Pharmacokinetics, Pharmacodynamics and Immunogenicity of AC02, a Novel Synthetic Derivate Peptide of Human Adrenocorticotropic Hormone for Infantile Spasms

Objectives: AC02, a novel synthetic peptide derived from ACTH, is being developed as a potential therapeutic alternative to porcine ACTH1-39 for use in infantile spasms. Methods: The study comprised single-ascending dose cohorts (0.02, 0.04, 0.08, 0.16 mg/kg AC02) and multiple-ascending dose cohorts (0.04, 0.08 mg/kg AC02 daily for 5 days). A separate positive-control arm received porcine ACTH1-39 (25 U/day for 5 days). PD effects (free and total cortisol) were compared head-to-head with the positive control. Plasma concentrations of AC02, porcine ACTH1-39, free and total cortisol were quantified by validated LC-MS/MS methods, and anti-drug antibody responses were measured using a validated electrochemiluminescence bridging immunoassay. Population PK/PD modeling characterized the concentration–response relationships for free cortisol. Results: Across the 0.02–0.16 mg/kg dose range, AC02 exhibited approximately dose-proportional pharmacokinetics and no accumulation after multiple doses. At 0.04 and 0.08 mg/kg, the baseline-corrected effects on free cortisol were generally consistent with those of porcine ACTH1-39. Dynamic monitoring of the free cortisol fraction revealed a biphasic pattern across all groups: an early peak followed by a later rise. Total cortisol, by contrast, showed only a monophasic decline, indicating the limitations of total cortisol as a sole PD biomarker. No unexpected safety signals were observed. At 0.04 mg/kg, AC02 demonstrated pharmacodynamic responses comparable to those of marketed ACTH product based on the biologically active component of free cortisol, with favorable safety and pharmacokinetic profiles. Conclusions: This first-in-human study demonstrates that AC02 has favorable pharmacokinetic properties, and an acceptable safety profile.