AHA25: Ionis's Tryngolza lowers triglyceride levels below high-risk threshold in sHTG

In pursuit of a label expansion for Tryngolza (olezarsen), Ionis Pharmaceuticals provided additional colour on the recent late-stage success of its antisense oligonucleotide (ASO) in patients with severe hypertriglyceridaemia (sHTG) at the American Heart Association (AHA) scientific sessions on Saturday. 

The drugmaker had claimed wins for Tryngolza in the two Phase III CORE studies in September, laying plans to file for FDA approval in sHTG by year-end.

If given the green light, Ionis would significantly expand the drug's reach beyond its initial approval last year in familial chylomicronaemia syndrome (FCS), a rare subtype of sHTG with about 3000 US patients; the broader sHTG indication affects some 3 million people in the country. Prior to the top-line CORE readouts, Ionis had predicted Tryngolza would bring in up to $80 million in 2025 sales, but now, given the positive sHTG data, analysts are modelling more than $1 billion in peak revenue for the drug (see – Vital Signs: Ionis' second chance at its first product launch).

Half of high-dose patients reach normal triglyceride levels 

The CORE and CORE2 studies together enrolled a total of 1063 participants with sHTG who were required to remain on standard lipid-lowering therapy throughout the trial period.

Ionis previously reported that at the six-month mark, an 80-mg monthly dose of the apoC-III-targeting ASO lowered fasting triglyceride levels by 72% in the CORE study and 55% in the CORE2 study compared to placebo, a statistically significant result that met the trials' primary endpoint. At AHA, the drugmaker further revealed that reductions were sustained through 12 months.

In patients with baseline fasting triglyceride levels above 880 mg/dL — which is associated with the highest risk of acute pancreatitis — 89% and 88% of patients receiving 50-mg and 80-mg doses of Tryngolza, respectively, saw their triglyceride levels fall below that threshold. Of those with starting levels above 500 mg/dL, the risk threshold for sHTG and acute pancreatitis, both the high and low doses of Tryngolza reduced triglyceride levels below that point in 86% of patients. 

Furthermore, 34% and 54% of patients receiving 50-mg and 80-mg doses, respectively, achieved normal triglyceride levels below the 150 mg/dL threshold. 

Pooled data across both studies showed that Tryngolza led to a highly statistically significant 85% reduction in adjudicated acute pancreatitis events at 12 months, scoring a win on a key secondary endpoint.

"CORE and CORE2 are the first studies to show a significant reduction in acute pancreatitis events in sHTG, with most patients on olezarsen achieving triglyceride levels below the risk threshold for these potentially life-threatening episodes,” said Nicholas Marston, the presenting author at AHA and a cardiologist at Brigham and Women's Hospital, Harvard Medical School. "Given the modest effects of conventional therapies, these impactful data are a welcome advance and underscore the potential of olezarsen to transform the way we treat sHTG." 

The ASO also led to significant reductions in apoC-III levels, remnant cholesterol and non-HDL-C.

On the safety front, Tryngolza had a favourable tolerability profile, with a lower rate of serious adverse events in each treatment arm compared to placebo (50 mg = 9%; 80 mg = 11%; placebo = 14%). The most common treatment-emergent events were injection site reactions, affecting 10% of patients in the low-dose group, 17% of those in the high-dose arm, and 1% of placebo recipients.

https://firstwordpharma.com/story/6518940