Lipid-efficacy RCT · Lancet 2025
PROLONG-ANG3 trial
Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial.
The bottom line
In adults with mixed dyslipidaemia on background statin therapy, solbinsiran 400 mg significantly reduced apoB levels compared with placebo and was generally well tolerated, though its effect on cardiovascular outcomes is still unknown.
Primary lipid endpoint met (400 mg only)US status: Investigational
At a glance
- Medicine
- Solbinsiran (GalNAc-conjugated siRNA targeting ANGPTL3) 100 mg, 400 mg, or 800 mg subcutaneous injection on days 0 and 90
- Compared with
- Placebo
- People
- 205
- Who took part
- Adults (aged ≥18 years) with mixed dyslipidaemia, receiving moderate-intensity or high-intensity statins, with fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L
- Design
- double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial
- Follow-up
- Followed up for at least 270 days
- Main question
- Percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand
Main result
The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg.
Effect on LDL cholesterol
Baseline median LDL-C was 3·16 mmol/L (2·57-3·82); specific placebo-adjusted percent change in LDL-C not reported in abstract
Other results
Not reported in abstract
Safety
Solbinsiran administration was well tolerated, with a low incidence of adverse events. The number of patients with treatment-emergent adverse events was 18 [60%] of 30 patients in the solbinsiran 100 mg group, 30 [52%] of 58 patients in the solbinsiran 400 mg group, 26 [44%] of 59 patients in the solbinsiran 800 mg group, and 37 [65%] of 57 patients in the placebo group.
In the trial's own words
“The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg.”
Quoted from the abstract of Lancet 2025, checked word for word against PubMed. PubMed 40179932 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Zodasiran and solbinsiran
Common questions
What did the PROLONG-ANG3 trial find?
In adults with mixed dyslipidaemia on background statin therapy, solbinsiran 400 mg significantly reduced apoB levels compared with placebo and was generally well tolerated, though its effect on cardiovascular outcomes is still unknown.
Who was in PROLONG-ANG3?
205 people. Adults (aged ≥18 years) with mixed dyslipidaemia, receiving moderate-intensity or high-intensity statins, with fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L.
What was PROLONG-ANG3's main result?
The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg.
How much did LDL cholesterol change in PROLONG-ANG3?
Baseline median LDL-C was 3·16 mmol/L (2·57-3·82); specific placebo-adjusted percent change in LDL-C not reported in abstract
Related trials
- 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.
- ESSENCE-TIMI 73b (2025)In patients with moderate hypertriglyceridemia and elevated cardiovascular risk, olezarsen significantly lowered triglyceride levels at 6 months compared with placebo, with similar rates of serious adverse events.
- PALISADE (2025)In patients with persistent chylomicronemia, plozasiran (siRNA against APOC3) sharply lowered triglycerides and reduced acute pancreatitis episodes compared with placebo, with a similar overall adverse event rate but a signal for hyperglycemia in those with prediabetes/diabetes.
- 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.
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