Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers

First phase 1 clinical study of FGLL (FG-Loop, "fibroblast growth-like loop") — synthetic 15-amino-acid peptide derived from the second fibronectin type III domain of the neural cell adhesion molecule (NCAM). The peptide was designed to mimic the NCAM-FGFR interaction, activating the FGF receptor to promote synaptic plasticity, neuroprotection and neural regeneration — therapeutic profile relevant to Alzheimer's disease.

The design was an open-label, dose-escalation study conducted over 8 days, involving 24 healthy male adult volunteers (mean age 42 years, range 24-55). Each sequential cohort received single intranasal dose of 25, 100 or 200 mg of FGLL. Primary outcomes were local and systemic tolerability, safety (ECG, vital signs, laboratory) and plasma pharmacokinetics.

Results were favorable to continued clinical development. All three doses were well tolerated, without clinically significant abnormalities in ECG, vital signs or laboratory tests. Only 5 adverse events were reported in 3 subjects (13%): transient nasal burning sensation (<3 min, in 2 subjects at the 200 mg dose) and watery eyes (<2 min, in 1 subject at the 25 mg dose). Pharmacokinetics was dose-proportional: mean Cmax 0.52 ng/mL (100 mg) and 1.38 ng/mL (200 mg); mean AUC₂₄ 1.27 and 4.05 ng·h/mL, respectively. At the 25 mg dose, plasma concentrations were below the detection limit.

This work established the feasibility of the intranasal route for FGLL and provided the basic pharmacokinetic parameters for planning phase 2 studies in Alzheimer's patients. FGLL had a complex clinical trajectory — initially developed by Enkam Pharmaceuticals and subsequently abandoned — but continues to be the subject of preclinical research in neurodegeneration, cerebral ischemia, epilepsy, and neonatal hypoxic-ischemic encephalopathy models. This article remains the only significant human clinical reference for the peptide.