Robert S. Rosenson, MD is a professor of cardiology at the Icahn School of Medicine at Mount Sinai.

Robert S. Rosenson, MD

Evinacumab May Lower Triglycerides in Severe Hypertriglyceridemia, With Robert Rosenson, MD

Evinacumab may be capable of lowering triglyceride concentrations in patients with 

 and a history of sHTG-associated acute pancreatitis (AP), according to a recent phase 2b study.

Evinacumab is a recombinant human monoclonal antibody which binds to and inhibits angiopoietin-like protein 3 (ANGPTL3), which leads to a reduction in LDL-C, HDL-C, and triglycerides. It reduces LDL-C irrespective of the presence of LDL receptors by promoting very low-density lipoprotein processing and clearance upstream of LDL formation.

“We know that individuals who have had episodes of pancreatitis are highly susceptible to having a recurrent hospitalization for pancreatitis in the next year. For these patients, the incident rate increases 24-fold,” Robert Rosenson, MD, professor of medicine and director of cardiometabolic disorders at the Icahn School of Medicine at Mount Sinai, said in an interview with 

. “These patients require our prompt attention with therapies that effectively lower triglycerides.”

Rosenson and colleagues conducted a phase 2b, randomized, double-blind, placebo-controlled study consisting of 3 periods – a screening period lasting ≥4 weeks, a double-blind treatment period of 52 weeks, and an off-drug safety follow-up of 20 weeks. Patients were eligible for inclusion if they had ≥1 of the following within 24 months prior to screening:

Fasting serum triglycerides >880 mg/dL with a history of 1 episode of HTG-associated AP

Fasting serum triglycerides >500 mg/dL with a history of ≥2 episodes of HTG-associated AP

Fasting serum triglycerides >500 mg/dL with a documented fasting triglyceride level of >1000 mg/dL and a history of ≥1 episode of HTG-associated AP

All patients were also required to be taking stable doses of lipid-lowering therapy for ≥8 weeks prior to the screening visit. Patients were excluded if they had FCS due to biallelic loss-of-function variants in LPL, if they had been hospitalized for AP within 4 weeks of screening, or if they had an AP episode within 12 weeks of screening.

Eligible patients were randomly assigned in a 1:1 ratio to intravenous evinacumab 20 mg/kg or matching placebo every 4 weeks for the duration of the 52-week treatment period. The study’s primary efficacy endpoint was the proportion of patients with ≥1 positively adjudicated episode of AP during this period. Key secondary endpoints included the percentage change from baseline to week 52 in fasting triglyceride and ApoC3 levels, as well as percentage change from baseline to week 52 in other lipid parameters like total cholesterol and non-HDL-C.

A total of 21 patients were enrolled and randomized to evinacumab (n = 11) or placebo (n = 10). However, the trial was terminated early by the sponsor. 20 patients did not complete the treatment period due to early termination (n = 16), adverse events (n = 2), patient decision (n = 1), and being lost to follow-up (n = 1). The 16 patients who discontinued due to the end of the trial terminated their treatments between days 1 and 169. Ultimately, 57.1% (n = 12) of patients completed the end-of-study visit.

The proportion of patients with ≥1 positively adjudicated AP episode during the treatment period was 27.3% (n = 3) with evinacumab versus 10% (n = 1) with placebo. All positively adjudicated AP episodes took place ≥58 days after the final dose, at which point evinacumab concentrations were near or below the limit of quantitation. Rosenson and colleagues also saw a median percentage change in triglycerides of -55.3% with evinacumab versus +1.5% with placebo. By week 16, evinacumab had reduced triglycerides by 95.7%, an effect which was maintained in 1 patient who received treatment through week 52.

Ultimately, although the sample size was too small to adequately determine whether it could prevent AP, investigators determined that the data gathered before the trial’s termination indicated evinacumab’s potential efficacy in lowering triglyceride concentrations in patients with sHTG and a history of sHTG-associated AP.

“I think this trial should encourage other pharmaceutical companies that have angiopoietin-like 3 inhibitors to explore this hypothesis with their inhibitors,” Rosenson said. “I’m not sure if this is going to be done with evinacumab again, but there are other RNA inhibitors of angiopoietin-like 3 that are in development by other companies, and this suggests that those inhibitors will have a profound effect on triglycerides and, hopefully, on the risk of acute pancreatitis.”

Rosenson RS, George RT, Sanchez RJ, et al. Efficacy of evinacumab in patients with severe hypertriglyceridemia and a history of severe hypertriglyceridemia-related acute pancreatitis: A phase 2B trial. Journal of Clinical Lipidology. Published online July 2025. 

Dingman R, Bihorel S, Gusarova V, Mendell J, Pordy R. Evinacumab: Mechanism of action, clinical, and translational science. 

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Rosenson explains the data gained from a terminated phase 2b trial, highlighting evinacumab’s potential as a triglyceride-lowering therapy.

Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), at a dose of 400 mg, achieved sustained reductions in apolipoprotein B concentration among patients with 

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, results from the Phase 2 PROLONG-ANG3 study showed solbinsiran was well tolerated, with a low incidence of adverse events, but its impact on cardiovascular outcomes has yet to be determined.

“These data related to the efficacy and the safety of the medication set the foundation for a phase three cardiovascular outcome trial,” trial investigator Robert S. Rosenson, MD, a professor of cardiology at the Icahn School of Medicine at Mount Sinai, told 

. “I'm quite excited about ANGPTL3 inhibitors as adjunctive therapy to what we have available today

Mixed dyslipidemia is characterized by raised levels of circulating triglycerides and low-density lipoprotein cholesterol (LDL) linked to an elevated likelihood of atherosclerotic cardiovascular disease (ASCVD). Solbinsiran achieved targeted reductions in both levels of triglycerides and LDL-C in a Phase 1 trial.

Investigators sought to further evaluate the therapy, specifically its durability and efficacy, in reducing concentrations of atherogenic lipoprotein in adults with mixed dyslipidemia. A double-blind, parallel-arm, randomized, placebo-controlled trial, the team enrolled adults with mixed dyslipidemia at 41 clinical units across 7 countries.

Enrollment criteria included patients receiving moderate-intensity or high-intensity statins, with concentrations of fasting triglycerides between 1.69 mmol/L and 5.64 mmol/L, LDL-C of >1.81 mmol/L, and non-HDL-cholesterol of ≥3.36 mmol/L.

Patients were randomly assigned 1:2:2:2 to either solbinsiran 100 mg or solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on Days 0 and 90. Follow-up occurred for at least 270 days in all patients. The primary outcome was the percent change in apoB concentration from baseline to Day 180 with solbinsiran, compared with placebo, as analyzed by an efficacy estimand: patients who received ≥1 dose of solbinsiran.

Among 585 screened patients, 205 were enrolled between July 2022 and March 2024. The population was more than half (54%) female, and the median age was 57 years. Randomization assigned patients to solbinsiran 100 mg (n = 30), solbinsiran 400 mg (n = 58), solbinsiran 800 mg (n = 59), or placebo (n = 58).

Baseline mean concentrations were 111 mg/dL for apoB, 2.64 mmol/L for triglycerides, and 3.16 mmol/L for LDL-C. Upon analysis, the placebo-adjusted percent change in apoB concentration at Day 180 was –2.8% (95% CI, –15.5 to 11.9; 

 =.69) for solbinsiran 100 mg, –14.3% (95% CI, –23.6 to –3.9; 

 =.0085) for solbinsiran 400 mg, and –8.3% (95% CI, –18.3 to 2.9; 

Safety analysis revealed treatment-emergent adverse events in 18 (60%) of 30 patients in the solbinsiran 100 mg cohort, 30 (52%) of 58 patients in the solbinsiran 400 mg cohort, 26 (44%) of 59 patients in the solbinsiran 800 mg cohort, and 37 (65%) of 57 patients in the placebo cohort. Notably, the 400 mg dose was associated with reductions in hepatic fat fraction of 27.6%.

“By these therapies, often we're thinking about adverse changes in the liver with statins, fibrates, and other agents. These data contrast and actually show improvement in the hepatic fat fraction,” Rosenson told 

. “I'm quite encouraged about the opportunities for some of our very difficult to treat patients.”

Learn more about the trial in an interview with Rosenson at ACC.25.

Solbinsiran Significantly Reduces apoB in Mixed Dyslipidemia in Phase 2 Trial

Ray, Kausik K 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, Volume 0, Issue 0. March 31, 2025. Accessed March 31, 2025.

Ray KK, Linnebjerg H, Michael LF, et al. Effect of ANGPTL3 inhibition with solbinsiran in preclinical and early human studies. JACC (in press) 10.1016/j.jacc.2025.03.005

At ACC.25, Robert S. Rosenson, MD, discusses the efficacy and safety of solbinsiran, an ANGPTL3 inhibitor, in a population with mixed dyslipidemia.

Robert S. Rosenson, MD

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