Inclisiran Durably Lowers Low-Density Lipoprotein Cholesterol and Proprotein Convertase Subtilisin/Kexin Type 9 Expression in Homozygous Familial Hypercholesterolemia

Abstract

omozygous familial hypercholesterolemia (HoFH) is a genetic disorder characterized by extremely high low-density lipoprotein (LDL) cholesterol (LDL-C) plasma levels, leading to premature atherosclerotic cardiovascular disease (ASCVD). 1 Deleterious variants in both alleles of the gene encoding the LDL receptor are most common among patients with HoFH.Receptor-defective variants reduce LDL receptor function by up to 75% (2% to 25% normal activity), whereas receptor-negative (or null) variants completely eliminate its function (<2% normal activity). 1Receptor-negative variants are generally associated with extremely high levels of LDL-C and poor response to therapy. 1 Guideline-recommended LDL-C levels 1 are rarely achieved in HoFH because established therapies are insufficient, not tolerated, or unavailable (eg, lipoprotein apheresis).Additional effective, well-tolerated LDL-C-lowering agents are needed to optimize the treatment of patients with HoFH.Inclisiran is an siRNA that inhibits hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis.In the phase 3 ORION-9, ORION-10, and ORION-11 trials, inclisiran twice yearly lowered LDL-C by at least 50% in individuals with heterozygous familial hypercholesterolemia or ASCVD/ASCVD equivalents. [2][3]][4] To evaluate the efficacy and safety of inclisiran in patients with HoFH and to confirm the dose and regimen for a subsequent phase 3 trial, the open-label, single-arm, multicenter ORION-2 proof-of-concept study was conducted in patients with HoFH receiving maximally tolerated lipid-lowering therapy (statins/ezetimibe).Inclisiran sodium 300 mg SC was administered on day 1 and either day 90 or 104 if mean PCSK9 levels were not suppressed by >70% compared with baseline at day 60 or 90.The primary efficacy end point was percentage change from baseline in LDL-C on days 90 and 180; secondary end points included absolute change in LDL-C and changes in PCSK9 levels and other lipids and lipoproteins over time.Safety and tolerability were also evaluated.After day 180, participants continued in the study until the observed LDL-C reduction was <20% of the absolute reduction from baseline to day 90.Patients with a genetic or clinical diagnosis of HoFH (defined according to European Atherosclerosis Society consensus: history of untreated LDL-C >500 mg/dL and either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents) were enrolled. 1Lipid-lowering therapy should have been stable for 4 weeks, with no planned medication/dose changes.Patients should not have received apheresis or PCSK9-inhibiting monoclonal antibodies within 8 weeks or mipomersen or lomitapide within 5 months of screening.

Topics & Concepts