LDL-C target achievement after adding evinacumab in 2 patients with autosomal recessive hypercholesterolemia

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare form of genetic hypercholesterolemia
consequent to pathogenic variants in the low-density lipoprotein receptor adaptor protein 1
(LDLRAP1) gene, coding for a protein responsible for moving LDL-receptor (LDL-R) to its site of activity.
ARH is characterized by very high levels of LDL cholesterol (LDL-C), leading to aggressive and frequently
premature atherosclerotic cardiovascular disease (ASCVD). Lowering of LDL-C is the main target of
treatment; however, classical lipid-lowering agents, for example, statins, frequently have a modest response,
in view of their selective LDL-R–raising activity.
OBJECTIVE: Among newer agents with an LDL-R–independent mechanism, evinacumab has been
shown to be effective in homozygous familial hypercholesterolemia, but few data are available
in LDLRAP1 variant carriers.
METHODS: We here report 2 cases of this extremely rare form of familial hypercholesterolemia with
a surprising response to evinacumab. Evinacumab was added to maximally tolerated background
therapy.
RESULTS: In the first patient, who had severe ASCVD and a prior inadequate response to statins,
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and lomitapide, evinacumab reduced
time-averaged LDL-C by 82% (from 549 to 62 mg/dL). In the second patient, evinacumab achieved a
sustained 73.8% LDL-C reduction, maintaining levels < 55 mg/dL and allowing discontinuation of
the PCSK9 inhibitor.
CONCLUSION: These cases demonstrate a marked and clinically meaningful LDL-C–lowering effect
of evinacumab in ARH, supporting its use as an effective LDL-R–independent therapeutic option.