Icosabutate Shows Promise in Lowering Triglycerides in Humans

Marlene Busko

June 01, 2015

AMSTERDAM, THE NETHERLANDS — The first-in-class, structurally enhanced omega-3 fatty acid icosabutate (Pronova BioPharma) safely lowered triglyceride levels in individuals with hypertriglyceridemia, a small proof-of-concept study has shown[1].

In this 12-week study, 89% of patients randomized to icosabutate were able to achieve a target triglyceride level of less than 500 mg/dL, starting from a median baseline level of 650 mg/dL, Dr Harold Bays (Louisville Metabolic and Atherosclerosis Research Center, KY) reported here at the International Symposium on Atherosclerosis 2015.

Moreover, the 600-mg dose of icosabutate was 15% of the typical 4-g/day dose of natural omega-3 fatty acids, Bays noted.

Patients who received icosabutate also had significantly lower levels of very low-density lipoprotein (VLDL) cholesterol, remnant lipoprotein (RLP) cholesterol, apolipoprotein C3 (apoC3), and non-HDL cholesterol and significantly higher levels of HDL cholesterol and LDL cholesterol compared with patients who received placebo.

Cochair Dr John Chapman (INSERM, Paris, France) wanted to know whether there was a shift away from small dense atherogenic particles toward larger, more buoyant particles in the patients who received icosabutate. Bays agreed that this was a likely mechanism.

More Potent Form of Omega-3 Fatty Acid

In rodent models of dyslipidemia and in a small phase Ib human study, icosabutate, a derivative of eicosapentaenoic acid, lowered triglyceride and apoC3 levels, Bays said.

This phase 2a trial aimed to evaluate the triglyceride-lowering efficacy of icosabutate in a slightly larger study and to assess the drug's safety and effect on other lipids and markers of inflammation and glucose metabolism.

The researchers randomized 87 patients to receive 600-mg icosabutate once daily (n=43) or placebo (n=44) for 12 weeks.

The men and women were 18 to 79 years old and had severely elevated triglyceride levels (500 mg/dL to 1500 mg/dL) with or without statin therapy. Most participants were white, male, overweight or obese, and in their 50s, Bays said.

Their baseline median lipid values were: triglycerides 650 mg/dL, VLDL cholesterol 113 mg/dL, RLP-cholesterol 44 mg/dL, LDL cholesterol 87 mg/dL, non-HDL cholesterol 217 mg/dL, HDL cholesterol 32 mg/dL, and apoC3 29 mg/dL.

At week 12, median triglyceride levels were reduced by 51.4% in the icosabutate group and by 17.1% in the placebo group — for a 32.8% greater reduction in the treatment group.

In addition, compared with patients who received placebo, those in the icosabutate group had 35.7% lower levels of VLDL-cholesterol, 33.5% lower levels of RLP-cholesterol, 34.8% lower levels of apoC3, and 7.1% lower levels of non-HDL cholesterol. However, they also had 18.3% higher levels of HDL cholesterol and 28.4% higher levels of LDL cholesterol.

Patients in the icosabutate-treated group also had a greater reduction in lipoprotein-associated phospholipase A2 (Lp-PLA2). There was no significant change in apolipoprotein B or C-reactive protein.

Interestingly, HbA1C levels did not change much and fasting plasma glucose levels did not decrease, but homeostasis model assessment-estimated insulin resistance (HOMA-IR) did decrease, Bays observed. "In many of the clinical trials that were done with omega-3 fatty acids, there's often a trend to increased glucose levels that tend to level off over time . . . but in this pilot study, there appeared to be some improvement in glucose metabolism," he said.

The rate of treatment-emergent adverse events was similar in the two patient groups: 28 patients (65%) in the icosabutate group vs 32 patients (74%) in the placebo group. Although prescribing information for prescription omega-3 fatty acids warns about a possible elevation of liver enzymes, liver-enzyme levels decreased in the current study, Bays noted. No serious adverse events were reported, and one patient in the icosabutate group discontinued treatment due to a jittery feeling.

"Icosabutate is therefore a potent triglyceride-lowering drug designed for a convenient once-a-day oral administration" that showed clinically relevant reductions in triglycerides in this preliminary study, Bays concluded.

The study was sponsored by Pronova BioPharma. Bays has served as a clinical investigator for and has received research grants from Pronova BioPharma and many other pharmaceutical companies.

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