Isis Pharmaceuticals has initiated a phase 3 study evaluating ISIS-APOCIIIRx in patients with familial chylomicronemia syndrome (FCS).  FCS is a rare orphan disease, characterised by extremely high triglyceride levels, that affects an estimated 3,000 to 5,000 patients worldwide. The phase 3 study of ISIS-APOCIIIRx is a randomised, double-blind, placebo-controlled, six month study in approximately 50 patients diagnosed with FCS.  The study will evaluate the efficacy and safety of a 300 mg once weekly dose of ISIS-APOCIIIRx. The primary endpoint of the study is percent change in fasting triglycerides from baseline after three months of dosing.

"FCS is a rare and very serious genetic disorder that is often associated with triglyceride levels higher than 2,000 mg/dL.  Because of their extremely high triglyceride levels, FCS patients are at significant risk of many serious health conditions, including frequent episodes of pancreatitis, which can require hospitalisation and can be life-threatening.  Current treatment options do not reduce triglyceride levels enough to reduce the risk of serious illness in patients with FCS," said 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.  "ISIS-APOCIIIRx provides a unique therapeutic approach in that it is designed to reduce triglyceride levels by reducing apoC-III, an important regulator of triglyceride clearance. The phase 2 data strongly support advancing ISIS-APOCIIIRx into phase 3 studies in patients with severely elevated triglycerides like FCS."

In a Phase 2 study, FCS patients treated with ISIS-APOCIIIRx experienced decreases in triglycerides of up to more than 1,500 mg/dL.  Isis has also evaluated ISIS-APOCIIIRx in a broad phase 2 programme.  In these studies in patients with very high to extremely high triglyceride levels, patients treated with ISIS-APOCIIIRx achieved substantial lowering of triglycerides (mean percent reductions of up to 71 per cent ) and apoC-III (mean percent reductions of up to 88 per cent ) and increasing of HDL-cholesterol (mean percent increases of up to 78 per cent ).

"Our focus is to bring ISIS-APOCIIIRx to the market for patients with severely elevated triglycerides.  These patients are at significant health risk because they cannot reduce their triglycerides to safe levels with currently available medicines.  We are pleased with the data from our phase 2 programme in which substantial triglyceride lowering was achieved when ISIS-APOCIIIRx was dosed as a single agent or in combination with fibrates in patients with a wide range of incoming triglycerides, including FCS patients," said Richard Geary, Ph.D., senior vice president of development at Isis. "Our broad experience developing drugs to treat lipid disorders, including the good working relationships we have established with the physicians and centers that treat many FCS patients should support the rapid advancement of this programme.  We currently plan to advance ISIS-APOCIIIRx without seeking a partner."

ISIS-APOCIIIRx is designed to target apoC-III, a protein produced in the liver that plays a central role in the regulation of serum triglycerides.  ApoC-III is a genetically validated target for lowering triglycerides.  Independent studies have demonstrated a link between lower apoC-III activity, which results in lower triglyceride levels, and reduced cardiovascular disease.  

In addition to developing ISIS-APOCIIIRx for patients with FCS, Isis is also developing ISIS-APOCIIIRx for patients with severely elevated triglycerides, greater than 880 mg/dL, a condition that affects an estimated 50,000 patients in the United States and Europe.  These patients not only have a high risk of pancreatitis but also have a high risk of type 2 diabetes and cardiovascular disease. Currently available therapies do not reduce triglycerides sufficiently in many of these patients to reduce these health risks.   Isis plans to initiate the phase 3 programme in patients with severely elevated triglycerides in 2014.