Tolerability, Safety and Pharmacokinetics of the FGLL Peptide, a Novel Mimetic of Neural Cell Adhesion Molecule, Following Intranasal Administration in Healthy Volunteers
ABSTRACT 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.
To determine the tolerability, safety and pharmacokinetics of ascending, single intranasal doses of FGL(L) 25, 100 and 200mg in healthy subjects.
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.
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).
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.
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- "Although FGL did show benefits in Aβ-injected rats, to our knowledge it has not been tested in published AD mouse models. FGL showed no toxicity in rats, dogs or monkeys in preclinical studies, and an 8-day safety trial in 24 males of one intranasal FGL dose showed no serious adverse effects (Anand et al. 2007). In Europe, FGL is currently in clinical trials in AD patients, scheduled to end in 2014 (Development of a novel FGL therapy and translational tests for regenerative treatment of neurological disorders 2012). "
ABSTRACT: Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.Journal of Neuroimmune Pharmacology 09/2013; 9(2). DOI:10.1007/s11481-013-9501-5 · 4.11 Impact Factor
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- "FGL was able to revert neuropathological changes and cognitive impairment that occurred (Klementiev et al., 2007), whilst rats undergoing training in fear-conditioning tasks or water maze learning exhibited long-lasting facilitation of memory after posttraining injections of FGL (Cambon et al., 2004). Currently, the compound has passed initial safety tests in preclinical (rats, dogs) and Phase I clinical trials (Anand et al., 2007). Digressing from NCAM mimetics, Schwann cells engineered to express PSA-NCAM (encoding sialyl-transferase X which adds PSA on to NCAM) when transplanted rostrally into lesioned spinal cord in a mouse model of spinal cord injury, show a remarkable ability to migrate into and fully populate the injury site, differentiating into a myelinating state as well as promoting endogenous Schwann cells recruitment from the periphery and contributing to remyelination . "
ABSTRACT: Neural cell adhesion molecule (NCAM) has been studied extensively. But it is only in recent times that interest in this molecule has shifted to conditions such as Alzheimer's disease, Multiple Sclerosis and Schizophrenia, focusing on its role in neurodegeneration and abnormal neurodevelopment. NCAM is important in neurite outgrowth, long-term potentiation in the hippocampus and synaptic plasticity. Reduced as well as increased levels in NCAM have been linked to pathology in the brain suggesting that a shift in the equilibrium may be the key. Hence, increasing our understanding of the role of NCAM in health and disease should clear some of the ambiguity surrounding the molecule and even lead to newer potential therapeutic targets. This review consolidates our current understanding of NCAM, focusing on the consequences of dysregulation, its role in neurodegenerative and neurodevelopmental disorders, and the future of NCAM plus potential options for therapy. Copyright © 2012 Elsevier B.V. All rights reserved.Multiple Sclerosis and Related Disorders 01/2013; 2(1):13–20. DOI:10.1016/j.msard.2012.08.002 · 0.88 Impact Factor
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- "The injected form of the peptide is dimeric and consists of two FGL monomers linked at the N-terminal. This dimeric form was previously selected for clinical development (Anand et al., 2007). "
ABSTRACT: Neuroglial activation is a typical hallmark of ageing within the hippocampus, and correlates with age-related cognitive deficits. We have used quantitative immunohistochemistry and morphometric analyses to investigate whether systemic treatment with the Neural Cell Adhesion Molecule (NCAM)-derived peptide FG Loop (FGL) specifically alters neuroglial activation and population densities within the aged rat hippocampus (22 months of age). A series of 50 μm paraformaldehyde/acrolein-fixed sections taken throughout the dorsal hippocampus (5 animals per group) were immunostained to detect astrocytes (GFAP and S100ß) and microglial cells (CD11b/OX42 and MHCII/OX6), and analysed using computerised image analysis and optical segmentation (Image-Pro Plus, Media Cybernetics). FGL treatment reduced the density of CD11b+ and MHCII+ microglia in aged animals, concomitant with a reduction in immunoreactivity for these phenotypic markers. FGL treatment also markedly reduced GFAP immunoreactivity within all hippocampal subfields in aged animals, without exerting an appreciable effect on the density of S100ß+ cells. These results demonstrate that FGL can indeed regulate neuroglial activation and reduce microglial cell density in the aged hippocampus, and support its potential use as a therapeutic agent in age-related brain disorders.Experimental Neurology 12/2011; 232(2):318-28. DOI:10.1016/j.expneurol.2011.09.025 · 4.70 Impact Factor