In this guest commentary, Andres Gelrud, MD, associate professor of medicine at University of Chicago Medicine, discusses an investigational drug, volanesorsen, that was shown to reduce triglyceride levels in patients with an increased risk for pancreatitis due to familial chylomicronemia syndrome in the phase 3 APPROACH trial.
Triglycerides are the third most common cause of pancreatitis. While most cases of pancreatitis are due to secondary causes such as poorly controlled diabetes or alcoholism, a minority are due to inherited mutations that affect triglyceride metabolism.
Familial chylomicronemia syndrome (FCS) describes a genetic disorder characterized by refractory, severely high triglycerides, which presents a risk for recurrent acute pancreatitis and potentially fatal pancreatitis. FCS is caused by a deficiency of lipoprotein lipase, an enzyme that helps to break down triglycerides. There are currently no approved treatment options available for FCS. The enzymatic efficiency also limits patients’ responsiveness to conventional lipid-lowering drugs such as niacin or fibrates. Earlier this month, phase 3 results from the APPROACH study were announced regarding an investigational drug that indicates the potential to address this unmet medical need.
The phase 3 clinical trial of 66 patients with FCS showed that the investigational antisense drug volanesorsen (Ionis Pharmaceuticals) reduced triglyceride levels in these patients. The study also found that patients who took volanesorsen experienced reductions in pancreatitis events and abdominal pain.
In this double blind, placebo-controlled study, patients achieved a statistically significant mean reduction in triglycerides of 77% from baseline after 3 months of treatment, compared with a mean increase of 18% in placebo-treated patients (P < .0001). The treatment effect was sustained over the 52-week treatment period. Further, volanesorsen-treated patients with the highest documented frequency of pancreatitis attacks experienced no attacks during the 52-week treatment period (P = .02). The researchers observed a reduction in abdominal in volanesorsen-treated patients compared with placebo-treated patients.
There were no treatment-related liver adverse events, including no liver fat increases and no treatment-related renal adverse events. The most common adverse event was injection site reactions, which were mostly mild. Further, researchers observed declines in platelet counts in many patients. These platelet declines were generally well managed with monitoring and dose adjustment. Five patients discontinued participation in the study due to platelet count declines. Upon discontinuation of volanesorsen, platelet count returned to normal in these patients.
Volanesorsen is an antisense drug 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. It is currently in development for two rare metabolic disorders: FCS and familial partial lipodystrophy (FPL).
In a previous phase 3 study known as the COMPASS study, five FCS patients treated for 3 months with volanesorsen experienced a 73% average decrease in triglycerides, which represented a mean absolute reduction of 1,511 mg/dL. In a previous phase 2 study, three FCS patients treated with volanesorsen had an average triglyceride reduction after 3 months of 69%. Results from this study were published in the New England Journal of Medicine.
As gastroenterologists, familiarity with FCS is important because, while it is not common, it can be easily missed. Diagnosis is critical because it can enable provision of dietary counseling, and care coordination with lipid specialists, gastroenterologists, dieticians and primary care providers. Although correlation between elevated triglyceride levels and an increased risk for severe and potentially fatal attacks of pancreatitis has been long established, in many cases it takes several years for patients to receive an accurate diagnosis of FCS. Lack of an accurate diagnosis can present significant challenges to patients, including continued risk for pancreatitis, development of complications in the pancreas or other organs, exposure to unnecessary procedures and in appropriate disease management strategies due to wrong diagnosis.
The lack of effective therapies to treat FCS continues to leave patients at risk for morbidity and mortality, including pancreatitis. No other investigational drug has been found in clinical trials to have the magnitude of reductions in triglyceride levels observed in clinical trials with volanesorsen. The findings in volanesorsen trials for the first time hold out the potential for FCS patients to achieve reduced triglyceride levels.
Gaudet D, et al. New Engl J Med. 2015;doi:10.1056/NEJMoa1400283.
Ionis Pharmaceuticals. The APPROACH study: A study of volanesorsen (formerly ISIS-APOCIIIRx) in patients with Familial Chylomicronemia syndrome. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). Accessed: April 7, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02211209?term=volanesorsen&rank=3 NLM Identifier: NCT02211209.
Ionis Pharmaceuticals. The COMPASS Study: A Study of volanesorsen (formally ISIS-APOCIIIRx) in patients with hypertriglyceridemia. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). Accessed: April 7, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02300233?term=volanesorsen&rank=4 NLM Identifier: NCT02300233.
Disclosures: Gelrud reports he is a consultant for Akcea Therapeutics. Writing assistance provided by Berry & Company was funded by Akcea Therapeutics.