T.M. Nork

Effect of H-7 and Lat-B on Retinal Physiology

Purpose: To investigate the effects of H-7 and Latrunculin B (Lat-B) on retinal vascular permeability and electrophysiology at concentrations that increase outflow facility in monkeys. Methods: One eye of 1 rhesus and 22 cynomolgus monkeys received an intravitreal bolus injection of H-7 or Lat-B; the opposite eye received vehicle. Multifocal electroretinograms (mfERGs), and photopic and scotopic full-field electroretinograms (ffERGs, sERGs) were recorded in subsets of monkeys at baseline and at multiple time-points post-H-7 or Lat-B. Vitreous fluorophotometry (VF) and fluorescein angiography (FA) were also performed. Results: No differences between the H-7 or Lat-B treated and control eyes were found in ffERGs, mfERGs, sERGs, or in FAs in any monkey. No significant difference was found in vitreous fluorescein levels between H-7 treated or Lat-B treated vs. control eyes. Conclusions: No effect on retinal vascular permeability or retinal electrophysiology was apparent after intravitreal administration of H-7 or Lat-B at doses that increase outflow facility and lower IOP when given intracamerally.

Implications of retinal effects observed in chronic toxicity studies on the clinical development of a CNS-active drug candidate

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.