Abstract: FR-PO0833
First-in-Human Trial of XH-S003, a Small Molecule Complement Factor B Inhibitor, Shows Favorable Pharmacokinetics and Complete Suppression of Alternative Pathway in Healthy Volunteers in Australia
Session Information
- Glomerular Clinical Trials: From Data to Impact
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Newchurch, Jonathan, CMAX Clinical Research Pty Ltd, Adelaide, South Australia, Australia
- Li, Xiang, Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd., Shanghai, China
- Wang, Xingli, Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd., Shanghai, China
- Xiao, Yue, Beijing Fosun Pharmaceutical Research and Development Co., Ltd, Beijing, China
- Liu, Zhihua, Beijing Fosun Pharmaceutical Research and Development Co., Ltd, Beijing, China
- Zhou, Chao, Beijing Fosun Pharmaceutical Research and Development Co., Ltd, Beijing, China
- Hu, Lin, Beijing Fosun Pharmaceutical Research and Development Co., Ltd, Beijing, China
- Chen, Cheng, Beijing Fosun Pharmaceutical Research and Development Co., Ltd, Beijing, China
Background
The aberrant activation of alternative pathway (AP) of complement system contributes to inflammation and glomerular damage in multiple renal disorders, such as immunoglobulin A nephropathy and C3 glomerulopathy. XH-S003 is a highly selective and potent complement factor B inhibitor, which has demonstrated effective suppression of AP and terminal complement activation in vitro. The efficacy in a passive Heymann nephritis rat model suggested the potential of XH-S003 to treat patients with glomerular damage.
Methods
This is a first-in-human Phase I study conducted in Australia, including single ascending dose (SAD), multiple ascending dose (MAD) and food effect (FE) components to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of XH-S003 in healthy volunteers. AP activity was measured via the Wieslab assay and fragment Bb levels were determined with a validated commercial ELISA kit.
Results
A total of 77 healthy volunteers were enrolled and administered XH-S003 orally. It was well tolerated at all doses, from 25 mg to 1000 mg (SAD) and from 25 mg to 150 mg QD for 14 days. There were no deaths, serious adverse events (AEs) nor treatment-related AEs leading to drug withdrawal or study discontinuation. Most AEs were mild, with no dose-dependent effects. XH-S003 exhibited rapid-onset and sustained suppression of AP activity, achieving >95% inhibition within 1–2 hours (hrs) (SAD) and nearly 100% inhibition over 24 hrs at steady state (MAD). Levels of fragment Bb decreased rapidly by around 50% relative to baseline within 1 hr, with a dose-dependent and persistent effect at steady state (>12 to 72 hrs). PK studies showed rapid drug absorption, moderate clearance and no evidence of food effect with high-fat meal. The terminal half-life was about 31.9-45.6 hrs, supporting the once daily dosing. Inhibition of AP was correlated with plasma concentration of XH-S003 without delay.
Conclusion
Overall, XH-S003 is safe and well-tolerated as a single dose up to 1000 mg and as multiple doses up to 150 mg for 14 days. In addition, it exhibited rapid-onset, sustained and dose-dependent AP suppression and a favorable PK profile. These results support further clinical development of XH-S003. (NCT05946876)
Funding
- Commercial Support – Fosun Pharma and S-INFINITY Pharmaceuticals Co., Ltd