Two agents targeting ANGPTL3 successful at lowering lipids in phase 2 trials
Key takeaways:
- Two agents targeting angiopoietin-like protein 3 safely lowered lipid levels in phase 2 trials.
- Solbinsiran and SHR-1918 will be further studied in patients with high lipid levels in phase 3 trials.
CHICAGO — Two novel agents targeting angiopoietin-like protein 3 demonstrated safety and lipid-lowering capabilities in phase 2 trials, according to findings presented at the American College of Cardiology Scientific Session.
In the PROLONG-ANG3 trial, solbinsiran (Eli Lilly), an N-acetylgalactosamine-conjugated small interfering RNA, reduced apolipoprotein B in patients with mixed dyslipidemia. In a phase 2 trial of the monoclonal antibody SHR-1918 (Jiangsu Hengrui Pharmaceuticals Co.), the agent was associated with reductions in LDL, triglycerides and other lipids in patients with suboptimally treated hyperlipidemia.
PROLONG-ANG3
PROLONG-ANG3 included 205 patients (median age, 57 years; 54.1% women) with mixed dyslipidemia. They were randomly assigned 1:2:2:2 to solbinsiran 100 mg, solbinsiran 400 mg, solbinsiran 800 mg or placebo, Kausik K. Ray, FMedSci, director of the Imperial Centre for Cardiovascular Disease Prevention and the Imperial Clinical Trials Unit and head of ICTU-Global at Imperial College London, said during a presentation. The results were simultaneously published in The Lancet.
“For most of us, most of our atherogenic cargo is LDL cholesterol, and we have pretty good treatments for that,” Ray said during a presentation. “But there’s a whole group of people [who] have this additional cholesterol cargo ... the so-called triglyceride-rich lipoproteins. For those patients, we really haven’t seen effective therapies to reduce that and therefore reduce the risk of cardiovascular events. ... If we have loss of function of ANGPTL3, not only do we have a lower level of ANGPTL3, but we have lower levels of a whole host of lipoproteins — triglycerides, LDL, non-HDL, ApoB ... and a lower risk of cardiovascular disease, suggesting this is an important target. ... In preclinical studies, solbinsiran reduced messenger RNA for ANGPTL3 and also circulating levels of ANGPTL3. When we moved on to test that in humans, we could see that a single injection of solbinsiran in a dose-dependent fashion produced reduction in triglycerides.”
The primary outcome was percent change in ApoB at 180 days. The placebo-adjusted percent change in ApoB at 180 days was –2.8% (95% CI, –15.5 to 11.9; P = .69) for solbinsiran 100 mg; –14.3% (95% CI, –23.6 to –3.9; P = .0085) for solbinsiran 400 mg and –8.3% (95% CI, –18.3 to 2.9; P = .14) for solbinsiran 800 mg, according to the researchers.
The results for solbinsiran 400 mg were sustained to 270 days, Ray said.
Compared with placebo, solbinsiran 400 mg also lowered angiopoietin-like protein 3 (ANGPTL3) at 180 and 270 days, triglycerides at 180 and 270 days, VLDL at 180 and 270 days, LDL at 180 days, non-HDL at 180 and 270 days and HDL at 180 and 270 days, he said.
In addition, solbinsiran 400 mg and 800 mg lowered hepatic fat fraction at 180 days (P < .0001 and P = .0013, respectively), he said.
There were no deaths and few serious adverse events. The rates of treatment-emergent adverse events were 60% in the solbinsiran 100 mg group, 52% in the solbinsiran 400 mg group, 44% in the solbinsiran 800 mg group and 65% in the placebo group, according to the researchers.
“Solbinsiran was well tolerated with an extremely reassuring hepatic safety profile,” Ray said during the presentation. “The 400 mg dose in particular resulted in durable reductions in ANGPTL3 over 270 days, and this resulted in significant reductions in ApoB, triglycerides, very low-density lipoprotein and non-HDL in patients with high residual risk for future cardiovascular disease. This suggests that this particular therapy merits further evaluation in future studies.”
Phase 2 trial of SHR-1918
For the phase 2 study of SHR-1918, simultaneously published in the Journal of the American College of Cardiology, the researchers randomly assigned 333 patients with hypercholesterolemia who did not achieve optimal LDL after 4 to 8 weeks of standard lipid-lowering therapies to placebo or SHR-1918 150 mg every 4 weeks, SHR-1918 300 mg every 4 weeks, SHR-1918 600 mg every 4 weeks or SHR-1918 600 mg every 8 weeks. The mean age was approximately 58 years and about 60% of patients were men.
“LDL and triglycerides are important risk factors for CVD,” Xiaojie Xie, MD, PhD, from the department of cardiology at State Key Laboratory of Transvascular Implantation Devices of The Second Affiliated Hospital of Zhejiang University School of Medicine, in Hangzhou, China, said during a presentation. “ANGPTL3 is involved in the regulation of lipid metabolism and can reduce the clearance of triglycerides and LDL by inhibiting lipoprotein lipase and endothelial lipase. SHR-1918 is an ANGPTL3 monoclonal antibody developed to inhibit ANGPTL3 activity, thereby lowering the serum levels of triglycerides and LDL.”
At 16 weeks, compared with placebo, LDL was lowered by –21.7% in those assigned SHR-1918 150 mg every 4 weeks, –27.3% in those assigned SHR-1918 300 mg every 4 weeks, –29.9% in those assigned SHR-1918 600 mg every 4 weeks and –22.5% in those assigned SHR-1918 600 mg every 8 weeks (P < .0001 for all), Xie said.
All SHR-1918 groups had lower triglyceride levels at 16 weeks compared with placebo (P < .0001 for all), she said.
Xie said all doses of SHR-1918 conferred absolute reductions in LDL, triglycerides, ApoB and ApoA-I.
The SHR-1918 groups all had reduced non-HDL at 16 weeks compared with placebo (P < .0001 for all), but there was no effect on lipoprotein(a), Xie said.
Treatment-emergent adverse events were similar between the groups, according to the researchers.
“SHR-1918 demonstrated favorable efficacy in reducing both LDL and triglyceride levels at moderate or higher risk of atherosclerotic CVD patients, with a manageable safety profile during the core treatment period,” Xie said during the presentation. “These findings support SHR-1918 as a potential therapeutic option for hyperlipidemia on standard lipid-lowering treatment.”
References:
- Xie X, et al. Clinical and investigative horizons II. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).
- Ray KK, et al. Lancet. 2025;doi:10.1016/S0140-6736(25)00507-0.
- Xie X, et al. J Am Coll Cardiol. 2025;doi:10.1016/j.jacc.2025.03.008.
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Ray KK, et al. Featured clinical research IV. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).