spd-502 and Neuralgia

Chronic neuropathic pain is inadequately treated using current therapies, with less than half of patients achieving clinically significant pain relief (defined as more than 50% pain reduction). In this study, we evaluated the AMPA/GluR5 receptor antagonist NS1209 for efficacy, safety, and tolerability in comparison with placebo and lidocaine for the treatment of chronic neuropathic pain and allodynia in patients with peripheral nerve injury.. A randomized, double-blind, placebo-controlled, three-way crossover study was designed to recruit patients with chronic neuropathic pain for IV treatment with NS1209 (322 mg), lidocaine (5 mg/kg), and placebo. Measures of spontaneous current pain and pain evoked by brush, pinprick, cold, and heat stimulation were performed at screening and at 0, 2, 4, 6, 8, and 24 h after the start of the treatment session.. Thirteen patients completed the study. Neither NS1209 nor lidocaine showed a statistically significant effect over placebo on the primary end-point spontaneous current pain, but both compounds exhibited a statistically significant effect on the secondary end-point pain relief of overall spontaneous pain compared with placebo. Similar to lidocaine, NS1209 was superior to placebo in alleviating some key symptoms of neuropathic pain, i.e., evoked types of pain, including mechanical and cold allodynia.. These findings are consistent with those reported for NS1209 in other models of pain and suggest that there is a role for AMPA receptor involvement in neuropathic pain in humans. Furthermore, NS1209 was safe and well tolerated at the given doses with a safety profile similar to placebo.

Topics: Adult; Aged; Analgesia; Anesthetics, Local; Chronic Disease; Cross-Over Studies; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Humans; Hyperalgesia; Infusions, Intravenous; Lidocaine; Male; Middle Aged; Neuralgia; Pain Measurement; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Pyrroles; Receptors, AMPA; Receptors, Kainic Acid; Tetrahydroisoquinolines; Time Factors; Treatment Outcome; Young Adult

Preclinical Research The selective AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist, NS1209 (also known as SPD 502) has been explored in several research and development campaigns since its selection as a lead drug candidate in the early 1990s by the Danish biotechnology company, NeuroSearch. The compound was successively tested in animal models of stroke, neuropathic pain and epilepsy. The preclinical data to support development for the treatment of stroke were incomplete, as the compound was administered after the stroke episode, and did not protect subcortical areas of the brain. Preclinical data for neuropathic pain and epilepsy appeared more promising, but the design of the Phase IIa studies in both indications was suboptimal, and an exploratory study in neuropathic pain, like one in refractory epilepsy gave inconclusive results. Preclinical data in pain models were much less convincing than reported by the authors in abstract and discussion sections. Due to a long preclinical sequential testing phase and insufficiently powered clinical trials, NS 1209 disappeared from the CNS development pipeline, while its patent protection exclusivity was markedly reduced due to the unfortunate slow speed in development-a phenomenon far from unusual in CNS drug discovery. NeuroSearch ceased operations as an R&D entity in 2012 and its R & D portfolio was transferred to Teva Pharmaceuticals and to a spin off, Saniona A/S. Based on an in-depth case analysis of the development of NS 1209, a number of recommendations are given to reduce chances of failure during clinical development of neuropathic pain compounds and, more generally, of CNS compounds. Drug Dev Res 78 : 75-80, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Epilepsy; Humans; Neuralgia; Pyrroles; Receptors, AMPA; Stroke; Tetrahydroisoquinolines; Treatment Outcome