LDL–C TARGET ACHIEVEMENT AFTER ADDING EVINACUMAB IN A PATIENT WITH A RARE HOMOZYGOUS AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA

Abstract Homozygous Autosomal Recessive Hypercholesterolemia (ARH) is a rare form of genetic hypercholesterolemia caused by mutations in low density lipoprotein receptor adaptor protein 1(LDLRAP1) characterized by very high levels of low–density–lipoprotein–cholesterol (LDL–C), leading to aggressive and premature atherosclerotic cardiovascular disease. The gold standard treatment is LDL–apheresis. Novel therapies are thus needed for this severe hypercholesterolemia. Evinacumab is a new monoclonal antibody against angiopoietin–like protein3 (ANGPTL3) with LDL–receptor independent mechanism. 60 yo man with homozygous LDLRAP1 gene variant NM_015627.3:c.431dup, p. (His144Ginfs*27) causing ARH identified after genetic analysis at age 47.The earliest clinical signs, age 8 tendon xanthomas. Elevated lipid levels (TC 667,TG 62,HDL–C 47,LDL–C 608mg/dL) had been kwown from the age of 13. During adolescence he had received cholestyramine at increasing doses. At age 23 he had received for 4–years colestyramine 16g+simvastatin 20mg with inadequate LDL–C reduction(›400mg/dL). At age 27 he presented to our Lipid Clinic. He was smoking, with a negative family history of hyperlipidemia or premature myocardial infarction (MI). He had received colestyramine 8g+atorvastatin 40mg+probucol 1gr for seven–years with a significant LDL–C reduction (mean 179mg/dL). At the age of 31 a twice–weekly LDL–apheresis was started. At age 42 a severe stenosis of the left internal carotid was uncovered and successfully treated by endarterectomy. In 2008 a trivasal coronary–artery–disease required coronary–artery bypass surgery. From 2009 to 2011 he was switched to rosuvastatin (maximal dosage tollerated 30mg) +ezetimibe 10mg+ fenofibrate 145mg with good initial results but progressive loss of efficacy (LDL–C 194mg/dL). Between 2010–2011 he was enrolled in a clinical trial with Lomitapide 5mg with excellent results (LDL–C 44mg/dL), but onset of progressive liver steatosis and subjective intolerance leading to discontinuation. From 2016 to 2018,treatment with a PCSK9–inhibitor (evolocumab 140mg s.c. before and 420mg later) given every 2–weeks and discontinued in 2018 due to poor efficacy. In 2024 evinacumab i.v. every 4–weeks was added. After 8–months,his time–averaged LDL–C decreased by 82% (from 229 to 42mg/dL), despite reduced LDL–apheresis frequency (from 2–weeks to 3–weeks). No adverse events have been reported with an improved quality of life,confirming the excellent indication of Evinacumab for ARH.