Plozasiran, an Investigational RNAi Therapy, Reduces Triglyceride Levels in Adults with Mixed Hyperlipidemia

Among adults with mixed hyperlipidemia, subcutaneous plozasiran, an investigational RNA interference (RNAi) therapeutic, significantly lowered triglyceride levels by 50% or more across 3 dose levels, with proportionate reductions observed in levels of atherogenic triglyceride rich lipoproteins (TRL), according to findings presented at the European Atherosclerosis Society 92nd Congress, May 26-29, 2024, in Lyon, France.¹

The results, from the phase 2b MUIR study, were published simultaneously in the New England Journal of Medicine.

Plozasiran silences apolipoprotein C-3 (APOC3), a component of TRLs and key to regulation of triglyceride metabolism via its effects on hepatic clearance of these and other lipids. Atherogenic TRLs are a genetically validated target linked with an elevated risk of atherosclerotic cardiovascular disease (ASCVD), according to the study.¹

“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, chief of cardiovascular research; director of the Center for Cardiometabolic Disease Prevention, Baylor College of Medicine; and principal MUIR investigator, said in a statement.²

The MUIR study

MUIR was an international 48-week double-blind, randomized, placebo-controlled phase 2b trial to evaluate the safety and efficacy of 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-C >100 mg/dL. Participants were randomly assigned in a 3:1 ratio to receive 10, 25, or 50 mg plozasiran or placebo on day 1 and at week 12 (quarterly doses) or 50 mg plozasiran or placebo on day 1 and week 24 (semi-yearly dose).¹

The study’s primary endpoint was mean percent change in fasting triglyceride levels at week 24, according to the study, with secondary endpoints including changes from baseline in the APOC3 level at week 24, in the fasting triglyceride level through week 48, and in the fasting levels of APOC3, non-HDL cholesterol, apoB, LDL cholesterol, and HDL cholesterol at week 24 through week 48.¹

The final cohort for random treatment assignment numbered 353 (53% men) who had a mean age of 61 years. Nearly all (97%) were on stable doses of statin drugs, with 56% receiving a high-intensity statin.

FINDINGS¹

At week 24, Ballantyne et al reported significant reductions in fasting triglyceride levels with plozasiran, with differences, vs placebo, in least-squares mean (LSM) percent change from baseline of –49.8%, –56%, and –62% with the the 10-, 25-, and 50-mg doses, respectively (P <.001 for all).

The researchers also found at week 24 that the majority of participants assigned to treatment with plozasiran reached normalized fasting triglyceride levels (<150 mg/dL), from 79% in the 10-mg group to 92% in the 50-mg quarterly groups and 77% in the 50-mg half-yearly group.

The reductions observed in APOC3 levels were commensurate, according to the study results, with LSM differences, compared with placebo, of –57.3%, –72.5%, and –78.5% at the 10-, 25-, and 50-mg quarterly doses respectively, Further, the investigators noted “strong positive correlations” with changes in triglyceride levels.

Other secondary outcomes also reflected changes in atherogenic TRLs including reductions in non-HDL-C levels with plozasiran, of –16.7%, –17.5%, and –24.2% with the 10-, 25-, and 50-mg doses, respectively.

According to Ballantyne and colleagues, the reductions observed in non-HDL-C levels were driven predominantly by reductions in levels of remnant cholesterol, with LSM differences of –43%, –49%, and –48% seen at doses of 10-, 25-, and 50-mg, respectively. Changes in these levels, similar to those seen with reductions in APOC3, also had strong correlations with the changes observed in triglyceride levels. Compared with placebo, treatment with plozasiran was also associated with reductions in apoB levels (LSM differences of –10.3%, –13%, and –19%) and reductions in LDL-C levels (LSM differences –4.1%, –2.7%, and –13.6%) at the 10, 25, and 50 mg doses, respectively.

The investigators reported the effects of plozasiran “remained evident” at study week 48, 35 weeks following the last dose of the drug.

The plozasiran safety profile in MUIR was noted as favorable in the published study, with overall rates of treatment-emergent adverse events (TEAEs) and discontinuations 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.¹

“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.”²

"A clinical outcomes trial is warranted," authors concluded.¹

References

1. Ballantyne CM, Vasas S, Azizad M, Clifton P, Rosenson RS, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med. Published online May 28, 2024. Accessed May 28, 2024. doi:10.1056/NEJMoa2404143
2. Arrowhead Pharmaceuticals presents new phase 2 data of plozasiran in patients with mixed hyperlipidemia. News release. 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/