Olezarsen reduces triglycerides, cutting pancreatitis risk by 85%

Olezarsen reduces triglycerides, cutting pancreatitis risk by 85%

Key takeaways:

• Monthly olezarsen is the first treatment to significantly reduce acute pancreatitis events along with triglyceride levels.
• The drug manufacturer plans to seek a new FDA indication.

NEW ORLEANS — Monthly olezarsen reduced triglycerides by 65% for people with severe hypertriglyceridemia, resulting in a greater than 85% reduction in acute pancreatitis, data show.

Findings from the pivotal CORETIMI 72a and CORE2TIMI 72b phase 3 trials were presented at the American Heart Association Scientific Sessions and simultaneously published in The New England Journal of Medicine. Healio reported the topline data in September.

“Severe hypertriglyceridemia is not terribly uncommon — it affects about one in a hundred patients,” Nicholas A. Marston, MD, MPH, assistant professor of medicine at Harvard Medical School and member of the TIMI Study Group and cardiologist at Brigham and Women’s Hospital, told Healio. “The higher the triglyceride levels, the more there is a risk for acute pancreatitis. This can affect quality of life and health, and lead to hospitalizations and even critical illness and death. The current therapies — fibrates, omega-3 fatty acids, statins if indicated —do not do a great job. They are more modest in their treatment effect. We are left with a lot of patients with severe hypertriglyceridemia despite being on these therapies, and no trials have shown a reduced risk for acute pancreatitis.”

A ’doubling of what is available clinically’

For the two trials, researchers analyzed data from 1,061 adults with severe hypertriglyceridemia on background lipid-lowering therapies assigned olezarsen (Tryngolza, Ionis) 50 mg, olezarsen 80 mg or placebo monthly for 12 months. The primary outcome was the percent change from baseline in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group. Secondary outcomes included the percent change from baseline in triglyceride levels at 12 months and in the levels of apolipoprotein C-III, remnant cholesterol,

and non-HDL cholesterol at 6 and 12 months. Researchers assessed acute pancreatitis events during both trials.

In CORETIMI 72a, at 6 months, compared with placebo, patients assigned olezarsen 80 mg had a reduction of 72.2 percentage points in fasting triglycerides and those assigned olezarsen 50 mg had a reduction of 62.9 percentage points (P for both < .001).

In CORE2, at 6 months, compared with placebo, patients assigned olezarsen 80 mg had a reduction of 54.5 percentage points in fasting triglycerides and those assigned olezarsen 50 mg had a reduction of 49.2 percentage points (P for both < .001).

“When we are talking about a 65% reduction [in triglycerides] with olezarsen, that is more than a doubling of what is available clinically,” Marston told Healio.

Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol and non-

HDL cholesterol were similarly greater with olezarsen than with placebo (P for all < .001).

The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio = 0.15; 95% CI, 0.05-0.4; P < .001; number needed to treat to prevent one event at 1 year = 20).

Assessing safety

Adverse events were similar across trial groups, Marston said.

“The 80 mg groups experienced an increase in liver function tests greater than three times the upper limit of normal, but the 50 mg groups did not,” Marston said during an interview. “Neither dose had liver function tests greater than five times the upper limit of normal or any cases of Hy’s law, which can be dangerous. There was a small increase in HbA1c, about a quarter percentage point, seen in patients with preexisting diabetes. We have seen these things with other apoC-III inhibitors and statins.”

The researchers also conducted an MRI substudy to measure hepatic fat fraction, noting an absolute increase of 2% and 4% with the two doses, Marston said.

“But this was not associated with transaminases or with the FIB4 index, which is a measure of a score for fibrosis,” Marston told Healio. “As of right now, it is an imaging finding without clear clinical significance. We are continuing to follow the MRIs in an open-label extension to learn more. “

In a press release, Ionis said the company plans to submit a supplemental new drug application for both the 50- and 80-mg doses to the FDA by the end of the year.