RNAi Therapy Reduces Acute Pancreatitis in Chylomicronemia, Meets Phase 3 Primary Endpoint


Other of the company’s RNAi therapies have recently shown promising data in hyperlipidemia and asthma.

Arrowhead Pharmaceuticals’ phase 3 PALISADE trial (NCT05089084) evaluating plozasiran RNA interference therapy (RNAi) in people with clinically diagnosed familial chylomicronemia syndrome (FCS) has met its primary endpoint of lowering triglycerides and met all key secondary endpoints, including reducing the incidence of acute pancreatitis compared to placebo.1

“The strong results from the Phase 3 PALISADE study, evaluating plozasiran in patients with FCS, significantly build upon the promising results from the Phase 2 SHASTA-2 and MUIR studies in patients with severe hypertriglyceridemia and mixed hyperlipidemia, recently published in JAMA Cardiology and the New England Journal of Medicine. These findings highlight the potential of plozasiran as a promising therapy for patients with various cardiometabolic disorders,” Bruce Given, MD, chief medical scientist, Arrowhead, said in a statement.1 “We look forward to discussing results at our June 25th Cardiometabolic event as part of our 2024 Summer Series of R&D Webinars and presenting the full PALISADE data at upcoming medical conferences.”

The primary endpoint in the PALISADE study was placebo adjusted median change in triglycerides at Month 10, at which point patients treated with quarterly doses of 25 and 50 mg plozasiran achieved median reductions of -80% and -78%, respectively, with a maximal reduction of -98%. At month 12, these patients achieved median reductions of -78% and -73%, respectively, with a maximal reduction of -99%. Patients in the placebo arm had median reductions of -17% at month 10 (P <.001) and -7% at month 12. Treated participants also had mean reductions of -88% and -94% in Apolipoprotein C-III (APOC3) at month 10, respectively.1

The trial also met secondary endpoints of percent change from baseline at Months 10 and 12 (averaged) in fasting triglycerides; percent change from baseline at Month 10 in fasting APOC3; percent change from baseline at Month 12 in fasting APOC3; and incidence of positively adjudicated events of acute pancreatitis during the randomized period. Plozasiran had a favorable safety profile with similar rates of treatment emergent adverse events (AEs) in plozasiran and placebo groups.1

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In addition to PALISADE, Arrowhead has had a busy month presenting data updates from phase 2 studies evaluating other RNA interference therapies zodasiran and plozasiran in people with mixed hyperlipidemia, and a phase 1 study evaluating ARO-RAGE in people with mild-to-moderate asthma.2,3,4

These studies are termed ARCHES-2 (NCT04832971), MUIR (NCT04998201), and ARORAGE-1001 (NCT05276570), respectively. Safety profiles were manageable for all 3 RNAi therapies, with no serious treatment-related AEs.

Similar results were seen between the studies of zodasiran, which targets ANPTL3, and plozasiran, which targets APOC3, at week 24. Zodasiran at 50, 100, and 200 mg on day 1 and week 12 was associated with triglyceride reductions of -51%, -57%, and -63% (all P <.001), respectively, and plozasiran at 10, 25, and 50 mg was associated with triglyceride reductions of -50%, -56%, and -62% (all P <.001), respectively.2,3

In ARORAGE-1001, single and multiple doses of ARO-RAGE in healthy volunteers led to dose dependent reductions in soluble receptor for advanced glycation end products (RAGE) in both bronchoalveolar lavage fluid and serum. In patients with mild to moderate asthma, serum sRAGE was reduced up to 88% with a mean maximum reduction up to 77% after 2 doses of ARO-RAGE.4

1. Arrowhead Pharmaceuticals Reports Successful Topline Results for Plozasiran from the Pivotal Phase 3 PALISADE Study in Patients with Familial Chylomicronemia Syndrome. News release. Arrowhead Pharmaceuticals. June 3, 2024. https://www.businesswire.com/news/home/20240603389820/en/
2. Arrowhead Pharmaceuticals Presents New Phase 2 Data of Zodasiran in Patients with Mixed Hyperlipidemia. News release. May 29, 2024. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-presents-new-phase-2-data-of-zodasiran-in-patients-with-mixed-hyperlipidemia/
3. Arrowhead Pharmaceuticals Presents New Phase 2 Data of Plozasiran in Patients with Mixed Hyperlipidemia. News release. Arrowhead Pharmaceuticals. May 28, 2024. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-presents-new-phase-2-data-of-plozasiran-in-patients-with-mixed-hyperlipidemia/
4. Arrowhead Pharmaceuticals Presents New Clinical Data Showing ARO-RAGE Achieves High Level of Gene Knockdown in Patients with Asthma. News release. Arrowhead Pharmaceuticals. May 20, 2024. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-presents-new-clinical-data-showing-aro-rage-achieves-high-level-of-gene-knockdown-in-patients-with-asthma/
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