Discussion
FCS, reductions in fasting triglycerides, sHTG
HYPERTRIGLYCERIDEMIA, EVENTS
As severely elevated levels of serum concentrations are an established risk factor for AP, effective triglyceride-lowering therapies are required to improve patient outcomes. In this phase 2, randomized, placebo-controlled study in individuals with sHTG (fasting serum triglycerides >500 mg dlThe treatment response to evinacumab was highly variable, in part influenced by the molecular etiology of sHTG. For example, during the placebo-controlled period cohort 1 (consisting of patients with FCS due to bi-allelic mutations in known FCS genes) had no reduction in triglycerides, while reductions were observed in both cohort 2 (only one FCS gene mutation) and cohort 3 (no identified FCS gene mutations). The reduced response in cohort 1 during the DBTP may be due to the markedly diminished LPL activity expected in these patients. Patients in cohort 3, observed to have a median reduction in triglycerides of –81.7% with evinacumab, are likely to have high polygenic risk scores for hypertriglyceridemia, whereas patients in cohort 2 may have a combination of rare variants in the context of a high polygenic risk score backgroundThe inter-individual variability in evinacumab exposure likely contributed to the observed variability in triglyceride-lowering response. Other sources of variability in triglyceride responses may include inconsistent adherence to diet and exercise, known effects of some background lipid-lowering therapies and the use of a single post-treatment assessment of triglycerides (in contrast to three measurements used to determine baseline values).The decreases in remnant cholesterol and ApoB48 support a role for evinacumab in promoting chylomicron remnant catabolism. Parallel decreases in ApoC3 and ApoB100, despite an increase in LDL-C, are consistent with the broader role of evinacumab in triglyceride-rich lipoprotein (TRL) cholesterolApoC3 is an important regulator of triglyceride metabolism via inhibition of LPL-mediated hydrolysis of TRLs to smaller remnant particles and impaired removal of TRL remnantsTreatment with evinacumab was generally well tolerated. During the DBTP, there were no clinically meaningful differences in TEAE frequency between the evinacumab and placebo groups. TEAEs also occurred in a similar proportion of patients in the DB evinacumab and DB placebo groups during the SBTP. Notably, treatment with evinacumab had no effect on liver transaminases or hepatic fat as measured by MRI in contrast to a recent report of an antisense oligonucleotide targeted to ANGPTL3 (ref. Over the duration of the study (including the off-drug follow-up period) a total of 25 AP events were reported. During the DBTP, all patients had serum triglycerides >1,000 mg dlLimitations of this trial include the small number of patients studied, the relatively short duration of treatment, the variability of serum triglycerides and the variability in evinacumab exposure. These limit the assessment of the long-term safety and efficacy of evinacumab in patients with sHTG.sHTG-associated AP is a substantial source of morbidity, mortality and reduced quality of life as well as a financial burden to the health systems caring for these patients. Neither diet nor current pharmacological therapies have substantially addressed these consequences of sHTG. In this study, while the prespecified primary end point of mean percent change in triglyceride was not met, a post hoc analysis of median triglyceride suggested reductions in fasting triglycerides following evinacumab, except in patients with FCS lacking functional LPL. These data support the critical need to further assess the effects of evinacumab in subjects with sHTG, especially in those with a history of sHTG-associated AP.