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
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Background Mixed dyslipidaemia, characterised by elevated concentrations of circulating triglycerides and LDL cholesterol (LDL-C), is associated with an increased risk of atherosclerotic cardiovascular disease. Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), reduced triglycerides and LDL-C concentrations in a phase 1 study. This study aimed to assess the durability and efficacy of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidaemia. Methods This double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial enrolled adults (aged ≥18 years) with mixed dyslipidaemia at 41 clinical research units across seven countries. Patients receiving moderate-intensity or high-intensity statins, and with concentrations of 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 were included. Using an interactive web-response system, patients were randomly assigned (1:2:2:2) to receive either solbinsiran 100 mg, solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on days 0 and 90. Patients were followed up for at least 270 days. The primary outcome was percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand (in patients who received at least one dose of the study…
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Among patients with hypertriglyceridemia and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated marked triglyceride reductions across phase I-III clinical trials.
“Among patients with HTG and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated marked TG reductions and favorable effects on non–HDL-C, apoB, and very-low-density lipoprotein cholesterol (VLDL-C) across phase I–III clinical trials (Gaudet et al., 2024; Huynh, 2024; Ray et al., 2025; Bornfeldt, 2024; Schwabe et al., 2020; Lim, 2024).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
Among patients with hypertriglyceridemia and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated favorable effects on non-HDL-C, apoB, and VLDL-C across phase I-III clinical trials.
“Among patients with HTG and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated marked TG reductions and favorable effects on non–HDL-C, apoB, and very-low-density lipoprotein cholesterol (VLDL-C) across phase I–III clinical trials (Gaudet et al., 2024; Huynh, 2024; Ray et al., 2025; Bornfeldt, 2024; Schwabe et al., 2020; Lim, 2024).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
Compared with placebo, small interfering RNA therapy increased HDL-C by a pooled mean difference of 20.6% (95% CI, −8.4 to 49.6; I2 = 99.3%), not statistically significant.
“Compared with placebo, the pooled mean difference in HDL-C was 20.6% (95% CI, −8.4 to 49.6; I2 = 99.3%), indicating a not statistically significant increase in HDL-C with small interfering RNA therapy (Figure 4A).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting ANGPTL3, triglycerides were significantly reduced compared with placebo (MD, −50.8%; 95% CI, −71.5 to −30.1).
“Compared with placebo, triglyceride levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −50.8%; 95% CI, −71.5 to −30.1)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
Compared with placebo, small interfering RNA therapy reduced VLDL-C by a pooled mean difference of −49.5% (95% CI, −60.1 to −38.9; I2 = 72.4%), a statistically significant reduction.
“Compared with placebo, the pooled mean difference in VLDL-C was −49.5% (95% CI, −60.1 to −38.9; I2 = 72.4%), indicating a statistically significant reduction in VLDL-C with small interfering RNA therapy (Figure 6A).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting APOC3, LDL-C was not significantly reduced compared with placebo (MD, 0.6%; 95% CI, −5.7 to 6.9).
“but LDL-C levels were not significantly reduced in patients receiving siRNA targeting APOC3 (MD, 0.6%; 95% CI, −5.7–6.9)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
Compared with placebo, small interfering RNA therapy reduced non-HDL-C by a pooled mean difference of −21.9% (95% CI, −26.1 to −17.6; I2 = 56.1%), a statistically significant reduction.
“Compared with placebo, the pooled mean difference in Non-HDL-C was −21.9% (95% CI, −26.1 to −17.6; I2 = 56.1%), indicating a statistically significant reduction in Non-HDL-C with small interfering RNA therapy (Figure 5A).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting APOC3, HDL-C was significantly increased compared with placebo (MD, 40.9%; 95% CI, 31.6 to 50.2).
“In contrast, patients receiving siRNA therapy targeting APOC3 had a significant increase in HDL-C levels (MD, 40.9%; 95% CI, 31.6–50.2)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting ANGPTL3, HDL-C was significantly reduced compared with placebo (MD, −20.2%; 95% CI, −25.4 to −14.9).
“Compared with placebo, HDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −20.2%; 95% CI, −25.4 to −14.9).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting APOC3, triglycerides were significantly reduced compared with placebo (MD, −53.6%; 95% CI, −58.8 to −48.4).
“triglyceride levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −53.6%; 95% CI, −58.8 to −48.4)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting APOC3, non-HDL-C was significantly reduced compared with placebo (MD, −20.5%; 95% CI, −23.2 to −17.8).
“non-HDL-C levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −20.5%; 95% CI, −23.2 to −17.8)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
Compared with placebo, small interfering RNA therapy reduced triglycerides by a pooled mean difference of −52% (95% CI, −57.9 to −46.2; I2 = 62.1%), a statistically significant reduction.
“Compared with placebo, the pooled mean difference in triglycerides was −52% (95% CI, −57.9 to −46.2; I2 = 62.1%), indicating a statistically significant reduction in TG with small interfering RNA therapy (Figure 2A).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting ANGPTL3, LDL-C was significantly reduced compared with placebo (MD, −13.2%; 95% CI, −20.1 to −6.2).
“Compared with placebo, LDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −13.2%; 95% CI, −20.1 to −6.2)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
Compared with placebo, small interfering RNA therapy reduced LDL-C by a pooled mean difference of −3.7% (95% CI, −10.4 to 3.1; I2 = 69.1%), not statistically significant.
“Compared with placebo, the pooled mean difference in LDL-C was −3.7% (95% CI, −10.4 to 3.1; I2 = 69.1%), indicating a not statistically significant reduction in LDL-C with small interfering RNA therapy (Figure 3A).”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting ANGPTL3, non-HDL-C was significantly reduced compared with placebo (MD, −28.1%; 95% CI, −45.7 to −10.5).
“HDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −28.1%; 95% CI, −45.7 to −10.5)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting APOC3, VLDL-C was significantly reduced compared with placebo (MD, −53.6%; 95% CI, −63.2 to −44).
“VLDL-C levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −53.6%; 95% CI, −63.2 to −44)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
In patients receiving siRNA targeting ANGPTL3, VLDL-C was significantly reduced compared with placebo (MD, −41%; 95% CI, −52.8 to −29.1).
“Compared with placebo, VLDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −41%; 95% CI, −52.8 to −29.1)”
From Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis (2026) · cites this paper as Ray et al., 2025
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References 30 · Cited by 81
- Authors
- Ray, K. K., Oru, E., Rosenson, R. S., Jones, J., Ma, X., Walgren, J., Haupt, A., Verma, S., Gaudet, D., Nicholls, S. J., & Ruotolo, G.
- Affiliations
- Imperial College London (GB)
- Eli Lilly (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
- St. Michael's Hospital (CA)
- Université de Montréal (CA)
- Monash University (AU)
- Corresponding author
- Ray, Kausik K
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2025-05
- Volume
- 405
- Issue
- 10489
- Pages
- 1594-1607
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W4409111255
- Cited by
- 81
- References
- 30
- Citations by year
- 2026: 57 · 2025: 24
- FWCI
- 56.59
- Type
- journal article
- Language
- en
- Update notices
- erratum (2025-05-03)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- NIHR Imperial Biomedical Research Centre
- Eli Lilly and Company (LY35611774)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- GalNAc-conjugated siRNA, ANGPTL3, mixed dyslipidemia, hypertriglyceridemia, LDL cholesterol, apolipoprotein B, atherogenic lipoproteins, atherosclerotic cardiovascular disease, statin-treated patients, triglyceride-lowering therapy, dose comparison, non-HDL cholesterol
- MeSH terms
- Angiopoietin-Like Protein 3, Acetylgalactosamine, Aged, Apolipoproteins B, Double-Blind Method, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Triglycerides, Treatment Outcome, RNA, Small Interfering, Dyslipidemias
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