Plozasiran Paves RNA Interference Path to Triglyceride Reduction

The liver APOC3-targeted RNA interference agent plozasiran proved its triglyceride-lowering effects in people with mixed hyperlipidemia in the phase IIb MUIR trial.

In such individuals, known to be at increased risk of atherosclerotic cardiovascular disease (ASCVD), plozasiran at various doses conferred significantly larger reductions over placebo in fasting triglyceride level from baseline to week 24 — ranging from 44.2 percentage points with the 50-mg-half-yearly dose to 62.4 percentage points with the 50-mg-quarterly dose (P<0.001 for all tested doses) — on top of usual statins and other medications.

Plozasiran also achieved reductions in atherogenic lipoproteins, such as non-HDL cholesterol, apolipoprotein B (ApoB), and remnant cholesterol. Effects persisted at week 48, 36 weeks after the last dose had been received, reported Christie Ballantyne, MD, of Baylor College of Medicine and the Texas Heart Institute in Houston, and colleagues.

“Historically, reductions in both non-HDL cholesterol and ApoB, effected through decreases in the LDL cholesterol level, have translated into clinical benefit. In contrast, our findings indicate that the reductions in the non-HDL cholesterol level that were observed … were brought about by reductions in the level of cholesterol remnants rather than reductions in the LDL cholesterol level,” they wrote in the New England Journal of Medicine.

The MUIR trial was also presented at the 2024 European Atherosclerosis Society Congress.

The authors reported that safety events generally occurred at similar rates between study arms — save a signal of glycemia in the quarterly and half-yearly 50-mg dose plozasiran groups. Worsening glycemic control was observed in 10% of the placebo arm vs 12% of 10-mg-quarterly dose group, 7% of the 25-mg-quarterly dose group, 20% of those receiving the 50-mg-quarterly dose group, and 21% of the 50-mg-half-yearly dose group.

However, Ballantyne’s group suggested that some may question the clinical significance of worsening glycemic control.

Volanesorsen (Waylivra), an APOC3-targeting antisense oligonucleotide, was previously also associated with this outcome but has shown no actual harm on glucose homeostasis over the course of 5 years in people with familial chylomicronemia syndrome, the investigators noted. “Similar findings of worsening glycemic control have been described with other lipid-lowering treatments, including statins, and the condition has proved to be manageable and offset by clinical benefit,” they added.

Even so, only the 25-mg-quarterly dose of plozasiran is moving forward into phase III trials in mixed hyperlipidemia and severe hypertriglyceridemia (i.e., SHASTA-3, SHASTA-4).

Mixed hyperlipidemia is a common disorder characterized by elevated LDL cholesterol and triglyceride levels. Despite the effectiveness of medications for lowering LDL cholesterol, affected patients have an unmet need for reducing the residual ASCVD risk attributed to remnant cholesterol in triglyceride-rich lipoproteins.

Plozasiran is being developed to meet that need as it was designed to reduce production of APOC3, a component of triglyceride-rich lipoproteins and a regulator of triglyceride metabolism.

Indeed, the MUIR investigators found their plozasiran groups had reductions in APOC3 ranging from 57% to 79%. Additionally, 77% to 92% normalized their fasting triglycerides to levels below 150 mg/dL, whereas the placebo arm showed no such changes.

“The promising results from treatment with plozasiran in the MUIR study help to lay the groundwork for a more extensive study to potentially test whether plozasiran reduces ASCVD risk,” Ballantyne said in a press release.

Plozasiran is not alone in that stage of the pipeline. Another APOC3-targeting therapy being developed is olezarsen, an antisense oligonucleotide targeting mRNA therapy administered subcutaneously once a month. This spring, olezarsen was also shown to slash triglycerides in higher risk or moderate hypertriglyceridemia patients and people with familial chylomicronemia syndrome.

Additionally, plozasiran’s developer, Arrowhead Pharmaceuticals, has another iron in the fire with zodasiran, a hepatocyte-targeted small interfering RNA therapy that blocks ANGPTL3 production for the control of triglyceride-containing particles.

MUIR was conducted at 36 centers across several continents and enrolled people with mixed hyperlipidemia, namely triglycerides 150-499 mg/dL and either an LDL cholesterol level of ≥70 mg/dL or a non-HDL cholesterol level of ≥100 mg/dL. Participants were eligible if they maintained a stable diet for at least 2 weeks, stayed on a maximally-tolerable statin for at least 4 weeks, and were receiving background medications at stable doses.

There were ultimately 353 patients randomized 3:1 to plozasiran at various quarterly/half-yearly doses or placebo.

The cohort had a mean age of 61 with 56% men. Average BMI was 32, and 61% of the cohort had diabetes. At baseline, the mean plasma triglyceride level was 244 mg/dL, fasting LDL cholesterol 103 mg/dL, non-HDL cholesterol 151 mg/dL, and mean remnant cholesterol 47 mg/dL. Additionally, 18% had LDL cholesterol <70 mg/dL. Existing therapies used by the group included statins (92%), high-intensity statins (54%), and PCSK9 inhibitors (2%).

Baseline characteristics of the participants were generally balanced across the four trial groups, with the exception of the relatively fewer women and statin users in the 50 mg half-yearly plozasiran group.

The investigational therapy was associated with increased HDL cholesterol across recipients in the trial.

Meanwhile, no participants receiving a quarterly dose of plozasiran in MUIR had increased levels of alanine aminotransferase or aspartate aminotransferase.

FDA has given the therapy orphan drug designation and fast track designation.

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