SHR-1918 — a fully human ANGPTL3 monoclonal antibody developed by Jiangsu Hengrui Medicine — demonstrates a 64.2% reduction in LDL-C relative to placebo in homozygous familial hypercholesterolemia (HoFH) patients in a Phase III study presented as a Late-Breaking Abstract at the ESC 2026 Congress.
• ESC 2026 LBA — Late-Breaking Abstract presentation
• Fully human ANGPTL3 monoclonal antibody — first-in-class approach for HoFH
• 64.2% LDL-C reduction vs placebo at week 12
• Favorable safety profile — comparable to placebo
• Developed by — Jiangsu Hengrui Medicine
Introduction: The Unmet Need in HoFH
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder affecting approximately 1 in 300,000 individuals worldwide. Patients with HoFH have severely elevated LDL-C levels — often exceeding 10 mmol/L — due to mutations in both alleles of the LDL receptor gene. These patients experience accelerated atherosclerosis and often suffer from cardiovascular events in early childhood or adolescence.
Traditional lipid-lowering therapies — statins, ezetimibe, and PCSK9 inhibitors — are largely ineffective in HoFH because they depend on functional LDL receptors for their mechanism of action.
ANGPTL3 (angiopoietin-like protein 3) is a liver-secreted protein that inhibits lipoprotein lipase and endothelial lipase. ANGPTL3 inhibition reduces LDL-C through an LDL receptor-independent mechanism, making it a promising target for HoFH.
At the ESC 2026 Congress, investigators presented the Phase III results of SHR-1918 — a fully human ANGPTL3 monoclonal antibody developed by Jiangsu Hengrui Medicine — demonstrating significant LDL-C reduction in HoFH patients.
Mechanism of Action
SHR-1918 is a fully human IgG4 monoclonal antibody that binds with high affinity to ANGPTL3, neutralizing its activity. ANGPTL3 inhibition:
- Increases lipoprotein lipase activity — enhancing clearance of triglyceride-rich lipoproteins
- Reduces hepatic VLDL production — decreasing secretion of apolipoprotein B-containing lipoproteins
- Lowers LDL-C through an LDLR-independent pathway — providing benefit even in patients with absent LDL receptor function
Phase III Study Design
The Phase III study was a randomized, double-blind, placebo-controlled, multicenter trial conducted in patients with HoFH.
| Parameter | Details |
|---|---|
| Number of patients | 85 patients with HoFH |
| Dosing | SHR-1918 300 mg subcutaneous every 4 weeks |
| Duration | 12-week double-blind period |
| Primary endpoint | Percent change in LDL-C from baseline to week 12 |
| Key secondary endpoints | Safety, tolerability, changes in other lipid parameters |
Key Results
Primary Endpoint: LDL-C Reduction
- SHR-1918 group — mean LDL-C reduction of 64.2% from baseline at week 12
- Placebo group — mean LDL-C reduction of 0.5%
- Treatment difference — -63.7 percentage points (95% CI: -70.2 to -57.2; p < 0.0001)
Secondary Lipid Parameters
- Triglycerides — reduced by 52% from baseline
- Apolipoprotein B — reduced by 58% from baseline
- Lp(a) — no significant change (consistent with ANGPTL3 mechanism)
Safety and Tolerability
- Treatment-emergent adverse events — comparable between SHR-1918 and placebo (65% vs 62%)
- Injection-site reactions — mild and transient
- No significant liver enzyme elevations — no ALT/AST elevations above 3x ULN
- No neutralizing antibodies detected
Significance and Clinical Implications
The Phase III results of SHR-1918 have several important implications:
- First Chinese-developed ANGPTL3 inhibitor — demonstrating clinical efficacy in HoFH
- LDLR-independent mechanism — providing benefit where other therapies fail
- Subcutaneous administration — convenient every-4-week dosing
- Favorable safety profile — supporting long-term use in a rare disease population
As the investigators noted: "SHR-1918 demonstrated robust LDL-C lowering in HoFH patients with a favorable safety profile, supporting its potential as a new therapeutic option for this challenging patient population."