HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH) REQUIRES QUADRUPLE LIPID-LOWERING THERAPY TO ACHIEVE APPROPRIATELY LOW LDL-C

Abstract

Therapeutic Area: Pharmacologic Therapy Case Presentation: Ms. X is a mid-40-year-old woman presented with a history of LDL-C >400 mg/dL initially identified while she was in college. She has no physical stigmata (i.e., arcus, xanthelasmas, tendon xanthomas). She has a family history of elevated cholesterol in her maternal ancestry but no ASCVD (Atherosclerotic cardiovascular disease) events. Seen for consultation in 2019, she was found to have a coronary artery calcium (CAC) score of 116 (95th percentile) and Lp(a) of 114 mg/dL. Formal genetic testing identified two different LDLR pathogenic variants and an APOB variance of unknown significance (VUS), consistent with a diagnosis of HoFH.She had been prescribed simvastatin 80 mg in her 20s and did not tolerate this. She was switched to atorvastatin 40 mg but did not tolerate it, and this was reduced to 20 mg. However, she was not consistent with this. Her 2018 LDL-C was 385 mg/dL. She started rosuvastatin 40 mg and ezetimibe 10 mg, reducing LDL-C to 318 mg/dL. Repatha 140 mg/mL was added within a month. However, she developed GI symptoms on Repatha and was switched to Praluent 75 mg (on rosuvastatin 40 mg and ezetimibe 10 mg), achieving an LDL-C of 252 mg.One year later, on follow-up, she had stopped her Praluent and ezetimibe due to GI symptoms and was again inconsistent with her statins. Follow-up LDL-C was 396 mg/dL. Her rosuvastatin 40 mg was restarted, and LDL-C was reduced to 308 mg/dL. After discussing Leqvio, lipid apheresis, and evinacumab as adjunctive therapies, she received baseline and 90-day injections of Leqvio. She developed myalgias due to rosuvastatin and stopped this. Follow-up LDL-C at her 90-day Leqvio was 420 mg/dL.Considering statin myalgias on three different statins, Nexlizet 180/10 (bempedoic acid and ezetimibe) was prescribed but was not approved by insurance. Rosuvastatin and ezetimibe were restarted, and the follow-up LDL-C was 235 mg/dL (3 months after a 90-day Leqvio injection). Repatha was successfully restarted two months later, and in addition to rosuvastatin 40 mg and ezetimibe 10 mg, LDL-C was 171 mg/dL.We discussed lipid apheresis or evinacumab as a fourth therapy. She chose evinacumab based on her lifestyle, occupation, and overall health goals. However, evinacumab authorization was denied, and despite two letters of medical exception and a letter of appeal, it remained denied by insurance.Through patient assistance, she was provided a once-a-month evinacumab infusion. On quadruple therapy, rosuvastatin 40 mg, ezetimibe 10 mg, Repatha 140 mg/mL, and evinacumab, her first follow-up LDL-C was 138 mg/dL. One month later, it was 116 mg/dL. After five months of quadruple therapy, she achieved an LDL-C was 72 mg/dL (see graph). Background: Heterozygous FH (HeFH) and HoFH are mutations of one or more of four genes: LDLR, APOB, PCSK9, and LDLRap1. HoFH has a prevalence estimated at 1:1,000,000. ASCVD events, when they occur, do so in the first and second decades of life. As mutations in HoFH affect two genes, traditional pharmacologic therapies are usually less effective, and given the magnitude of LDL-C numbers, even combination therapy rarely achieves therapeutically reduced LDL-C. Hence, plasma apheresis is the principal therapy for those with HoFH. US (United States) Lipid-lowering guidelines recommend LDL-C levels of less than 100 mg/dL for those with baseline levels >190 mg/dL. While consistent data demonstrates an increasing risk of ASCVD events with the presence of coronary calcium, there are no current prospective clinical trials completed with data showing reduced events with treatment. Here, Ms. X has coronary artery disease CAC, and an LDL-C goal of less than 70 mg/dL would be reasonable. Conclusions: Despite genetically confirmed pathogenic mutations of two LDLR variants as well as an APOB VUS with baseline LDL-C of over 400 mg/dL, Ms. X has not developed any physical stigmata of severe hypercholesterolemia. She does not have any family history of early events. While she has survived to her fourth decade without suffering any acute ASCVD events, she has developed early coronary atherosclerosis, as evidenced in her 95th percentile CAC score.Through ongoing education, discussion, communication, and persistence, we were able to retrial statin, ezetimibe, and PCSK9i mAB therapies and add ANGPTL3i mAB as well to achieve an LDL-C of 72 mg/dL. It is unclear why the PCSK9i siRNA therapy had less of an impact on LDL-C than the mAB.