PALISADE: PLOZASIRAN DECREASES THE RISK OF ACUTE PANCREATITIS AND MAY IMPROVE QUALITY OF LIFE IN FAMILIAL CHYLOMICRONEMIA SYNDROME

Abstract

Therapeutic Area

ASCVD /CVD Risk Reduction

Background

FCS causes life-threatening Acute Pancreatitis (AP) and may be due to genetic defects in the enzyme lipoprotein lipase (LPL) which impair the circulatory clearance of chylomicrons (CMs) and triglycerides (TGs). Other clinical manifestations collectively impair QoL. Plozasiran is a siRNA that reduces hepatic apolipoprotein (apo) C-III, thereby effectively lowering extremely high TGs. We describe effects of plozasiran on AP outcomes and QoL in patients with FCS.

Methods

PALISADE was a Phase 3 double blind, placebo-controlled trial of 75 adults with FCS (59% were genetically confirmed) on best standard-of-care. Patients were randomized to quarterly dosed plozasiran (25 or 50 mg SC) or placebo for 12 months. TG lowering was the primary endpoint and adjudicated rates of AP were a key (alpha-controlled) secondary endpoint. Qualitative patient reported outcomes on composite measures of QoL, EORTC-QLQ-C30, PAN-26 and EQ-5D-5L were exploratory.

Results

Plozasiran lowered median TG levels from >2000 to 544 mg/dL at 12 months (p<0.001), independent of a confirmed FCS genotype. All key secondary endpoints (previously reported) showed significant benefits of plozasiran. Nine AP episodes in 7 patients were positively adjudicated: patients receiving plozasiran achieved an 83% reduction in the risk of developing AP versus placebo, (p<0.03). Placebo patients with AP transitioned to open label treatment, limiting the ability to assess cumulative events. Plozasiran was well-tolerated. Severe and serious events were less common with Plozasiran than placebo.

AP severity differed: 6 severe and 1 moderate event occurred on placebo vs 1 moderate and 1 mild event on Plozasiran. Placebo patients spent 47 days in the hospital vs 10 days with Plozasiran. More patients in placebo experienced abdominal pain leading to AP.

Absolute changes in various domain scores of the selected patient reported outcomes correlated with improvements. Most symptom domains improved in the QoL assessments, some with clinically meaningful scores > -10 points, i.e. significant improvements in appetite loss, -15.9, insomnia, -16.8 (p<0.05, both). Functional domain scores improved, some with clinically meaningful scores > +10 points, i.e. improvements in role function, +14.8 and emotional function, +11.8 (p<0.05, both), and health care satisfaction, +14.7. Clinically meaningful improvements were shown for appetite loss, insomnia, cognitive functioning, emotional functioning, and role functioning in the plozasiran treated subjects compared to placebo (nominal p-values of <0.05).

Conclusions

Plozasiran significantly reduced TG and AP while improving QoL in the PALISADE trial.