Ionis Reports Positive Results from Phase 3 Balance Study of Olezarsen for FCS

Rare Daily Staff

Ionis Pharmaceuticals reported full results from its phase 3 Balance study of its lead independent experimental medicine, olezarsen, for the treatment of adults with familial chylomicronemia syndrome.

The olezarsen 80 mg monthly dose met the primary endpoint of significantly reducing triglycerides in patients with genetically validated familial chylomicronemia syndrome (FCS) at six months. In addition, olezarsen demonstrated robust and sustained reductions in TGs and serum apolipoprotein C-III levels and reduced the incidence of acute pancreatitis events over the 12-month treatment period compared to placebo. Olezarsen also demonstrated a favorable safety and tolerability profile.

The results were presented in an oral presentation at the 2024 American College of Cardiology Annual Meeting in Atlanta, Georgia and published simultaneously in The New England Journal of Medicine. Based on these data, Ionis is pursuing regulatory approval of olezarsen as a potential breakthrough treatment for adults with FCS.

FCS is a rare, genetic disease characterized by extremely elevated triglyceride levels. It is caused by impaired function of the enzyme lipoprotein lipase (LPL). Because of limited LPL production or function, people with FCS cannot effectively break down chylomicrons, lipoprotein particles that are 90 percent triglycerides. FCS is estimated to impact one to 13 people per million in the U.S. People living with FCS are at high risk of acute pancreatitis in addition to other chronic health issues such as fatigue and severe, recurrent abdominal pain, often leaving them unable to work and adding to the burden of disease.

Currently, there are no U.S. FDA-approved therapies for the treatment of FCS and standard triglyceride lowering therapies are generally ineffective in patients with FCS. People living with this condition currently rely solely on nutrition management through extremely restrictive and difficult to manage diets to navigate the health risks associated with FCS.

Olezarsen is an RNA-targeted experimental lIgand conjugated antisense medicine being evaluated for people at risk of disease due to elevated triglyceride levels that is designed to inhibit the body’s production of serum apolipoprotein C-III, a protein produced in the liver that regulates triglyceride metabolism in the blood. The U.S. Food and Drug Administration granted olezarsen Orphan Drug, Fast Track, and Breakthrough Therapy designations for the treatment of FCS. In addition to FCS, Ionis is evaluating olezarsen for the treatment of severe hypertriglyceridemia in phase 3 clinical trials.

Balance is a global, multicenter, randomized, double-blind, placebo-controlled phase 3 study that enrolled 66 patients aged 18 and older with confirmed FCS. Patients in the study received background therapies including statins, fibrates, and omega-3 fatty acids. Patients were randomized in a 1:1:1 ratio to receive olezarsen 80 mg or 50 mg or placebo via subcutaneous injection once every four weeks for 53 weeks. The primary endpoint was the percent change from baseline in fasting triglyceride levels at six months compared to placebo. Secondary endpoints included percent changes in triglyceride levels at 12 months, percent changes in other lipid parameters, and adjudicated acute pancreatitis event rates over the treatment period.

In the 80 mg group, olezarsen met the primary endpoint, with a statistically significant placebo-adjusted reduction in triglyceride levels from baseline to six months that were sustained through 12 months, achieving a 59 percent reduction in triglycerides. Apolipoprotein C-III placebo-adjusted reductions were also robust and sustained at six (74 percent) and 12 months (81percent) reductions.

In the 50 mg group, olezarsen reduced triglyceride levels, however this difference was not statistically significant at six months compared to placebo. Reductions from six to 12 months were improved, with olezarsen 50 mg achieving a placebo-adjusted 44 percent reduction in triglyceridess. Olezarsen-treated patients also had markedly fewer acute pancreatic events during the 12-month period, compared to placebo.

“Balance is the first clinical study to validate the association of reduced triglyceride levels with reduced incidence of acute pancreatitis events in patients with severely elevated triglycerides,” said Brett Monia, CEO of Ionis. “This important finding supports the potential for olezarsen to be the standard of care for patients with FCS, if approved.”

Based on the study results, Ionis plans to working closely with the FDA to advance the first potential treatment for FCS in the United States, and a first independent commercial launch later this year, assuming priority review.

Photo: Brett Monia, CEO of Ionis