Safety and dosing are likely to be “key differentiators” for Arrowhead Pharmaceuticals as it looks to challenge Ionis Pharmaceuticals’ lead in the severe hypertriglyceridemia market.
Arrowhead Pharmaceuticals’ touted placebo-like safety for its RNA interference therapy plozasiran in two late-stage studies of severe hypertriglyceridemia—but analysts are left conflicted over the assets competitive prospects.,
Detailed late-stage results “are favorable and arguably support a best-in-class profile” for plozasiran, Stifel wrote in a Sunday note. Plozasiran is currently approved as Redemplo for familial chylomicronemia syndrome, a rare genetic disease that causes high triglyceride levels.
Meanwhile, BMO Capital Markets on Monday favored the currently commercially available choice, Ionis Pharmaceuticals’ antisense oligonucleotide Tryngolza.
In the Phase 3 SHASTA-3 and SHASTA-4 trials, total treatment-emergent adverse events (TEAE) were similar between plozasiran and placebo arms, but serious TEAEs only occurred in 8.3% of patients on plozasiran versus 10% on placebo comparators.
The detailed safety data were presented Sunday at the European Society of Cardiology’s 2026 meeting in Munich, and could support a supplemental FDA submission to expand Redemplo into severe hypertriglyceridemia, a filing that Arrowhead said is planned for later this year.
Stifel zeroed in on safety and dosing, which it argued “are really the key differentiators here” versus Tryngolza, which snagged approval for severe hypertriglyceridemia in December 2024. Arrowhead’s plozasiran is meant to be dosed once every three months, while Tryngolza is a monthly injection.
In particular, the firm pointed to the absence of anaphylaxis or hypersensitivity reactions with plozasiran as compared with an approximate 7% rate of “possible” hypersensitivity events for Tryngolza. There were also no meaningful liver enzyme elevations with plozasiran—a safety event that according to Stifel was documented in around 7% of patients on Tryngolza.
Of note, however, Arrowhead reported three deaths in plozasiran-treated patients—two cardiovascular deaths and one linked to chronic myelomonocytic leukemia—though none were deemed related to the study drug.
BMO, on the other hand, focused on the worsening glycemic control observed in 14.3% of patients on plozasiran, as per Arrowhead’s Sunday announcement—a signal that could potentially affect “positioning among patients with comorbid diabetes.” Ionis’ drug has the edge here, the analysts continued, which in turn “may provide a modest competitive advantage” for Tryngolza.
On the efficacy front, Sunday’s readouts for SHASTA-3 and SHASTA-4 were “consistent” with topline data shared last month, showing median triglyceride reductions of 79% and 81%, respectively, after a year. In both cases, the therapeutic effect was statistically significant. Around 750 patients were enrolled across SHASTA-3 and SHASTA-4.
Plozasiran’s triglyceride-lowering effect was stronger in those with baseline levels at least 880 mg/dL. In this subgroup, median triglyceride reduction hit 85%. SHASTA-3 and SHASTA-4 also found that 52% and 55% of patients on plozasiran reached triglyceride levels below 150 mg/dL at 12 months, respectively, versus 7.9% and 2% of placebo comparators.
Pre-specified analyses also found that across both late-stage studies, plozasiran reduced acute pancreatitis (AP) events by 78% versus placebo, an effect that appeared stronger in those with higher baseline triglyceride levels and who had any prior AP history.
In all, Stifel believes that the SHASTA data “support a differentiated safety profile” for plozasiran, “which, with Q3M dosing, should position ARWR/plozasiran to be best-in-class.”
There are no head-to-head studies directly comparing plozasiran with Tryngolza, and Stifel concedes that the severe hypertriglyceridemia market “is big enough for multiple significant products.”
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