Arrowhead's Plozasiran Reduces Triglyceride Rich Lipoproteins in Patients with Mixed Hyperlipidemia

Arrowhead Pharmaceuticals, Inc. today announced results from the Phase 2b double blind, randomized MUIR study of investigational plozasiran (formerly ARO-APOC3) in patients with mixed hyperlipidemia. Treatment with plozasiran in the MUIR study achieved reductions in triglyceride rich lipoproteins, a genetically validated target associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). These data were presented in an oral presentation today at the European Atherosclerosis Society (EAS) 92nd Congress and simultaneously published in the New England Journal of Medicine.​​​​​​​

“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,” said Christie M. Ballantyne, M.D., Baylor College of Medicine, and Principal Investigator for the MUIR study. “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. 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.”

Results from the MUIR study of plozasiran in patients with mixed hyperlipidemia are encouraging and we are excited to present data at EAS and publish the results today in the New England Journal of Medicine. 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, M.D., Interim Chief Medical Scientist, Arrowhead​​​​​​​

Select MUIR Results

By silencing Apolipoprotein C-III (APOC3), plozasiran significantly reduced triglycerides and atherogenic triglyceride rich lipoproteins and increased HDL, across all dose levels at Week 24 in patients with mixed dyslipidemia.

At week 24, representing trough effect after 2 quarterly doses, plozasiran treatment was associated with placebo adjusted reductions in triglycerides of -50%, -56%, and -62% (all p<0.001) at the 10, 25, and 50 mg doses, respectively. Fasting triglyceride levels were normalized (achieved levels below 150 mg/dL) in most patients (79-92%) randomized to a treatment arm. Commensurate reductions in APOC3 of -57%, -73%, and -79%, with strong positive correlations with changes in triglyceride levels were observed.

Changes in other atherogenic lipoprotein parameters were also observed. At week 24, for the quarterly doses of 10, 25, and 50 mg, the following placebo adjusted changes were observed: non-HDL-C levels -17%, -18%, and -24%; apoB levels -10%, -13%, and -19%; and remnant cholesterol levels -43%, -49%, and -48% with strong correlations with changes in triglyceride levels.

Safety and Tolerability

Plozasiran demonstrated a favorable safety profile in the MUIR study. The overall rates of occurrence of treatment-emergent adverse events (TEAEs) and discontinuations were similar for plozasiran and placebo throughout the 48 weeks of observation. Observed adverse events generally reflected the comorbidities and underlying conditions of the study population. TEAEs occurring in 5 or more patients were COVID-19, worsening glycemic control, upper respiratory tract infection, urinary tract infection, headache, and bronchitis.

Arrowhead is also presenting data from the SHASTA-2 study of plozasiran and the ARCHES-2 study of zodasiran (formerly ARO-ANG3) at EAS. Details about the EAS presentations are listed below.

European Atherosclerosis Society (EAS) 92nd Congress – May 26-29, 2024

Title: PLOZASIRAN (ARO-APOC3), DECREASES APOC3 AND TRIGLYCERIDES (TG) IN PATIENTS WITH MIXED DYSLIPIDEMIA: MUIR FINAL RESULTS
Date/Time: May 28, 2024, 12:04 p.m. CEST
Presenter: Christie M Ballantyne, M.D.
Session: New Therapeutics

Title: PLOZASIRAN (ARO-APOC3), AN INVESTIGATIONAL RNAI THERAPEUTIC, DEMONSTRATES PROFOUND AND DURABLE REDUCTIONS IN APOC-3 AND TRIGLYCERIDES (TG) IN PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA (SHTG), SHASTA-2 FINAL RESULTS
Date/Time: May 28, 2024, 2:49 p.m. CEST
Presenter: Daniel Gaudet, M.D., Ph.D.
Session: SaaG Session: The Enigmas of TG-rich Lipoproteins

Title: ZODASIRAN SILENCES HEPATIC ANGPTL3 LEADING TO DEEP AND DURABLE REDUCTIONS IN ATHEROGENIC LIPIDS AND LIPOPROTEINS IN MIXED DYSLIPIDEMIA PATIENTS: FINAL RESULTS FROM ARCHES-2, DOUBLE-BLIND PERIOD
Date/Time: May 29, 2024, 11:30 a.m. CEST
Presenter: Robert Rosenson, M.D.
Session: Late Breaker Session 2: New Therapeutic Agents

Presentation material may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website after each presentation concludes.

Source:

Arrowhead Pharmaceuticals

Journal reference:

Ballantyne, C. M., et al. (2024). Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia. New England Journal of Medicine. doi.org/10.1056/nejmoa2404143.

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