PALISADE: Plozasiran Offers Hope for Treating Familial Chylomicronemia Syndrome

New phase 3 data from plozasiran, a small interfering RNA therapy, presented at the European Society of Cardiology (ESC) Congress 2024 indicates there could be hope on the horizon for patients with familial chylomicronemia syndrome (FCS).

The trial, named the PALISADE trial, found use of plozasiran, which targets hepatic production of apolipoprotein C-III and circulating triglycerides, was associated with a statistically significant reduction in triglycerides levels and a lower incidence of pancreatitis relative to placebo therapy. Following the presentation, Arrowhead Pharmaceuticals announced their intent to file a New Drug Application with the US Food and Drug Administration before the end of 2024.¹

“People living with extremely high triglyceride levels, like those in the PALISADE study, have a substantially higher risk of developing acute pancreatitis and associated long-term sequelae, including a poor quality of life,” explained Gerald F. Watts, DSc, MD, PhD, Winthrop Professor of Cardio-metabolic Medicine at the University of Western Australia, Perth.² “There are currently no approved therapies in the US to specifically treat FCS, so as physicians we have very few options to help our patients other than various triglyceride-lowering medications which provide minimal benefit, and very strict diet restrictions that take a significant toll on patients and their families.”

Presented less than 3 months after Arrowhead Pharmaceuticals announced topline results from the trial indicating use of achieved statistically significant reductions in triglyceride levels up to 80%, with the potential to lower APOC3 up to 94%, at the primary endpoint of 10 months. PALISADE was designed as a double-blind, randomized, placebo-controlled trial aimed at assessing the efficacy and safety of plozasiran among adult patients with genetically confirmed FCS or symptomatic persistent chylomicronemia.^1,3

For inclusion in the study, patients needed to be 18 years of age or older, have a diagnosis of severe hypertriglyceridemia resistant to standard lipid-lowering therapy, have a documented history of a fasting triglyceride level of more than 1000 mg/dl on at least 3 occasions, and at least 1 of the following criteria:

• A previous genetic diagnosis of FCS,
• Absent or low post-heparin lipoprotein lipase activity
• A history of acute pancreatitis not caused by alcohol or cholelithiasis
• Recurrent hospitalizations for severe abdominal pain without another identified cause,
• Childhood pancreatitis
• A family history of hypertriglyceridemia-induced pancreatitis

Of note, the trial’s original protocol was designed to only include patients with genetically confirmed FCS, but the design was amended at the request of a regulatory agency.¹

A total of 75 patients were screened, deemed eligible for inclusion, and randomized in a 2:1:2:1 ratio to receive 25 mg of plozasiran or volume-matched placebo or to receive 50 mg of plozasiran or volume-matched placebo subcutaneously every 3 months for 12 months. Investigators pointed out this randomization ratio was used with the aim of achieving a 1:1 assignment for the comparison of each plozasiran dose with pooled placebo.¹

The 75-person cohort included in the study was 51% women, 73% were White, the median BMI was approximately 25 kg/m2, and the median triglyceride level was 2044 (interquartile range, 1333 to 2955) mg/dL. Of the 75 patients randomized, 26 were assigned to the 25 mg plozasiran group, 24 were assigned to the 50 mg plozasiran group, and 25 were assigned to the placebo group.¹

The primary endpoint of interest for the trial was the median percent change from baseline in fasting triglycerides at 10 months. Secondary endpoints of note included the percent change in the fasting triglyceride level from baseline to a mean of the levels at 10 months and 12 months and the incidence of positively adjudicated events of acute pancreatitis.¹

At 10 months, results indicated the median change from baseline in triglyceride levels were -80% with plozasiran 25 mg, -78% for plozasiran 50 mg, and -17% for placebo (P <.001). Further analysis demonstrated plozasiran’s benefit on secondary endpoints, including mean of the triglycerides levels at 10 months and 12 months from baseline where there was a change of −60 percentage points (95% Confidence Interval [CI], −92 to −28; P <.001) in the plozasiran 25 mg group and −51 percentage points (95% CI, −84 to −18; P <.001) in the plozasiran 50 mg group relative to placebo group. Additionally, an 83% reduction in relative likelihood of acute pancreatitis (Odds Ratio, 0.17; 95% CI, 0.03 to 0.94; P = .03).¹

“Plozasiran demonstrated very deep reductions in triglycerides in the PALISADE study and is the only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS in a controlled study,” Watts added. “These results are encouraging and offer hope to people living with FCS and their physicians who are in desperate need of new safe and effective treatment options.”

References:

1. Watts GF, Rosenson RS, Hegele RA. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. New England Journal of Medicine. Published online September 2, 2024. doi:10.1056/NEJMoa2409368
2. Arrowhead Pharmaceuticals Inc. Arrowhead Pharmaceuticals presents New pivotal phase 3 data at ESC 2024 from Palisade Study of Plozasiran in patients with familial chylomicronemia syndrome. Arrowhead Pharmaceuticals, Inc. September 2, 2024. Accessed September 2, 2024. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-presents-new-pivotal-phase-3-data-at-esc-2024-from-palisade-study-of-plozasiran-in-patients-with-familial-chylomicronemia-syndrome/.
3. Iapoce C. Palisade: Plozasiran lowers triglycerides in familial chylomicronemia syndrome. HCP Live. June 3, 2024. Accessed September 2, 2024. https://www.hcplive.com/view/palisade-plozasiran-lowers-triglycerides-familial-chylomicronemia-syndrome.