title: Implications of retinal effects observed in chronic toxicity studies on the clinical development of a CNS-active drug candidate.
abstract: The development path described for JNJ-26489112 provides perspectives on interpretation of retinal effects observed in nonclinical studies and their implications for clinical development. JNJ-26489112 is a CNS-active investigational drug that has potential as a novel treatment for treatment-resistant and bipolar depression, epilepsy, and neuropathic/inflammatory pain. In a 6-month toxicity study in albino rats, retinal atrophy was observed at supratherapeutic exposures to JNJ-26489112. The histopathological changes and topography of the lesions were characteristic of light-induced damage specific to albino rats. The species/strain specificity is supported by an absence of any ocular effects in dogs and in pigmented and albino rats, housed under standard and reduced lighting, respectively. To further evaluate its potential to cause ocular effects, in vivo functional and structural ocular analyses were included in a 9-month monkey toxicity study. Reductions in rod- and cone-mediated electroretinograms were observed at supratherapeutic exposures but without any histopathologic changes. These data suggested that the effects of JNJ-26489112 in monkeys were neuromodulatory and not neurotoxic. Taken together, data related to the light-induced atrophy in albino rats and reversible neuromodulatory effects in monkeys, supported the safe evaluation of JNJ-26489112 in a clinical proof-of-concept study that included comprehensive functional and structural ocular monitoring.
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Department: 1000 Route 202 South, Raritan, NJ 08869, USA. Electronic address: geichenb@its.jnj.com.
authors.forename: G
authors.initials: G
authors.lastname: Eichenbaum
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Department: 1000 Route 202 South, Raritan, NJ 08869, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, PO Box 776, Welsh & McKean Roads, Spring House, PA 19382, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Kelley
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Roosen
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Department: 1000 Route 202 South, Raritan, NJ 08869, USA.
authors.forename: P
authors.initials: P
authors.lastname: Costa-Giomi
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, PO Box 776, Welsh & McKean Roads, Spring House, PA 19382, USA.
authors.forename: C
authors.initials: C
authors.lastname: Louden
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Department: 1000 Route 202 South, Raritan, NJ 08869, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Di Prospero
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA.
authors.forename: G
authors.initials: G
authors.lastname: Pandina
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Singh
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ford
authors.affiliation: Janssen Research & Development, LLC, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Moyer
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave F4/336, Madison, WI 53792-3220, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Nork
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave F4/336, Madison, WI 53792-3220, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Ver Hoeve
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Aguirre
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D004146:Dioxanes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D004285:Dogs; D004596:Electroretinography; D005260:Female; D008027:Light; D008252:Macaca fascicularis; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000473:pathology*; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*
chemical_list: D002491:Central Nervous System Agents; D004146:Dioxanes; C585982:N-((6-chloro-2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)sulfamide; D013449:Sulfonamides
keywords: Drug development; Electroretinogram; Ocular; Retina; Risk assessment