AIT-082 NeoTherapeutics Inc.
AIT-082 (an analog of hypoxanthine) is an orally-active nerve growth factor (NGF) agonist under development by NeoTherapeutics as a potential treatment for Alzheimer's disease (AD), stroke and motor neuron disease. A phase II safety and efficacy trial in AD, originally scheduled to begin in the summer of 1997 [283677], began in May 1998 [286975,285562]. The study will enroll more than 60 AD patients [286975]. In February 1998, NeoTherapeutics began a phase I multiple-dose pharmacokinetic study of AIT-082 in 24 healthy elderly volunteers. Subjects of the phase I study will be administered AIT-082 once a day for 7 consecutive days at doses of 100 to 2000 mg per dose [279422]. A limited double-blind, placebo-controlled phase I/II trial in 10 AD patients commenced in Canada in the first quarter of 1997. Treatment with 4000 mg improved memory in 60% of the patients within 3 h, as determined by the word recall test. A decrease in memory was observed in 80% of placebo-treated patients [257132]. A phase I US trial, conducted by the Alzheimer's Disease Cooperative Study, with funding from the National Institute of Aging, began in July 1997. AIT-082 was administered to eight healthy, elderly volunteers as part of an escalating single-dose study. Oral administration of AIT-082 was well-tolerated at high doses [284325] AIT-082 also enhanced memory function in both young adult and aged mice within 2 h of oral administration. Prophylactic treatment prevented or delayed the onset of age-induced memory deficits in mice when administered in drinking water. When memory impairment was produced by brain lesions, the drug restored memory performance and increased the genetic expression of neurotrophin-3 (NT-3), a natural protein growth factor associated with nerve cell function [284325]. AIT-082 appears to have at least three effects on the growth of PC-12 cells in culture. Firstly, it stimulates outgrowth of neurites, secondly it potentiates the growth effects of neurotrophin, and thirdly, it stimulates the synthesis of certain neurotrophins (nerve growth factor, neurotrophin-3 and fibroblast growth factor) and pleiotrophins by astrocytes. These progrowth mechanisms are thought to form the basis of the ability of AIT-082 to restore and prevent age-related working memory deficits in mice [195438]. In October 1997, further preclinical results were presented, demonstrating that treatment with AIT-082 produced an increase in neurotrophic factors following spinal cord injury in rats. This study was conducted at NeoTherapeutics and McMaster University, and was partially funded by the Amyotrophic Lateral Sclerosis Society of Canada. After 7 days of treatment, rats with spinal cord injuries showed an increase in the levels of CNTF and BDNF, naturally occurring growth factors in the spinal cord [267514].
Geerts
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Director of Cell Physiology, Life Sciences, Janssen Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium. hgeerts@janbelc1.ssw.jnj.com