Ionis Achieves Remarkable Phase III Victory in Rare Genetic Disease and Sets Sights on NDA Submission

In a momentous achievement, Ionis Pharmaceuticals has unveiled compelling topline data from the Phase III Balance study, demonstrating the remarkable efficacy of olezarsen, their antisense candidate. The study revealed that olezarsen met its primary endpoint by significantly reducing triglyceride levels in patients grappling with familial chylomicronemia syndrome (FCS).

Bolstered by these exceptional results, Ionis is gearing up to submit a New Drug Application (NDA) to the FDA early next year, in addition to regulatory filings within the European Union. It’s worth noting that olezarsen had previously secured the FDA’s coveted Fast Track designation for FCS, promising an expedited review period for its application.

Brett Monia, Ionis’ CEO, expressed great optimism, stating, “We believe olezarsen has the potential to become the new standard of care for patients with FCS.” If granted approval, olezarsen would not only mark the first FDA-authorized treatment for FCS in the United States but also represent Ionis’ maiden wholly-owned asset to reach the market.

Delving into the Balance study, patients administered an 80-mg dose of olezarsen experienced a significant reduction in triglyceride levels compared to those on a placebo. This noteworthy effect was observed at the six-month mark and continued to improve over the course of 12 months. Perhaps even more remarkable, olezarsen treatment achieved a staggering 100% reduction in acute pancreatitis events, a pivotal secondary endpoint in the study.

Ionis is set to unveil comprehensive data and analysis from the Balance study at an upcoming medical conference.

The Balance study, marked by its rigorous design as a randomized, double-blinded, and placebo-controlled trial, enrolled 66 FCS patients. Notably, these patients were concurrently receiving background therapies such as statins, fibrates, and omega-3 fatty acids.

In addition to the 80-mg subcutaneous dose, olezarsen was administered at a 50-mg injection level. While the lower dose also exhibited reductions in triglyceride levels and acute pancreatitis events, these outcomes narrowly missed statistical significance.

Safety findings from the Balance study paint olezarsen as a well-tolerated and safe option, with the majority of side effects classified as mild or moderate in severity. Importantly, there were no instances of hepatic or renal toxicity, and injections did not trigger substantial reductions in platelet counts.

It is worth mentioning that there was one unfortunate patient death; however, it was determined to be unrelated to the study drug.

Notably, Ionis recorded significant impacts on biomarkers. At the 80-mg dose level, olezarsen achieved a remarkable reduction of at least 75% in Apolipoprotein C-III, a pivotal protein involved in regulating triglyceride metabolism in the bloodstream.

ApoC-III is known to target and inhibit the lipoprotein lipase (LPL) enzyme, whose activity is compromised in FCS, resulting in the pathological inability to break down chylomicrons.

Chylomicrons, composed of 90% triglycerides, are lipoprotein particles. When LPL function is impaired, chylomicrons accumulate in the blood, leading to elevated triglyceride levels—a hallmark of FCS. This condition manifests in symptoms such as milky blood, abdominal pain, and acute pancreatitis.

Presently, there are no FDA-approved treatments for FCS, leaving patients to rely on highly restrictive diets to mitigate the health risks associated with this debilitating disease.

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