DISCUSSION
SECONDARY, HOFH
ORION-5 did not meet its primary objective of detecting a statistically significant difference in the percentage change in LDL-C levels from baseline to day 150 between the inclisiran and placebo groups. Placebo-corrected changes in PCSK9 levels from baseline to day 150 were observed with inclisiran treatment and were sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant changes were observed in the levels of other lipids and lipoproteins (apoB, non–HDL-C, lipoprotein[a], and total cholesterol) between the inclisiran and placebo groups.In the ORION-2 proof-of-concept study, 3 of the 4 patients with HoFH showed a substantial reduction in LDL-C levels that was maintained for 180 days.Patients with HoFH often show high genetic variability, and the response to LDL-C–lowering therapies is affected by sequence variations mainly related to the A small study population with a heterogeneous set of genetic variants might have affected the treatment responses to inclisiran in the current study, leading to the study not meeting its primary end point and several secondary end points. There were 13 null/null patients with a homozygous or compound heterozygous In the real world, suboptimal adherence and persistence to daily LDL-C–lowering therapy is the most likely reason for not achieving the guideline-recommended LDL-C goals in many patients.Lipoprotein apheresis is often used as an adjunct therapy in patients with HoFH who do not achieve sufficient lowering of LDL-C level despite optimum LDL-C–lowering therapy.HoFH is difficult to treat, and patients often require treatment with multiple therapies.