MUIR: Plozasiran Reduces Triglyceride Levels in Mixed Hyperlipidemia

Christie M. Ballantyne, MD

Credit: Baylor University

New data from the phase 2b, double-blind, randomized MUIR study revealed investigational plozasiran achieved reductions in triglyceride levels in patients with mixed hyperlipidemia at 24 weeks.¹

By targeting apolipoprotein C-III (APOC3), plozasiran, formerly known as ARO-APOC3, significantly reduced triglyceride and atherogenic triglyceride-rich lipoproteins, a genetically validated target linked with an elevated risk of atherosclerotic cardiovascular disease (ASCVD).

“Plozasiran demonstrated potent and durable reductions of atherogenic lipoproteins, such as non-HDL-C, ApoB, and remnant cholesterol in the Phase 2 MUIR study that supports its further development in Phase 3 studies for patients with increased risk for ASCVD,” Christie M. Ballantyne, MD, Baylor College of Medicine, and principal MUIR investigator, said in a statement.²

Elevated non-high-density cholesterol (HDL-C) levels driven by remnant cholesterol in triglyceride-rich lipoproteins put individuals with mixed hyperlipidemia at risk for ASCVD.¹ The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through APOC3-mediated inhibition of lipoprotein lipase. Plozasiran is a first-in-class investigational RNA interference (RNAi) therapeutic that reduces APOC3 levels.

The 48-week MUIR trial evaluated plozasiran versus placebo in patients with mixed hyperlipidemia, defined as fasting triglyceride levels between 150-499 mg/dL and either LDL-cholesterol (LDL-C) ≥70 mg/dL or non-HDL-cholesterol (HDL-C) >100 mg/dL. Participants were randomly assigned 3:1 to receive 10, 25, or 50 mg plozasiran or placebo on day 1 and week 12, or 50 mg plozasiran or placebo on day 1 and week 24.

With a primary endpoint of the percent change in fasting triglyceride levels at week 24 in MUIR, 353 participants with mixed hyperlipidemia underwent randomization. At week 24, the study demonstrated significant reductions in fasting triglyceride levels with plozasiran, compared with placebo, by 50%, 56%, and 62% at the 10, 25, and 50 mg doses, respectively (P <.001 for all).

Most patients (79–92%) randomized to a plozasiran treatment arm achieved normalized fasting triglyceride levels (<150 mg/dL). Corresponding reductions in APOC3 levels were observed with plozasiran treatment, with differences, compared with placebo, of –57%, –73%, and –79% at the 10, 25, and 50 mg, doses respectively, with strong positive correlations with changes in triglyceride levels.

Other changes in atherogenic lipoprotein parameters were identified in the analysis, including reductions in the non-HDL-C levels with plozasiran, by –17%, –18%, and –24% at the 10, 25, and 50 mg doses, respectively.

These reductions in non-HDL-C levels were driven primarily by changes in remnant cholesterol levels, with a difference of –43%, –49%, and –48% at the 10, 25, and 50 mg doses, respectively, with a strong correlation with adjustments in triglyceride levels. Reductions in apoB levels were additionally seen with plozasiran, with differences of –10.3%, –13%, and –19% at the 10, 25, and 50 mg doses, respectively.

The safety profile of plozasiran remained favorable in MUIR, with overall rates of treatment-emergent adverse events (TEAEs) and discontinuations remaining similar for plozasiran and placebo through the 48-week study. The TEAEs occurring in ≥5 patients with mixed hyperlipidemia were COVID-19, worsening glycemic control, upper respiratory tract infection, urinary tract infection, headache, and bronchitis.

“Despite advances in treatment, patients with mixed hyperlipidemia have elevated and persistent ASCVD risk due in part to high levels of atherogenic triglyceride-rich lipoproteins,” Ballantyne added.² “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.”

Plozasiran has previously received Orphan Drug Designation and Fast Track Designation by the US Food and Drug Administration (FDA) and Orphan Drug Designation by the European Medicines Agency.³

“We believe plozasiran shows promise in multiple diseases with substantial unmet need, including familial chylomicronemia syndrome, severe hypertriglyceridemia, and mixed hyperlipidemia, and we are eager to further investigate plozasiran in additional clinical studies,” Bruce Given, MD, interim chief medical scientist at Arrowhead, added in a statement.²

References

1. _{Ballantyne CM, Vasas S, Azizad M, Clifton P, Rosenson RS, et al. Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia. The New England Journal of Medicine. May 28, 2024. Accessed May 28, 2024. https://www.nejm.org/.}
2. _{Arrowhead Pharmaceuticals presents New phase 2 data of plozasiran in patients with mixed hyperlipidemia. Arrowhead Pharmaceuticals, Inc. May 28, 2024. Accessed May 28, 2024. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-presents-new-phase-2-data-of-plozasiran-in-patients-with-mixed-hyperlipidemia/.}
3. _{Arrowhead receives FDA Fast Track designation for aro-APOC3. Arrowhead Pharmaceuticals Inc. March 20, 2023. Accessed May 28, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-receives-fda-fast-track-designation-aro-apoc3.}