Larouche Miriam, Banerjee Poulabi, Brisson Diane, Pordy Robert, Gaudet Daniel
Université de Montréal and ECOGENE-21, Chicoutimi, QC G7H 7K9, Canada.
Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
J Endocr Soc. 2025 Feb 14;9(4):bvaf025. doi: 10.1210/jendso/bvaf025. eCollection 2025 Mar 3.
Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability.
To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab.
A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients.
After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L).
The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).
持续性乳糜微粒血症由脂蛋白脂肪酶缺乏症（LPLD）或脂蛋白脂肪酶（LPL）生物利用度缺乏引起。这种疾病的特征是血浆甘油三酯（TG）水平高于10 mmol/L，急性胰腺炎风险增加，以及家族性乳糜微粒血症综合征（FCS）的特征。evinacumab是一种血管生成素样蛋白3（ANGPTL3）单克隆抗体，其降低血浆TG水平的疗效取决于LPL的生物利用度。
在接受evinacumab治疗的持续性乳糜微粒血症患者中鉴定导致FCS的致病变异。
对严重高甘油三酯血症患者进行了一项使用evinacumab的II期临床试验。在基线时以及每2周测量一次血浆TG值，持续24周。三名已知与低肝素后LPL活性相关（经证实的LPLD）的LPL基因P234L致病变异纯合子的FCS患者（HoLPL P234L）参与了研究并用作追踪对象。将evinacumab降低其他参与者TG水平的基因型特异性疗效与HoLPL P234L患者所达到的疗效进行比较。
evinacumab治疗24周后，已知缺乏LPL的HoLPL P234L患者的TG水平降低<20%。同样，一名LPL基因外显子6中E282X变异的纯合子参与者，因其位置被怀疑具有致病性，对evinacumab无反应（TG降低<10%且仍>10 mmol/L）。
ANGPTL3抑制剂降低TG水平的疗效依赖于LPL。对evinacumab的不良反应支持了LPL基因中的E282X变异是致病性的且与持续性乳糜微粒血症（FCS表型）相关的证据。
