Familial chylomicronemia syndrome: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia (>10 mmol/L or >885 mg/dL) due to impaired chylomicron clearance. Caused primarily by bi-allelic loss-of-function variants in LPL (60-80% of cases) or genes regulating lipoprotein lipase activity (APOA5, APOC2, GPIHBP1, LMF1), FCS manifests with recurrent pancreatitis, abdominal pain, eruptive xanthomas, and lipemia retinalis [1][3][7]. Management centers on lifelong strict fat restriction (<20 g/day), though standard lipid-lowering therapies are largely ineffective [1][11]. Emerging RNA-targeted therapies (e.g., ApoC-III inhibitors) show promise in reducing triglycerides and pancreatitis risk [8][13].

Population

Estimated prevalence: 1–13 per million, with founder effects in Quebec and the Cayman Islands [1][17]
Typically presents in childhood/adolescence; ~40% experience ≥1 pancreatitis hospitalization annually [4][17]
Less than 30% receive care from lipid specialists despite high morbidity [4][9]

Burden

Clinical: Median 34 lifetime pancreatitis episodes; 40% require annual hospitalization [4][9][16]
Psychosocial: 58–82% report impaired mental health, employment limitations (94%), and restricted social functioning [4][14]
Economic: Mean 6.5-day hospital stays per pancreatitis episode; frequent specialist consultations and dietary management costs [4][9][14]

Therapies

Diet: First-line very low-fat diet (<10% of calories from fat) [1][3][16]
Pharmacotherapy: Volanesorsen (EU-approved ApoC-III inhibitor), olezarsen (FDA-approved RNA-targeted therapy), and investigational plozasiran (siRNA) [8][11][13]
Adjuncts: Medium-chain triglyceride (MCT) supplementation; avoidance of alcohol, refined carbohydrates, and estrogen [1][6]

Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism

Research Papers

269 drug discovery papers related to Familial chylomicronemia syndrome, with 5 first-in-class and 6 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:

2026-06-24 | Clinical Pharmacology of Plozasiran.

Hypertriglyceridemia can increase the risk of acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD). Patients with familial chylomicronemia syndrome are at an even higher risk of developing pancreatitis due to elevated triglycerides. A pathway involving small interfering RNA that selectively inhibits apolipoprotein C-III (APOC3) messenger RNA through RNA interference is currently being studied to reduce levels of apoC-III and thus, triglycerides. This review presents and discusses the current pharmacokinetic, pharmacodynamics, and clinical and scientific evidence pertaining to plozasiran, a small interfering RNA medicine.

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2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.

Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.

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2026-06-24 | Clinical Pharmacology of Plozasiran.

Open article ↗

2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.

Open article ↗

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Drug Discovery Landscape

10 orphan drug designations for Familial chylomicronemia syndrome, including 5 approved therapies.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
Olezarsen sodium [Tryngolza]	oligonucleotides	EMA	2024-08-21	2025-09-18	Swedish Orphan Biovitrum AB (publ)
olezarsen [Tryngolza]	RNAs	FDA	2024-02-14	2024-12-19	Ionis Pharmaceuticals
Synthetic double-stranded siRNA oligonucleotide directed against apolipoprotein C-III mRNA and covalently linked to a ligand containing three N-acetylgalactosamine residues [Redemplo]	RNAs	EMA	2021-07-19	2026-06-22	Arrowhead Pharmaceuticals Ireland Limited
plozasiran [Redemplo]	RNAs	FDA	2019-06-20	2025-11-18	Arrowhead Pharmaceuticals, Inc.
volanesorsen sodium, apolipotrotein C-III antisense oligonucleotide	oligonucleotides	FDA	2015-06-23	—	Akcea Therapeutics, Inc.
Phosphorothioate oligonucleotide targeted to apolipoprotein C-III [Waylivra]	oligonucleotides	EMA	2014-02-19	2019-05-08	Akcea Therapeutics Ireland Limited
Pradigastat	small molecules	EMA	2012-09-14	—	Novartis Europharm Limited
selective deacylglycerol acyltransferase 1 inhibitor	small molecules	FDA	2011-03-28	—	Novartis Pharmaceuticals Corporation
lomitapide	small molecules	FDA	2011-03-03	—	Chiesi Farmaceutici S.p.A.
Lomitapide	small molecules	EMA	2010-12-17	—	Chiesi Farmaceutici S.p.A.

Familial chylomicronemia syndrome

Familial chylomicronemia syndrome

Familial chylomicronemia syndrome

Overview

Population

Burden

Therapies

Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism

Research Papers

2026-06-24 | Clinical Pharmacology of Plozasiran.

2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.

2026-06-24 | Clinical Pharmacology of Plozasiran.

2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.

Drug Discovery Landscape

Updated: Jul 30, 2026