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Plozasiran: A novel approach to severe hypertriglyceridaemia

Presented by
Prof. Daniel Gaudet, University of Montreal, Canada
ACC 2024
Phase 2, SHASTA-2
Plozasiran targets apolipoprotein C3 (ApoC3) to tackle severe hypertriglyceridaemia. In the phase 2 SHASTA-2 study, it notably lowered triglyceride levels and ApoC3 concentrations, with over 90% of participants reaching triglyceride levels below the critical acute pancreatitis risk threshold.

Severe hypertriglyceridaemia, a risk factor for acute pancreatitis and cardiovascular disease, is still challenging to treat. Plozasiran selectively targets ApoC3, a regulator of triglyceride metabolism. The phase 2b SHASTA-2 trial (NCT04720534) assessed the safety and efficacy of plozasiran in individuals with severe hypertriglyceridaemia, defined as triglyceride levels >500 mg/dL and fasting triglyceride levels of 500–4,000 mg/dL [1]. Primary endpoints included percentage triglyceride change from baseline and over time, with evaluation at week 24 and week 48. Additionally, ApoC3, ApoB, LDL-cholesterol, non-HDL-cholesterol, HDL-cholesterol, and remnant cholesterol were assessed. Safety was also a key consideration.

Over 48 weeks, participants receiving 50 mg of plozasiran exhibited remarkable reductions in both triglyceride levels and ApoC3 concentrations:

    • ApoC3 levels decreased by 78% at week 24, persisting at a reduction of 48% by week 48 (P<0.0001);
    • triglyceride levels showed a significant reduction of 74% at week 24, with a sustained reduction of up to 58% by week 48 (P<0.0001; see Figure).
Figure: Plozasiran significantly decreased triglycerides in patients with severe hypertriglyceridaemia [1]

LS, least square; SEM, standard error of the mean.

Moreover, a vast majority of participants (over 90%) achieved triglyceride levels below 500 mg/dL, a critical threshold associated with elevated acute pancreatitis risk, by week 24. These reductions were accompanied by improvements in other atherogenic lipid parameters, including remnant cholesterol and non-HDL-cholesterol.

These promising results from the SHASTA-2 study underscore plozasiran's potential in severe hypertriglyceridaemia management. Thus, a phase 3 study in a broader patient population is underway.

    1. Gaudet D, et al. 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. LB4, Session 4115, ACC 2024 Scientific Session, 6–8 April, Atlanta, USA.

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