Etiology and emerging treatments for familial chylomicronemia syndrome

ABSTRACT

Introduction

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment is important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic treatment for FCS, namely biological inhibitors of apolipoprotein (apo) C-III and angiopoietin-like protein 3 (ANGPTL3).

Areas covered

FCS follows a biallelic inheritance pattern in which an individual inherits two pathogenic loss-of-function alleles of one of the five causal genes – LPL (in 60–80% of patients), GPIHBP1, APOA5, APOC2, and LMF1 – leading to the absence of lipolytic activity. Patients present from childhood with severely elevated triglyceride (TG) levels >10 mmol/L. Most patients with severe hypertriglyceridemia do not have FCS. A strict low-fat diet is the current first-line treatment, and existing lipid-lowering therapies are minimally effective in FCS. Apo C-III inhibitors are emerging TG-lowering therapies shown to be efficacious and safe in clinical trials. ANGPTL3 inhibitors, another class of emerging TG-lowering therapies, have been found to require at least partial lipoprotein lipase activity to lower plasma TG in clinical trials. ANGPTL3 inhibitors reduce plasma TG in patients with multifactorial chylomicronemia but not in patients with FCS who completely lack lipoprotein lipase activity.

Expert opinion

Apo C-III inhibitors currently in development are promising treatments for FCS.

KEYWORDS:

• Angiopoietin-like protein 3
• apolipoprotein C-III
• familial chylomicronemia syndrome
• hypertriglyceridemia
• olezarsen
• plozasiran
• volanesorsen

Article highlights

• Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition that is present from childhood and is characterized by severe hypertriglyceridemia (HTG), with triglyceride (TG) levels >10 mmol/L. Effective treatment is important as patients are at risk for severe, recurrent, and potentially fatal acute pancreatitis.

• There are currently no FDA approved treatments for FCS. A strict low-fat diet is the current first-line treatment for FCS, which is difficult to adhere to and has negative implications on patient quality of life.

• Apolipoprotein C-III inhibitors effectively lower plasma TG in patients with FCS and severe HTG and have been shown to have long-term efficacy and safety in phase 3 clinical trials to date (up to 51 months). Olezarsen and plozasiran may be preferred over volanesorsen as these drugs reduce plasma TG with no observed drug-induced thrombocytopenia.

• Angiopoietin-like protein type 3 (ANGPTL3) inhibitors are ineffective for reducing plasma TG in patients with FCS as they require at least partial lipoprotein lipase activity. They are, however, effective at lowering plasma TG levels in patients with multifactorial chylomicronemia syndrome.

• Results of ongoing phase 3 trials of apo C-III inhibitors will inform further clinical development and potential FDA approval of these drugs for FCS and severe HTG. The FDA has granted Fast Track designation to both olezarsen and plozasiran, which will facilitate development and expedite their review and potential approval for the treatment of FCS and severe HTG.

Declaration of interest

RA Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G. Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-21-0031455) and the Academic Medical Association of Southwestern Ontario (INN21–011). RA Hegele reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, Boston Heart, HLS Therapeutics, Pfizer, Medison, Novartis, Regeneron, Sanofi and Ultragenyx.

Reviewer disclosures

A reviewer on this paper is a founder and shareholder of the Swedish company Lipigon Pharmaceuticals dealing with drug development against hypertriglyceridemia.

Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was supported by the Academic Medical Organization of Southwestern Ontario [INN21-011], Government of Canada, Canadian Institutes of Health Research Foundation Award, and the Heart and Stroke Foundation of Canada [G-21-0031455].