Plozasiran lowers triglycerides for 48 weeks in patients with severe hypertriglyceridemia
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Key takeaways:
- Plozasiran reduced triglycerides, ApoC-III and non-HDL out to 48 weeks for patients with severe hypertriglyceridemia.
- Results supported moving forward with a phase 3 trial.
ATLANTA — Plozasiran provided sustained reduction in triglycerides, apolipoprotein C-III and remnant cholesterol out to 48 weeks for patients with severe hypertriglyceridemia, a speaker reported.
The final results of the SHASTA-2 trial of plozasiran, formerly ARO-APOC3 (Arrowhead Pharmaceuticals), were presented at the American College of Cardiology Scientific Session and simultaneously published in JAMA Cardiology.
“In severe hypertriglyceridemia therapy, the goal is to reduce triglyceride levels below the threshold of pancreatitis risk. ... Severe hypertriglyceridemia is defined by triglyceride levels above 500 mg/dL. Very severe hypertriglyceridemia, that is, those having triglycerides above 1,000 mg/dL, are two [rare] groups of patients with familial chylomicronemia syndrome, and the more frequent group of patients with multifactorial chylomicronemia syndrome. Severe triglycerides significantly increases the risk of cardiovascular disease, acute pancreatitis and other disease,” Daniel Gaudet, MD, PhD, clinician-researcher in lipidology and professor of medicine at the Université de Montreal, said during a presentation. “Limited options of treatment exist for patients affected by severe hypertriglyceridemia.”
Gaudet previously presented the results of the phase 2b SHASTA-2 trial at the 2023 American Heart Association Scientific Session. The trial enrolled 229 patients with severe hypertriglyceridemia randomly assigned 3:1 to subcutaneous plozasiran (10 mg, 25 mg or 50 mg) or placebo, and the primary endpoint was percent change in fasting triglycerides from baseline to 24 weeks.
As Healio previously reported, ApoC-III inhibition via RNA interference with plozasiran, was safe compared with placebo and was associated with a 66% to 74% reduction in fasting triglycerides from baseline (P < .0001). More than 90% of patients in the 25 mg dose and 50 mg dose groups achieved triglyceride levels of less than 500 mg/dL by week 4, which were sustained through week 24.
The present study evaluated the safety and efficacy of plozasiran out to 48 weeks.
At baseline, median range of triglycerides was 598 mg/dL to 696 mg/dL.
At 48 weeks, plozasiran was associated with reduced mean serum ApoC-III by up to 48% (P < .0001), according to the presentation.
Gaudet reported that triglycerides were reduced by up to 58% from baseline to 48 weeks in the plozasiran group (P < .0001) and more than 76% of patients in the 25 mg dose and 50 mg dose groups achieved triglyceride levels of less than 500 mg/dL by week 4, which were sustained through week 48.
Non-HDL was reduced up to 24% by 48 weeks (P = .0003) and LDL was reduced up to 45% (P = .05).
Moreover, the researchers determined that serious treatment-emergent adverse events were unrelated to plozasiran and consistent with comorbidities and underlying conditions associated with this patient population. All adverse events resolved without sequelae; however, the study did not include events related to plozasiran exposure out to 48 weeks.
“Plozasiran decreased the mean ApoC-III, triglycerides and remnant cholesterol while increasing HDL cholesterol substantially, even to week 24. ... And it was persistent until week 48,” Gaudet said during the presentation. “Ninety percent of the patients at week 24 achieved triglyceride levels below 500 mg/dL, and 50% below 150 mg/dL compared with 7% in the placebo group. Plozasiran had a favorable safety profile at week 48. These data suggest for the continuation of the development of the phase 3 program. Based on these results, the program will go on with the 25 mg as the target dose.”
Reference:
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Gaudet D, et al. Late-breaking clinical trials II. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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