Ionis' lipid-lowering drug hits phase 3 goal, raising hopes in untapped rare disease market

Ionis Pharmaceuticals' phase 3 lipid-lowering clinical trial has hit its primary endpoint, positioning it to file for an approval that would set up the company's first independent commercial launch. The study linked the high dose to a significant reduction in triglyceride levels and a 100% drop in acute pancreatitis events compared to placebo.

California-based Ionis designed the trial to assess the effect of its ligand-conjugated antisense medicine olezarsen in familial chylomicronemia syndrome (FCS) patients. The biotech previously filed for approval of another treatment for the rare condition, volanesorsen, but was rejected by the FDA in 2019. Now, Ionis thinks it has the data to get olezarsen over the line in the indication in the U.S. 

The data come from a phase 3 trial that randomized 66 adults to receive placebo or one of two monthly subcutaneous doses of olezarsen. After six months, Ionis saw a statistically significant drop in triglyceride levels in recipients of the higher 80-mg dose, causing the study to hit its primary endpoint with a p-value of 0.0009. The lower 50-mg dose was statistically no better than placebo at reducing triglycerides.

Ionis CEO Brett Monia, Ph.D., had previously identified the primary endpoint result as critical to the commercial fate of olezarsen in FCS, telling investors on a conference call last month that “what will really drive this market is substantial [triglyceride] lowering in this patient population.” 

On the same call, Eugene Schneider, M.D., chief clinical development officer at Ionis, named analyses of the “proportions of patients that get below particular clinically meaningful thresholds” as another measure of success. The goal was to achieve “reductions that are thought to be meaningful in terms of their risk for having acute pancreatitis events,” Schneider said. 

Ionis is yet to share a close look at the data but did reveal that no patient on the 80-mg dose suffered an acute pancreatitis event, a serious complication of FCS that can cause permanent damage and require urgent treatment in hospital. There were 11 events in the placebo group. Ionis also linked the 50-mg dose to a “substantial” reduction in pancreatitis.

The 80-mg dose reduced apoC-III, the target protein, by more than 75% and had “a favorable safety and tolerability profile,” according to Ionis. The biotech is yet to share safety and tolerability data, only saying that most adverse events in patients on olezarsen were mild and that there were no hepatic or renal toxicity events nor clinically meaningful platelet reductions. One death was ruled unrelated to the drug. 

Armed with the data, Ionis plans to file for FDA approval early next year, putting the fast-track program on course to deliver the first treatment for FCS in the U.S. Ionis is also running phase 3 trials in severe hypertriglyceridemia, a much larger patient population that underpins the biotech’s belief that olezarsen can generate blockbuster sales.