Plozasiran Notches Big Wins in Severe Hypertriglyceridemia

Treatment with plozasiran (Redemplo) significantly reduced triglycerides among patients with severe hypertriglyceridemia, two phase III studies showed.

Compared with placebo, the small interfering RNA therapy reduced triglycerides by 79% in the SHASTA-3 trial and by 81% in SHASTA-4 (P<0.0001 for both) starting at 3 months after the first injection and sustained over 12 months, according to Gerald Watts, MD, PhD, from the University of Western Australia in Perth.

At 12 months, 91-93% of plozasiran-treated patients in the trials achieved triglyceride levels below 500 mg/dL — the threshold for severe hypertriglyceridemia — as compared with 50-51% of those on placebo (P<0.001 for both). And more than 50% of patients randomized to plozasiran had levels reduced below 150 mg/dL, compared with less than 10% of the placebo recipients, he reported at the European Society of Cardiology (ESC) Congress in Munich.

“Two years ago, we presented the PALISADE trial for FCS [familial chylomicronemia syndrome], which is a disorder which is 500 times less frequent than this one. Now we’re presenting a disorder that is in day-to-day clinical practice,” said Watts. “If the clinical guidelines support this, if the regulators give it a label, this agent has a good chance really, a very good chance of being game-changing in the clinic.”

On the strength of PALISADE, plozasiran last year gained approval to reduce triglycerides in FCS — the most severe form of hypertriglyceridemia where triglycerides can stretch into the thousands.

Watts noted that regulators had asked for two trials to confirm benefit. Arrowhead, the company that makes plozasiran, said it plans to submit data from the SHASTA trials along with another study (MUIR-3) to the FDA for an approval in the broader population of patients with severe hypertriglyceridemia.

Severe hypertriglyceridemia is a heterogenous disorder driven by polygenic factors and secondary causes including obesity and type 2 diabetes, Watts explained. Apolipoprotein C-III (APOC3), a key regulator of triglyceride-rich lipoprotein metabolism, is produced in the liver and raises triglycerides by slowing catabolism. Plozasiran targets APOC3 and acts to reduce triglycerides by sustained silencing of APOC3 mRNA.

In a prespecified pooled analysis of the two SHASTA trials, acute pancreatitis events were also reduced by 78% in patients treated with plozasiran versus placebo (P=0.008), a 4.1% absolute risk reduction with a number needed to treat of 24 to prevent one pancreatitis event over 1 year.

In the highest risk subgroups, treatment reduced pancreatitis by 91% among patients with a history of acute pancreatitis versus placebo, and by 100% among those with triglycerides over 880 mg/dL and a history of pancreatitis.

ESC discussant Borge G. Nordestgaard, MD, from Copenhagen University Hospital in Denmark, said that these results with plozasiran complement those seen with another drug, olezarsen (Tryngolza), in severe hypertriglyceridemia. He also pointed out that these drugs, along with volanesorsen, now provide a lot of evidence that these agents reduce acute pancreatitis, “a huge unmet medical need until recently.”

“What we do need to know more about is that these patients have a lot of extra risk of [atherosclerotic cardiovascular disease], so that’s what we need to study in the future,” Nordestgaard concluded.

SHASTA-3 and SHASTA-4 were double-blind phase III studies comparing plozasiran 25 mg, given as a subcutaneous injection every 3 months for 12 months, with placebo. Across the two studies, 757 patients were randomized 2:1 to plozasiran versus placebo.

Patients could then enroll in an open-label extension trial at the same dose for up to 24 months.

No new safety signals were seen in the pooled safety analysis, Watts noted. Treatment-emergent adverse events occurred in 8.3% of patients receiving plozasiran and in 10% of those on placebo. Adverse events leading to study drug discontinuation were low, occurring in 1.4% and 0.8% of the treatment and placebo groups, respectively.

Worsening glycemic control was seen in 14% of treated patients versus 9% of the placebo recipients. HbA1c increased slightly in the first 3 months, but stabilized and appeared to regress back to normal at 12 months, Watts said. In a prespecified MRI substudy, there was no significant emergent increase in liver fat fraction.