Clinical trial with the angptl3 monoclonal antibody evinacumab identifies a new rare chylomicronemia causing variant in the lpl gene

Sustained chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of bioavailability. Sustained chylomicronemia is a rare metabolic disorder characterized by plasma triglyceride (TG) values chronically >10mmol/L. Evinacumab is an angiopoietin like protein 3 (ANGPTL3) monoclonal antibody (mab) with the potential to treat a spectrum of lipid disorders. The efficacy of Evinacumab in decreasing plasma TG levels depends on LPL bioavailability. To assess the LPL genotype and drug response in patients with sustained chylomicronemia treated with Evinacumab. A phase II clinical trial was conducted with Evinacumab to evaluate its safety and efficacy over 20 weeks in patients with severe hypertriglyceridemia and chylomicronemia. There were 3 cohorts in this study, one of which included patients with sustained chylomicronemia and LPLD. LPL genotypes were assessed in all patients. Plasma TG values were measured at baseline and every 2 weeks for 20 weeks. Genotype-specific response to Evinacumab was assessed by comparing pre-post TG values. This phase II trial identified one patient being homozygote for an undocumented mutation (E282X) in the LPL gene who did not respond to Evinacumab (TG decrease < 10% after 20 weeks), which is compatible with lack of LPL bioavailability. This variant is thus suspected to cause LPLD. Clinical trials for rare genetic diseases can reveal new disease-causing gene variants. A phase II clinical trial conducted with Evinacumab, a ANGPTL3mab, in patients with sustained chylomicronemia identified an undocumented E282X mutation in the LPL gene. This new variant is considered as being a LPLD causing (OMIM: 609708).