Lipid-efficacy RCT · JAMA Cardiol 2024
SHASTA-2 trial
Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial.
The bottom line
Plozasiran markedly and durably lowered triglycerides (with most patients falling below the acute pancreatitis risk threshold) and APOC3 in severe hypertriglyceridemia, with a favorable safety profile, though it raised LDL-C without increasing ApoB and its effect on clinical complications remains unproven.
Primary lipid endpoint metUS status: US-approved
At a glance
- Medicine
- Plozasiran (ARO-APOC3), 2 subcutaneous doses (10, 25, or 50 mg) on day 1 and week 12
- Compared with
- Matched placebo
- People
- 226
- Who took part
- Adults with severe hypertriglyceridemia (fasting triglyceride levels 500 to 4000 mg/dL) while receiving stable lipid-lowering treatment
- Design
- placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial
- Follow-up
- Followed up through week 48
- Main question
- Placebo-subtracted difference in means of percentage triglyceride change at week 24
Main result
Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001) at the highest dose
Effect on LDL cholesterol
Dose-dependent increases in LDL-C level, significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001); ApoB levels did not increase; non-HDL-C decreased significantly at all doses, placebo-adjusted change of -20% at the highest dose
Other results
Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL; driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose; significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48
Safety
Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death.
In the trial's own words
“Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose.”
Quoted from the abstract of JAMA Cardiol 2024, checked word for word against PubMed. PubMed 38583092 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Plozasiran (Redemplo)
Common questions
What did the SHASTA-2 trial find?
Plozasiran markedly and durably lowered triglycerides (with most patients falling below the acute pancreatitis risk threshold) and APOC3 in severe hypertriglyceridemia, with a favorable safety profile, though it raised LDL-C without increasing ApoB and its effect on clinical complications remains unproven.
Who was in SHASTA-2?
226 people. Adults with severe hypertriglyceridemia (fasting triglyceride levels 500 to 4000 mg/dL) while receiving stable lipid-lowering treatment.
What was SHASTA-2's main result?
Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001) at the highest dose
How much did LDL cholesterol change in SHASTA-2?
Dose-dependent increases in LDL-C level, significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001); ApoB levels did not increase; non-HDL-C decreased significantly at all doses, placebo-adjusted change of -20% at the highest dose
Related trials
- ARCHES-2 (2024)In adults with mixed hyperlipidemia, zodasiran (an RNAi therapy against ANGPTL3) produced significant, dose-dependent reductions in triglycerides and improvements in non-HDL-C, ApoB, and LDL-C compared with placebo, with a signal of transient HbA1c elevation in diabetic patients at the highest dose.
- Balance (2024)In patients with familial chylomicronemia syndrome, olezarsen 80 mg significantly lowered triglycerides and markedly reduced acute pancreatitis episodes compared with placebo, with the 50-mg dose not reaching significance for the triglyceride endpoint.
- Bridge-TIMI 73a (2024)In patients with moderate-to-severe hypertriglyceridemia and elevated cardiovascular risk, monthly olezarsen substantially lowered triglycerides, APOC3, apolipoprotein B, and non-HDL cholesterol compared with placebo, without major safety concerns.
- CTX310 phase 1 (2025)A single dose of the CRISPR-Cas9 gene-editing therapy CTX310 was generally well tolerated and produced dose-dependent reductions in ANGPTL3 levels, supporting further clinical development for dyslipidemia.
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