Endocrine Abstracts

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare inherited autosomal dominant disease (1/20000 Individuals) involving germline mutations in the LDL metabolism pathways (LDL receptor/PCSK9/APOB/lDLRAP) that results in very high levels of LDLc, usually >10 mmol/l, and premature cardiovascular disease. The EAS guidelines recommend the use of PCSK9 inhibitors (PCSK9i) as a third line therapy in HoFH, however they report no precision regarding the effect of monoclonal antibodies (MAB) vs small interfering RNA (siRNA) in this specific situation. Here we report a case of patient with HoFH and resistance to Inclisiran a siRNA PCSK9i.

Case series: Mrs M, 28-year-old woman, is a 4th of 6 siblings from a consanguineous (first degree cousins) marriage. She had a diagnosis of HoFH at the age of 10 with a baseline LDLc of 13.6 mmol/l (mutation LDLr: NM:000527.5:c.[(694+1_695-1)_(940+1_941-1)del]mat;[(694+1_695-1)_(940+1_941-1)del]pat). Despite an initiation of simvastatin and ezetimibe at a young age, LDLc remained very high due to adherence issues. Since 2023 we decided to conduct a stepped approach to treat her HoFH. We reinitiated rosuvastatin 40 mg plus ezetimibe 10 mg resulting in significant decrease of LDLc to 8.7 mmol/l. We then added inclisiran as a third line therapy for adherence purposes. However, LDLc decrease was insufficient: LDLc 7.5 mmol/l (additional 14% decrease) one month after the second injection. We then added bempedoic acid 180 mg and cholestyramine 3g/day, resulting in 16% additional decrease in LDLc (6.3 mmol/l). To better impact LDLc we decided to switch from inclisiran to evolocumab (MAB PCSK9i) since October 2023. In-fact, the patient’s brother carrying the same mutation at homozygous state, showed a spectacular response to evolocumab 280 mg every 15 days, with LDLc decreasing from 9 mmol/l to 4.8 mmol/l (46% decrease).

Discussion: This case corroborates the recent results of Orion 5 Study reporting a non-significant decrease of LDLc with inclisiran compared to placebo in HoFH despite a potent effect on circulating PCSK9¹. Real world data with monoclonal antibodies inhibiting PCSK9 in HoFH showed an excellent response (-57% of additional decrease in LDLc at 24 months) when added to other lipid lowering therapies².

Conclusion: in HoFH patients, the third line therapy after maximum statin/ezetimibe combination should be MAB PCSK9i, inclisiran showing poor efficacy in this context. Mechanisms explaining this discrepancy should be elucidated and future guidelines should precise this specificity.

References: 1. Raal F et al. ORION-5 Study Investigators. PMID: 37850379. 2. Arca M et al. PMID: 37850449.