Rare Disease Report

Progress in Research Related to Familial Chylomicronemia Syndrome (FCS)

MARCH 27, 2017
Seth Baum, MD
Familial chylomicronemia syndrome (FCS) is a severe, rare genetic disorder characterized by extremely high levels of triglycerides and the risk of recurrent, potentially fatal pancreatitis.  People with FCS are unable to effectively clear large, triglyceride-rich lipoprotein particles called chylomicrons due to a deficiency of lipoprotein lipase, an enzyme that helps to metabolize triglycerides.  While there is no therapy approved for the treatment of FCS, results from a pivotal Phase 3 clinical trial show that treatment with the investigational antisense drug volanesorsen significantly reduced triglyceride levels. Results also show that subjects treated with volanesorsen experienced reductions in pancreatitis events and abdominal pain.
The clinical trial – known as the APPROACH trial -- was a randomized, double-blind, placebo-controlled, 52-week Phase 3 study in 66 patients with FCS, a rare disease affecting approximately 3,000 to 5,000 patients worldwide. The average incoming triglyceride level of patients in the study was 2,209 mg/dL.  Patients treated with volanesorsen experienced reductions in triglycerides and related outcomes:   

  • For the primary endpoint of the study, volanesorsen-treated patients (n=33) achieved a statistically significant (P < .0001) mean reduction in triglycerides of 77% from baseline after three months of treatment, compared to a mean increase of 18% in placebo-treated patients (n=33).  This represented a mean absolute reduction of 1,712 mg/dL in treated patients.  

  • The treatment effect observed was sustained over the 52-week treatment period

  • 50% of the treated patients who entered the study with triglycerides ≥750 mg/dL achieved triglyceride levels less than 500 mg/dL after 3 months of treatment. By comparison, none of the placebo-treated patients achieved this level (P < .003).

  • Volanesorsen-treated patients with the highest documented frequency of pancreatitis attacks suffered no attacks during the 52-week treatment period (P = .02).

  • A reduction in abdominal pain was observed in volanesorsen-treated patients compared to placebo-treated patients.
In the study, there were no treatment-related liver adverse events, including no increases in liver fat.  There were no treatment-related renal adverse events.  The most common adverse event in patients in the studies was injection site reactions, which were mostly mild. In addition, declines in platelet counts were observed in many patients. These platelet declines were not clinically significant in most patients and were generally well managed with monitoring and dose adjustment. Five patients discontinued participation in the APPROACH study due to platelet count declines.  Upon discontinuation of volanesorsen, platelet count returned to normal in these patients.
Volanesorsen is an antisense drug in development for two rare metabolic disorders: FCS and familial partial lipodystrophy (FPL).  Volanesorsen is designed to reduce the production of ApoC-III, a protein produced in the liver that plays a central role in the regulation of plasma triglycerides and may also affect other metabolic parameters.
The APPROACH results were consistent with findings from a previous Phase 3 study as well as the Phase 2 program for volanesorsen.  In the previous Phase 3 study – known as the COMPASS study – five FCS subjects treated for three months with volanesorsen experienced a 73% average decrease in triglycerides, which represented a mean absolute reduction of 1,511 mg/dL. In the Phase 2 program, which was the subject of two separate publications in the New England Journal of Medicine, three FCS subjects had an average triglyceride reduction after three months of treatment with volanesorsen of 69% or a mean absolute reduction of 1,298 mg/dL. 
Applications for review of volanesorsen by the FDA and the EU are being prepared.   

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