Introduction
Chemotherapy-induced diarrhea (CID), a dose-limiting toxicity impairing treatment adherence and anticancer efficacy, lacks targeted prophylaxis. While short-acting glucagon-like peptide-2 (GLP-2) analog was approved for short bowel syndrome (SBS), the mucosal regenerative properties of GLP-2 suggest therapeutic potential for CID prevention. GLP-2 can also enhance the intestinal mucosal barrier and may provide a new treatment option for inflammatory bowel disease (IBD). In this study, we developed FT1, a long-acting GLP-2 analog engineered for sustained exposure, and reported first-in-human phase I trial data of FT1 in Chinese healthy adults.
Aims & Methods
This randomized, double-blind, placebo-controlled, single-center phase I study (NCT06610487) evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of FT1 to establish dosing rationale for the future CID trials. Single ascending dose (SAD: 0.05-0.4 mg/kg) and multiple ascending dose (MAD: 0.1-0.2 mg/kg, once weekly for 3 weeks) were administered subcutaneously. Participants were randomized 3:1 (SAD; except for 0.05 mg/kg: 2:1) or 4:1 (MAD) to receive FT1 or placebo. Plasma citrulline, a validated biomarker of enterocyte mass, served as the primary PD endpoint. Safety, PK, PD, and immunogenicity were assessed up to 28 days post-dose.
Results
Currently available analyzed data (n=50) revealed:
1. PK: FT1 exhibited dose-proportional exposure (Cmax/ AUC0-inf) across SAD doses (0.05-0.4 mg/kg). Median Tmax was 24 h with prolonged t1/2 = 67.6-69.1 h. MAD regimens showed moderate accumulation (1.42- 1.73-fold post-3rd dose).
2. PD: Citrulline elevation was dose- and regimen-dependent. SAD 0.4 mg/kg achieved maximal change in plasma citrulline (ΔEmax) = 3,340 ng/mL (baseline: 5,125 ng/mL) at 8.5 days post-dose. After weekly administration of FT1, the citrulline level was further enhanced. MAD 0.2 mg/kg induced 33% greater ΔEmax vs MAD 0.1 mg/kg (4,512 vs 3,390 ng/mL; both post-3rd dose), exceeding SAD 0.4 mg/kg response.
3. Safety: All adverse events were Grade 1-2 (CTCAE v5.0) with no dose-limiting toxicities or immunogenicity signals.
Conclusion
FT1 demonstrated favorable safety and linear PK up to 0.4 mg/kg (SAD) and 0.2 mg/kg weekly×3 (MAD) in healthy participants. The 0.2 mg/kg MAD regimen achieved superior enterotrophic effects (citrulline ΔEmax) versus lower doses while maintaining tolerability, supporting it as a priority candidate for further clinical evaluation in patients with once-weekly dosing.
References
1. McQuade RM, et al. Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front. Pharmacol. 2016, 7:414.
2. Barzał J, et al. Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage. Acta Biochim Pol. 2014; 61(4):615-31
Disclosure
Chengyong Tang, Mingxue Zhu, and Lei Wan have no conflicts of interest that are directly relevant to the content of this article. Kai Fan, Qing Chen, and Yanmin Bai are Chongqing Peg-Bio Biopharm Co., Ltd employees.