ACC: Ionis' rare metabolic disorder drug slides from 100% efficacy, but FDA ambitions unchanged

Ionis Pharmaceuticals previously touted that olezarsen was 100% effective in a rare metabolic disorder after a phase 3 readout. Now, the full data set is slightly denting that statistic while leaving plenty of room for a planned regulatory filing later this year.

Olezarsen is being tested in adults with familial chylomicronemia syndrome (FCS). An early late-stage readout in September 2023 linked a high 80-mg dose of the investigational ligand-conjugated antisense medicine to a significant reduction in triglyceride levels and a 100% drop in acute pancreatitis (AP) events compared to 11 for placebo but didn’t provide a deeper look at the data. AP events are a serious complication of FCS in which the pancreas suddenly becomes inflamed.

Now, Ionis has shared the full data set at an April 7 presentation at the 2024 American College of Cardiology (ACC) annual meeting in Atlanta. The secondary endpoint findings are telling a slightly different story.

There was one AP episode in the 80-mg olezarsen group, one in the 50-mg group and 11 episodes in the placebo group.

"In the course of fully analyzing the data, we identified an additional acute pancreatitis event, which is now in the full data report," an Ionis spokesperson told Fierce Biotech in an emailed statement.

Olezarsen-treated patients still had fewer AP events over a year compared to placebo, a reduction Ionis called “clinically meaningful” in the April 7 release. The data also revealed a substantially greater time to the first AP event with olezarsen (one year for the 80-mg arm and 102 days for the 50-mg group) compared to nine days for placebo. 

As previously announced, olezarsen met the trial’s primary endpoint with a statistically significant reduction of fasting triglycerides at six months for recipients of the higher 80-mg dose compared to placebo.

The full data set reveals that the 22 patients in the high-dose olezarsen group experienced a 44% placebo-adjusted reduction in triglyceride levels from baseline at six months. At 12 months, patients receiving olezarsen 80 mg achieved a 59% placebo-adjusted reduction in triglycerides, according to Ionis. 

The lower 50-mg dose was statistically no better than placebo at reducing triglycerides.

The exact reduction in triglyceride levels matter as Ionis gears up for market. The company faces competition in the form of Arrowhead Pharmaceuticals’ plozasiran, a phase 3 siRNA also being studied in FCS. That phase 3 program is expected to read out this month, with Arrowhead slated to share updates during a late-breaking session at ACC.

A further look at Ionis’ olezarsen finds no serious treatment-emergent adverse events (TEAEs) reported among 66 patients receiving the therapy. More TEAEs were reported for participants in the placebo group than in the olezarsen arms.

The most common adverse events were COVID-19, abdominal pain and diarrhea, none of which were more frequent in patients treated with olezarsen compared to placebo, according to Ionis.  

Of the 22 patients in the olezarsen high-dose group, serious adverse events occurred among 14% of participants, compared to 19% of the 21 patients in the low-dose olezarsen arm and 39% of the 23 patients receiving placebo.  

Based on the data, Ionis plans to submit for regulatory approval in FCS this year. To date, olezarsen has snagged FDA fast-track, orphan-drug and breakthrough-therapy tags in the disease. Currently, there aren’t any FDA-approved medicines designed to treat the genetic disease.

“Our team looks forward to working closely with the FDA to advance the first potential treatment for FCS in the U.S., and to successfully delivering Ionis’ first independent commercial launch later this year, assuming priority review,” Ionis CEO Brett Monia, Ph.D., said in an April 7 release.

Ionis is also testing olezarsen as a treatment for severe hypertriglyceridemia in phase 3 clinical trials.