for Leqvio (Novartis Pharmaceuticals Corporation) as an adjunct treatment with diet and statins for adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C). In addition, label updates included the removal of the “Limitations of Use” statement regarding the undetermined effect on cardiovascular morbidity and mortality, along with four adverse events (urinary tract infection, diarrhea, pain in extremity, and dyspnea), following the updated data from the VictORION cardiovascular clinical trial program (Deswal, 2023; Novartis, 2023).

Per Novartis Pharmaceuticals Corporation, "VictORION is an innovative and robust clinical program for Leqvio, comprising 27 trials and enrolling more than 60,000 patients in more than 50 countries worldwide. The program is designed to expand on the foundational evidence of LDL-C reduction with Leqvio in diverse patient populations to include implementation research, real-world evidence, and trials that establish its benefits on cardiovascular outcomes. A growing number of studies are planned to generate a vast array of data with major trials such as ORION-4 (secondary prevention), V (VictORION)-2-PREVENT (secondary prevention), V-1-PREVENT (high-risk primary prevention), V-INITIATE, V-INCEPTION, V-REAL, V-DIFFERENCE, and V-PLAQUE".

Ray et al (2023) state that three phase 3 lipid-lowering trials including patients at high risk of cardiovascular (CV) events have shown that inclisiran reduces circulating PCSK9 and LDL-C levels; however, it has yet to be determined if lowering LDL-C with inclisiran reduces the risk of CV events which is being evaluated in ongoing CV outcomes trials ORION-4 (NCT03705234) and VICTORION-2 Prevent (NCT05030428). To provide early insights into the potential for this therapeutic approach, the investigators pooled participant data from the phase 3 lipid-lowering trials, each with 18 months of follow-up and together comprised of 3655 individuals, to assess the relationship between inclisiran treatment or placebo on the risk of CV events. "Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both p < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58–0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50–1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41–1.81)]." The investigators concluded the their analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction; however, these findings await confirmation in the larger CV outcomes trials of longer duration.

Appendix

Appendix A - Clinical ASCVD

Appendix B - Statin-Associated Muscle Symptoms (SAMS) and Statin Re-Challenge

Statin re-challenge is NOT required for members who have experienced an elevation of CK level ≥10 times ULN after receiving lipid-lowering therapy (LLT) with a statin.

Appendix C - Contraindications to Statins

: Requires Precertification:

Precertification of inclisiran (Leqvio) is required of all Aetna participating providers and members in applicable plan designs. For precertification of

, call (866) 752-7021 (commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Criteria for Initial Approval

Aetna considers inclisiran (Leqvio) medically necessary for the treatment of primary hyperlipidemia when

of the following criteria is met:

Member meets

of the following:

Member will continue to receive concomitant statin therapy if no contraindication or intolerance (see

);

Member meets

of the following:

Member will continue to receive concomitant statin therapy if no contraindication or intolerance (see

).

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of inclisiran (Leqvio) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when

of the following criteria are met: