Funding This study was sponsored by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Medical writing and editorial support were provided by Elisabetta Lauretti, PhD, of Red Nucleus, and funded by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Background/Synopsis Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of deficient lipolytic capacity causing severe hypertriglyceridemia and increased acute pancreatitis risk. Olezarsen is a triantennary N-acetyl galactosamine–conjugated antisense oligonucleotide that targets hepatic APOC3 mRNA for degradation. In Balance (NCT04568434), a phase 3 study in patients with genetically-identified FCS, olezarsen 80 mg vs placebo significantly reduced triglycerides and was associated with reduced acute pancreatitis events. Olezarsen 80 mg is approved in United States as an adjunct to diet to reduce triglycerides in adults with FCS. In clinical laboratories, genetic testing results for FCS are reported as “positive” (or “pathogenic/likely pathogenic”) “indeterminate” or “negative.” However, publicly available databases may be incomplete or not up to date for all potentially pathogenic variants. Objective/Purpose This post hoc analysis from Balance examined the prevalence, baseline characteristics, and reclassification of initially indeterminate genetic test results in patients with suspected FCS. Methods After eligibility assessment and screening for enrollment in Balance, genetic testing was performed by a commercial laboratory (Prevention Genetics, Marshfield, WI). Prior to randomization, initial laboratory results were further adjudicated by a core laboratory (Western University, London, ON, Canada) using independent bioinformatics and non-public research registry data. Results Of 131 patients tested, 67 (51%) were initially designated positive, 10 (8%) negative, and 54 (41%) indeterminate for FCS, the latter because of “variants of uncertain significance” (VUSs). Compared with positive patients, initially indeterminate patients were more likely to be male, non-White, have a lower prevalence of pancreatitis, and have a lower value for chylomicron-triglycerides and higher values for ApolipoproteinC-III (ApoC-III), low-density lipoprotein-C (LDL-C), and apolipoprotein B (apoB) (Table 1). All initially positive and negative patients were adjudicated as such by the core laboratory. However, indeterminate laboratory results were subsequently reclassified as pathogenic/likely pathogenic in 15/54 (28%) patients and as negative in 39/54 (72%). Over 53 weeks, 7 initially positive (13%; 1 olezarsen 80 mg, 1 olezarsen 50 mg, 5 placebo) and 2 initially indeterminate patients (17%; both placebo) had adjudicated acute pancreatitis episodes. Conclusions Of patients with suspected FCS initially reported as indeterminate, a substantial proportion (28%) had genetically-confirmed FCS using a more comprehensive assessment. In patients with indeterminate genetic results, pending refinement of genetic testing, consideration should be given for using clinical risk scores to diagnose FCS. A global curated public database of FCS-related DNA variants in racially diverse populations may allow more accurate classification of pathogenic FCS variants.
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