Inclisiran for the treatment of dyslipidemia

ABSTRACT

Introduction: Dyslipidemia is one of the most important risk factors for cardiovascular disease. Insufficient reduction in LDL-C from existing therapies in patients at high risk of atherogenic cardiovascular disease is an unmet clinical need. Circulating PCSK9 causes hypercholesterolemia by reducing LDL receptors in hepatocytes.

Areas covered: PCSK9 inhibition has emerged as a promising new therapeutic strategy to reduce LDL-C. Inclisiran, a novel, synthetic, siRNA molecule, inhibits PCSK9 synthesis in hepatocytes. Inclisiran targets intracellular PCSK9 synthesis specifically, resulting in a dose-dependent, long-term, significant reduction in LDL-C. Inclisiran has been well tolerated and safe, without severe adverse events so far. This review discusses current PCSK9 inhibitors and the results of phase I and II clinical trials of inclisiran.

Expert opinion: Plasma PCSK9 enhances the degradation of LDL receptor, resulting in accumulation of LDL-C in the circulation. Current approaches with monoclonal antibodies sequester circulating PCSK9 but require frequent injections. Inclisiran inhibits translation of PCSK9 mRNA and thus switches off PCSK9 production and provides advantages over monoclonal antibodies with an infrequent dosing interval of twice a year to reduce LDL-C by over 50%. Ongoing studies will establish the long-term safety of inclisiran in patients with high cardiovascular risk and an elevated LDL-C.

KEYWORDS:

• Inclisiran
• proprotein convertase subtilisin/kexin type 9 synthesis inhibitor
• small interfering RNA
• LDL cholesterol
• apolipoprotein B-containing lipoprotein particles

Declaration of Interest

K. K. Ray has received personal fees (data safety monitoring board) from AbbVie, Inc.; consultant fees/honoraria from Aegerion, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis, Eli Lilly and Company, Ionis Pharmaceuticals, Kowa, Medicines Company, MSD, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Resverlogix, Sanofi, and Takeda; and research grants from Kowa, Pfizer, and Regeneron Pharmaceuticals, Inc. CD, MB-Bobanovic. T. Nishikido was supported by a grant from the Uehara Memorial Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.