AON is an acute inflammation of the optic nerve that leads to loss of myelin covering the optic nerve and the axons. At the onset of AON, patients often suffer from ocular pain increasing with eye movement, associated with a variety of visual impairments.
AON is associated with deterioration of visual acuity, color vision and presence of flashing lights. The loss of vision ranges considerably between patients from mild blurring to loss of perception of light. The condition tends to worsen over the first several days before starting to improve over the first two weeks. The recovery continues for as long as a year after onset.
When the inflammation recedes, remyelination often occurs but it is incomplete. Without the myelin sheath which normally protects the axon, neurons located in demyelinated segments become fragile and prone to death. Unfortunately, damaged axons cannot regrow, leading to permanent disability. Neuronal death in AON can be visualized using SD-OCT, where thinning of the retinal neural fiber layer (“RNFL”), which is made up of unmyelinated axons of the retinal ganglion cell (“RGC”) bodies, indicates significant AON-induced axonal loss. Thinning of RNFL and RGC layers correlates with diminished scores of visual acuity and visual field.
Corticosteroids have become the current standard of care, as the therapy acts to shorten the attack and accelerate recovery of acute visual symptoms. However, no therapeutic is currently approved that preserves vision and ganglion/retinal nerve integrity after an acute episode of AON.
OCS-05 has a novel mechanism of action (MoA) which activates Serum-Glucocorticoid Kinase-2 (SGK-2). It is hypothesized that SGK-2 is part of the neurotrophic factor signaling pathways, to support neuronal cell development, survival, and repair, including oligodendrocyte precursor differentiation and myelination. SGK-2 activation leads to: an upregulation of signaling molecules forkhead box O3 (FOXO3); which reduces apoptosis, the downregulation of glycogen synthase kinase 3 beta (GSK3B), which improves anti-oxidation; and an upregulation of N-myc downstream-regulated gene 1 (NDRG1) involved in oligodendrocyte development and differentiation.
Disease modulating activity of OCS-05 may distinguish it as a potential treatment for ophthalmic diseases involving neurological damage.
Pre-clinical studies suggest that OCS-05 is neuroprotective and has remyelinating activity. A European Phase 1 clinical trial (with 48 healthy volunteers) showed that OCS-05 was well tolerated with good pharmacokinetics (PK) correlation with its pre-clinical animal studies.
The results of these studies has enabled the advancement of OCS-05 into a First-in-Patient clinical proof-of-concept trial. The Acute OptiC NeUrITis of DemYelinating Origin (ACUITY) trial, a randomized, double-masked, placebo controlled, multiple center trial, is enrolling patients diagnosed with AON.
Positive outcomes in this trial could support the development of the compound for potential application in the treatment of other neuro-ophthalmic conditions including glaucoma, geographic atrophy, diabetic retinopathy, and neurotrophic keratitis.