Chapter 1: The validated technology behind TRYNGOLZA® (olezarsen) 

Familial chylomicronemia syndrome, or FCS, is an underdiagnosed form of severe hypertriglyceridemia.

Historically, treating patients with FCS was a challenge due to a lack of effective pharmacologic interventions.

TRYNGOLZA is the first FDA-approved therapy for adults with FCS, indicated as an adjunct to diet to reduce triglycerides.

Today, we will explore the underlying causes of FCS and the unique and targeted mechanism of action of TRYNGOLZA.

 

Chapter 2: Familial chylomicronemia syndrome (FCS): from pathology to presentation

Our understanding of the pathology of FCS begins with triglyceride-rich lipoprotein, or TRL, metabolism.

FCS manifests as hypertriglyceridemia from the impaired metabolism of TRLs, such as chylomicrons and very low-density lipoproteins, or VLDL.

Normally, TRLs are hydrolyzed by lipoprotein lipase, or LPL, which breaks down dietary and endogenous triglycerides.

In FCS, loss-of-function mutations in the LPL gene or its cofactor genes lead to reduced or absent LPL activity. This impairs fat processing, resulting in plasma triglyceride levels persistently 10 to 100 times above normal.

Apolipoprotein C-III, or apoC-III, regulates TRL metabolism by inhibiting LPL and one or more LPL-independent pathways such as hepatic clearance.

The triglyceride buildup raises the risk of acute pancreatitis, pancreatic necrosis, organ failure, and type 3c diabetes, making effective and substantial triglyceride lowering imperative.

 

Chapter 3: TRYNGOLZA: a highly targeted therapy

TRYNGOLZA is a GaINAc-conjugated antisense oligonucleotide, or ASO, that inhibits the production of apoC-III, a key regulator of TRL metabolism and hepatic clearance.

The conjugation of GalNAc to the ASO enables targeted delivery to the liver, where apoC-III messenger RNA, or mRNA, is generated.

GalNAc binds to the asialoglycoprotein receptor and allows TRYNGOLZA to enter the hepatocyte.

In the hepatocyte, TRYNGOLZA directly and selectively binds to apoC-III mRNA and induces RNase cleavage of apoC-III mRNA, leading to its degradation.

This can result in a decrease in serum apoC-III protein levels and lower plasma triglyceride levels, which are known to impact the risk of acute pancreatitis.

Building on validated GalNAc-conjugated ASO technology, the targeted design of TRYNGOLZA represents a designated breakthrough therapy for adults with FCS as an adjunct to diet, finally giving patients and physicians a targeted and potentially effective solution for this critical and often underrecognized condition.