Rare Disease Report

Antisense Drug Effective in Lowering Triglyceride Levels in Familial Chylomicronemia Syndrome

DECEMBER 04, 2014
James Radke

This week in the New England Journal of Medicine, Gaudet and colleagues report on the results of Phase 2 study examining the effects of  ISIS-APOCIIIRx in patients with familial chylomicronemia syndrome (FCS) - an ultra-rare genetic condition in which patients have extremely high triglyceride levels and are at risk for developing pancreatitis. 

The extremely small (n=3) open-label study showed that all patients with FCS given ISIS-APOCIIIRx (300 mg) over a 13 week period were able to lower their triglyceride levels from a range of 1,406 mg/dL to 2,083 mg/dL to below 500 mg/dL.

FCS is a very rare hereditary condition in which individuals lack properly functioning lipoprotein lipase (LPL), an enzyme that clears triglycerides from plasma. The disruption of the enzyme activity leads to very high concentrations of triglycerides, and particularly chylomicrons, in the plasma (chylomicronemia). Chylomicrons are lipoproteins that transport triglycerides from the gastrointestinal tract to other parts of the body. FCS affects approximately 1-2 out of a million people. 

Current treatment options (ie, low fat diet) do not properly reduce triglycerides and patients with FCS are at increased risk of recurrent and potentially fatal pancreatitis and other complications. 
ISIS-APOCIIIRx is an antisense drug designed to reduce apoC-III, which is known to regulate the LPL-dependent pathway. 

Daniel Gaudet, MD, PhD, from the department of medicine, Universite de Montreal  and scientific director of the Genome Quebec Biobank Technology Center said of the study:

"Because of their genetic defect, patients with FCS have very limited therapeutic options and diet and lifestyle changes are not sufficient to significantly reduce their triglycerides. These data published today, although collected from a small number of patients, are compelling and demonstrate the potential of ISIS-APOCIIIRx to produce substantial triglyceride lowering in patients with FCS.  They also suggest that apoC-III plays a critical role in fat management through a non-LPL dependent pathway, which would be a shift of paradigm."

Dr. Sotirios Tsimikas, M.D., professor of medicine and director of vascular medicine at the University of California, San Diego and vice president of clinical development and leader of the cardiovascular franchise at Isis said:

"The data published today provides support for a novel mechanism by which reducing apoC-III promotes triglyceride clearance in patients with FCS and gives us a great deal of optimism as we enter Phase 3 development of ISIS-APOCIIIRx.  In our Phase 2 studies, we showed that ISIS-APOCIIIRx lowered triglycerides equally well in patients with high to severely high triglycerides.  We also observed dramatic reductions in apoC-III and other lipid parameters and we observed an increase in HDL-cholesterol."

"We believe that there is a significant unmet medical need for an effective triglyceride-lowering drug for patients with FCS.  As such, we are encouraged with the robust results we have observed with ISIS-APOCIIIRx in FCS patients to date.  We have initiated our registration-directed Phase 3 study of ISIS-APOCIIIRx in patients with FCS and plan to initiate a second Phase 3 study in patients with severely high triglycerides early next year."

For more information about FCS, visit http://fcs.raredr.com/ 


Gaudet D, Brisson D, Tremblay K, et al. Targeting ApoC-III in the Familial Chylomicronemia Syndrome. N Engl J Med 2014:371:23:2200-2206. DOI: 10.1056/NEJMoa1400284

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