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

BACKGROUND

The FG loop peptide (FGL(L)), a novel mimetic of the neural cell adhesion molecule (NCAM), is in clinical development for neurodegenerative disorders such as Alzheimer's disease. Preclinical studies in rats, dogs and monkeys have demonstrated exposure in plasma and cerebrospinal fluid after parenteral or intranasal administration of FGL(L), with no systemic toxicity. This article reports on the results of the first administration of FGL(L) in humans.

OBJECTIVE

To determine the tolerability, safety and pharmacokinetics of ascending, single intranasal doses of FGL(L) 25, 100 and 200mg in healthy subjects.

METHODS

In an 8-day, open-label, phase I study, 24 healthy male volunteers (mean age 42 [range 24-55] years) received single intranasal doses of FGL(L) (25, 100 and 200mg) in accordance with an ascending dose, sequential-cohort design.

RESULTS

All three intranasal doses of FGL(L) were well tolerated and there were no clinical notable abnormalities in ECG recordings, vital signs or laboratory tests. Three subjects (13%) reported five adverse events. A transient (<3 minutes) burning sensation in the nose was reported in two subjects at the 200mg dose level while runny eyes (<2 minutes) were experienced in one subject at 25mg. These events had an onset immediately following intranasal administration, and a relationship to FGL(L) was suspected. One of the latter subjects who had experienced a burning sensation in the nose also experienced dizziness, vomiting and headache with onset >2 days after single-dose administration of FGL(L); no relationship to the study drug was suspected. Quantifiable plasma concentrations of FGL(L) were observed up to 1 hour after intranasal administration of the 100mg dose and up to 4 hours after the 200mg dose (plasma FGL(L) concentrations were undetectable at all timepoints for the 25mg dose). Increasing doses of FGL(L) were associated with higher systemic exposures: mean C(max) 0.52 ng/mL and 1.38 ng/mL (100mg and 200mg, respectively); mean AUC(24) 1.27 ng x h/mL and 4.05 ng x h/mL (100mg and 200mg, respectively).

CONCLUSIONS

Intranasal administration of FGL(L) (25, 100 and 200mg) was well tolerated in healthy male volunteers, with no safety concerns and a pharmacokinetic profile that was generally dose related. Further studies are currently being planned to evaluate the effects of FGL(L) in patients with Alzheimer's disease.