Focus – Solbinsiran, siRNA targeting ANGPTL3, shows promise in mixed dyslipidemia

30 July 2025

In the PROLONG-ANG3 trial, solbinsiran, an N-acetylgalactosamine-conjugated small interfering RNA (siRNA) targeting hepatic angiopoietin-like protein 3 (ANGPTL3) expression, reduced apolipoprotein (apo)B  in adults with mixed dyslipidemia. There was no evidence of adverse effects on hepatic fat fraction. Further study is merited. 

Ray KK, Oru E, Rosenson RS, et al. 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 Lancet 2025; https://doi.org/10.1016/S0140-6736(25)00507-0.

STUDY SUMMARY

Objective

To assess the durability and efficacy of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidemia. 

Study design

This was a double-blind, parallel-arm, randomized, placebo-controlled  trial in adults with mixed dyslipidemia. An interactive web-response system was used to randomize patients  (1:2:2:2) to treatment with solbinsiran 100 mg, 400 mg, or 800 mg, or placebo, administered by subcutaneous injection on days 0 and 90. Patients were followed up for at least 270 days. 

Study population 

Patients with mixed dyslipidemia, defined as fasting triglycerides between 1.69 and 5.64 mmol/L, and low-density lipoprotein cholesterol (LDL-C) of at least 1.81 mmol/L, and non-high-density lipoprotein cholesterol (HDL-C ) of at least 3.36 mmol/L, who were receiving stable moderate-intensity or high-intensity statin treatment.

Main study variables

Primary efficacy outcome: Percent change in apolipoprotein (apo)B from baseline to day 180.

Secondary efficacy outcome: Percent change from baseline to day 180 and from baseline to day 270 for ANGPTL3, triglycerides, non-HDL-C, LDL-C, and HDL-C.

Safety variables included adverse events, and routine clinical and laboratory assessments. The change in magnetic resonance imaging (MRI) hepatic fat fraction from baseline to day 180 was an exploratory endpoint.

Methods

All lipid-related concentration data were log-transformed and analysed using an analysis of covariance  model for repeated measures with the terms treatment, visit, treatment-by-visit interaction, baseline measurement, and screening triglycerides (<2.82 mmol/L or ≥2.82 mmol/L). 

Results

Of 585 patients screened, 205 (median age 57 years, 54% female) were enrolled and randomly assigned to treatment with solbinsiran 100 mg (n=30), solbinsiran 400 mg (n=58), solbinsiran 800 mg (n=59), or placebo (n=58). Overall, 189 (92%) completed the treatment period. Baseline atherogenic lipid concentrations were high; median (interquartile range) levels were 111 (96–130) mg/dL for apoB, 2.64 mmol/L (2.06–3.29) for triglycerides, 1.04 (0.80–1.37) mmol/L for very low-density lipoprotein cholesterol (VLDL-C), 3.16 (2.58–3.83) mmol/L for LDL-C, and 4.30 mmol/L (3.68–5.19) for non-HDL-C. 

Solbinsiran significantly reduced ANGPTL3 at day 180, by 54.3% with 100 mg, 69.8% with 400 mg, and 76.6% with 800 mg (adjusted for placebo, all p<0·0001). Placebo-adjusted changes in lipid parameters are summarized in Table 1. At day 180, solbinsiran 400 mg significantly reduced apoB, and all three doses significantly reduced triglycerides and VLDL-C. Both solbinsiran 400 mg and 800 mg significantly reduced LDL-C and non-HDL-C from baseline to day 180. 

Table 1. Placebo-adjusted change (95% confidence interval) in lipid parameters at day 180 and day 270

Solbinsiran 100 mg

Solbinsiran 400 mg

Solbinsiran 800 mg

Day 180

ApoB

–2.8% (–15.5 to -11.9) p=0.69

–14.3% (–23.6 to 

–3.9) p=0.0085

–8.3% (–18.3 to 2.9) p=0.14

Triglycerides

–36.3% (–45.8 to 

–25.1) p<0.0001

–50.3% (–56.·4 to 

–43.3) p<0.0001

–52.5% (–58.4 to 

–45.9) p<0.0001

VLDL-C

–41.6% (–52.4 to 

–28.3) p<0.0001

–50.1% (–57.·8 to 

–41.0) p<0.0001

–49.6% (–57.4 to 

–40.4) p<0.0001

LDL-C

–1.3% (–14.6 to 14.0) p=0.85

16.8% ( –26.0 to 

–6.4) p=0.0025

–12.1% (–21.9 to 

–1.1) p=0.033

Non-HDL-C

–10.8% (–21.1 to 0.9) p=0.068

25.5% (–32.6 to 

–17.6) p<0.0001

–23.8% (–31.1 to 

–15.7) p<0.0001

Day 270

ApoB

–10.8% (–22.2 to 2.3) p=0.10

–11.3% (–20.6 to 

–1.0) p=0.033

–10.9% (–20.3 to 

–0.6) p=0.040

Triglycerides

-28.3% ( –40.5 to

 –13.6) p=0.0005

–42.5% (CI –50.5 to –33.2) p<0.0001

-44.8% (–52.5 to 

–35.9) p<0.0001

VLDL-C

–26.7% (–40.3 to 

–10.1) p=0.0031

–43.2% (–51.7 to 

–33.1) p<0.0001

–43.5% (–52.0 to 

–33.4) p<0.0001

LDL-C

6.5% (–8.4 to 23.7)

p=0.041

–9.5% (–19.7 to 2.1) p=0.10

–5.4% (–16.2 to 6.7) p=0.36

Non-HDL-C

–4.1% (–15.2 to 8.5) p=0.51

–19.7% ( –27.2 to 

–11.3) p<0.0001

–19.4% (–27.0 to 

–11.0) p<0.0001

Solbinsiran was generally well tolerated with a similar incidence of adverse events across all three doses and placebo groups. There was a reduction from baseline to day 180 in hepatic fat in all dose groups (by 26.8% for 100 mg, 42.4% for 400 mg, and 35.9% for 800 mg; all p<0.0001).

Author conclusions

Solbinsiran 400 mg reduced apoB in patients with mixed dyslipidaemia and was generally well tolerated. The impact of solbinsiran on cardiovascular outcomes remains to be investigated.

Comment

Even when LDL-C is well controlled, patients with mixed dyslipidemia remain at high residual cardiovascular risk associated with elevated levels of triglyceride-rich lipoproteins and remnant cholesterol (1-3).  To date, however, few treatments targeting elevated triglycerides have demonstrated reduction in cardiovascular events in randomized clinical trials, underlining the need for new therapeutic approaches. ANGPTL3, which plays an important role in regulating triglyceride-rich lipoprotein metabolism, has attracted attention as a potential target, supported largely by evidence from genetic studies (4-7). 

 

While results with vupanorsen, an ANGPTL3 antisense oligonucleotide, raised hepatic safety concerns due to increased hepatic fat fraction and marked elevations in liver aminotransferases, leading to termination of development (8), alternative approaches using RNA interference have shown encouraging results (9). The latest of these agents, solbinsiran, was developed to inhibit hepatic translation of ANGPTL3 messenger RNA and in early studies in humans showed significant reductions in all atherogenic lipoproteins in mixed dyslipidemia (10). 

 

In the current study, solbinsiran 400 mg resulted in sustained reductions in  atherogenic lipids and lipoproteins (apoB, triglycerides, non–-HDL-C, and LDL-C) and was well tolerated, with no adverse hepatic safety signal. These findings support further evaluation of solbinsiran in patients with mixed dyslipidaemia at high cardiovascular risk. 

 

References

  1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
  2. Langsted A, Madsen CM, Nordestgaard BG. Contribution of remnant cholesterol to cardiovascular risk. J Intern Med 2020;288:116-27.
  3. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies — a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
  4. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377: 222–32.

5 Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69: 2054–63.

  1. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.
  2. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.
  3. Bergmark BA, Marston NA, Bramson CR, et al. Effect of vupanorsen on non-high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol:TRANSLATE-TIMI 70. Circulation 2022; 145: 1377–86.
  4. Kosmas CE, Bousvarou MD, Tsamoulis D, et al. Novel RNA-Based Therapies in the management of dyslipidemias. Int J Mol Sci 2025; 26: 1026.
  5. Ray KK, Linnebjerg H, Michael LF, et al. Effect of ANGPTL3 inhibition with solbinsiran in preclinical and early human studies. J Am Coll Cardiol 2025; doi.org/10.1016/j.jacc.2025.03.005. . 

Key words: Solbinsiran; ANGPTL3; apolipoprotein B; mixed dyslipidemia