A Study of Solbinsiran in Participants With Mixed Dyslipidemia - PROLONG-ANG3

Mar 31, 2025
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Author/Summarized by Author:
Luis Ortega Paz, MD, PHD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC
Trial Sponsor:
Eli Lilly and Company
Date Presented:
03/31/2025
Date Published:
03/31/2025
Original Posted Date:
03/31/2025
References

Contribution To Literature:

The PROLONG-ANG3 trial showed that solbinsiran at the 400 mg dose reduced apolipoprotein B (apoB) concentration in patients with statin-treated mixed dyslipidemia and was generally well tolerated.

Description:

The goal of the phase 2 trial was to assess the durability and efficacy of different doses of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidemia. Mixed dyslipidemia is characterized by elevated concentrations of circulating triglycerides and low-density lipoprotein cholesterol [LDL-C]).

Study Design

Participants from 41 clinical research units across seven countries were randomized in a 1:2:2:2 ratio to receive either subcutaneous doses of solbinsiran 100 mg (n=30), 400 mg (n=58), 800 mg (n=59), or placebo (n=58) on days 0 and 90. On days 0, 15, 30, 60, 90, 120, 150, 180, 210, 240, and 270, blood samples were collected to measure concentrations of ANGPTL3, apoB, total cholesterol, triglycerides, LDL-C, and high-density lipoprotein cholesterol (HDL-C).

  • Total number of enrollees: 205
  • Duration of follow-up: ≥270 days
  • Mean patient age: 57 years
  • Percentage female: 54%

Inclusion criteria:

  • Patients ≥18 years of age
  • Receiving moderate-intensity or high-intensity statins
  • BMI of 18.5-40.0 kg/m²
  • Fasting triglycerides between 1.69 mmol/L and 5.64 mmol/L
  • LDL-C of ≥1.81 mmol/L
  • Non–HDL-C of ≥3.36 mmol/L

Exclusion criteria:

  • Uncontrolled type 1 or 2 diabetes
  • NYHA class III or IV heart failure or LVEF <30%

Principal Findings:

Primary outcome:

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.

Secondary outcomes:

Dose-dependent, placebo-adjusted reductions in angiopoietin-like 3 (ANGPTL3) concentrations with solbinsiran at day 180 were –54.3% (95% CI, –63.3 to –43.1) with 100 mg, –69.8% (–74.8 to –63.9) with 400 mg, and –76.6% (–80.4 to –72.0) with 800 mg (all p<0.0001). At day 270, 180 days after the second dose, smaller but still significant placebo-adjusted reductions in angiopoietin-like protein 3 (ANGPTL3) concentrations were observed with solbinsiran.

The incidence of treatment-emergent adverse events was generally similar across groups: 60% in the solbinsiran 100 mg group, 52% in the 400 mg group, 44% in the 800 mg group, and 65% in the placebo group. The most common adverse events, occurring in >2% of patients, were COVID-19 (6%), gastroenteritis (4%), nasopharyngitis (4%), hypertension (3%), influenza (3%), urinary tract infection (3%), and injection site reaction (3%). The incidence of these events was similar between groups. Injection site reactions were generally low in the solbinsiran groups (2–5%) and were mild or moderate in severity. No deaths occurred during the study.

Interpretation:

Solbinsiran is an N-acetylgalactosamine-conjugated small interfering RNA that targets hepatic expression of ANGPTL3, a key regulator of triglyceride and lipoprotein metabolism. In the PROLONG-ANG3 phase 2 trial, solbinsiran 400 mg significantly reduced apoB by 14.3% at day 180 compared with placebo, meeting the primary endpoint in patients with mixed dyslipidemia. Solbinsiran also lowered levels of ANGPTL3, triglycerides, very-LDL-C, non–HDL-C, and LDL-C, and reduced hepatic fat fraction.

Most adverse events were mild or moderate, and no deaths were reported, suggesting a favorable safety profile. Among most common adverse events were injection site reactions and liver enzyme elevations, which were overall infrequent and transient. Given its efficacy and safety profile, solbinsiran is a promising candidate for further investigation in cardiovascular outcomes trials.

References:

Ray KK, Oru E, Rosenson RS, et al. Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidemia (PROLONG-ANG3): a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet 2025;Mar 31:[Epub ahead of print].

Presented by Dr. Kausik Kumar Ray at the American College of Cardiology Annual Scientific Session (ACC.25), Chicago, IL, March 31, 2025.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Prevention

Keywords: ACC25, ACC Annual Scientific Session, Apolipoproteins B, Dyslipidemia


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