Practical Pearls: Inclisiran: Where Will It Fit?

Inclisiran (Leqvio; Novartis) is now the first small interfering RNA (siRNA) therapy to be approved by the FDA to reduce low-density lipoprotein cholesterol (LDL-C). Inclisiran was previously approved in the EU on 9 December 2020 for use in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet and maximally tolerated statin use. Inclisiran is conjugated to triantennary N-acetylgalactosamine carbohydrates (GalNAc) to target hepatic PCSK9 synthesis in contrast to the monoclonal antibody inhibition of PCSK9 enzyme provided by alirocumab (Praluent) and evolocumab (Repatha). The GalNAc platform allows for precise, targeted uptake of the drug by hepatocytes. Following uptake into hepatocytes, the antisense strand of inclisiran (which specifically corresponds to human PCSK9 mRNA) is integrated into the RNA-induced silencing complex. This directs the catalytic breakdown of PCSK9 mRNA, thus preventing PCSK9 protein translation. Inhibited PCSK9 synthesis increases the recycling and expression of LDL-C receptors on the hepatocyte cell surface, in turn increasing LDL-C uptake and reducing circulating LDL-C levels.

Inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of patients with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia, who require additional lowering of LDL-C. The impact of inclisiran on cardiovascular morbidity and mortality outcomes has yet to be determined, but phase III trials are underway to evaluate this important information. The FDA approval is based on data from the comprehensive phase 3 ORION-9, -10, and -11 trials, in which all 3,457 patients with ASCVD or heterozygous familial hypercholesterolemia had elevated LDL-C while receiving a maximally tolerated dose of statin therapy. At month 17, inclisiran delivered effective and sustained LDL-C reduction of up to 52% compared to placebo; contrast this to evolucumab with a 59% LDL-C reduction in a similar patient population. The most common adverse effects from these trials included mild to moderate injection site reactions, joint pain, UTIs, diarrhea, upper respiratory symptoms, and limb pain.

Novartis proposes infrequent dosing of inclisiran will alleviate the long-standing problem of cholesterol medication non-adherence associated with statin therapy and will be a more tolerable regimen than monthly or biweekly subcutaneous PCSK9i. They plan to introduce the drug as a provider administered therapy rather than an at-home injectable. Due to this administration process for the drug , lipidologists and cardiologists will be faced with a procurement and billing process they are not as familiar with.

Leqvio is quoted to cost $3,250 per injection and therefore will be $9,750 for the first year and then $6,500 per year after that. The in-office administration will possibly allow for savings for Medicare part B patients as Medicare will cover 80% and the remainder might be covered by supplementary insurance. For commercial payers, patients may be eligible for Leqvio Co-pay Card.

Novartis has outlined the different ways patients will be able to receive this drug on Leqvio-access.com. One method of providing this therapy to patients is through the ‘Buy and Bill’ method for Medicare Part B members. This model
is frequently used in the Hematology/Oncology world for infusion based therapies.

For Medicare Part B Fee for Service patients, the provider may establish with and subsequently order through one of their many authorized distributors. After obtaining the drug the provider will assume responsibility for the medication which can be stored at room temperature. They will administer it in office and have the patient return in 3 to 6 months for further doses. The provider’s office will then be responsible for submitting a claim and managing reimbursement for both the medication and administration. If a claim is denied, then there is an appeal process that the LEQVIO Service Center can assist with.

For Medicare Part C and Medicare Advantage patients, providers may send a prescription to specialty pharmacies. The specialty pharmacy then contacts the patient, arranges the prior authorizations and appeals process, and then ships the product to the healthcare provider for administration. For patients with private insurance, providers can either use the specialty pharmacies or the Buy-and-Bill model.

Inclisiran may be an effective new tool in our arsenal for reducing LDL-C cholesterol and thereby reducing cardiovascular events. The durable effects of the medication will hopefully offer innovative means of use, such as in the United Kingdom where inclisiran is being used as a public health tool. It will be interesting to see how rapidly lipidologists, cardiologists, and others will add this to their toolkit given its atypical procurement. The proposed distribution model may raise problems for providers who do not already have the necessary infrastructure for in-office administration. Additionally, it might be more accessible for patients with Medicare Part B rather than other insurances. Inclisiran promises to be an exciting agent in cardiovascular disease treatment, and we look forward to seeing how its use unfolds in the ‘lipid armamentarium’.

Disclosure statement: Dr. Kesari has no financial disclosures to report. Dr. Merryman has no financial disclosures to report.
References are listed in the 2022 MWLAPLA LipidSpin .pdf on www.lipid.org.