- Chemerin, the endogenous agonist of chemerin receptor ChemR23, a specific member of the G protein coupled receptor (GPCR) class, activates immune cells at the inflammation site.
- Chemerin activates ChemR23 on circulating monocytes and macrophages, recruiting these cells to the inflammation site.
- Chemerin is also physiologically cleaved into smaller potent anti-inflammatory peptides that reprogram macrophages to repress inflammation inducing anti-inflammatory cytokines at the inflammatory site, thus restoring normal tissue structure and function.
- OK-101, OKYO’s lead drug candidate contains a stable chemerin-derived 10-mer peptide as the active anti-inflammatory component of the drug, along with a conjugated lipid component, producing both enhanced agonist potency along with wash resistance.
- One of the major challenges with topical administration of any drug designed for treating OED is drug wash-out through natural processes of tearing and blinking, minimizing drug ‘residence’ time at the ocular site needed to provide a pharmacologic benefit.
- Membrane Anchored Peptide (MAP) technology enabled the development of a long acting and stable OK-101 drug candidate.
- OKYO’s lead drug candidate OK-101 consists of a 10-mer C-terminal chemerin peptide sequence, a linker component, and an anchoring lipid domain.
- Unique MAP technology enabled the development of a drug with enhanced potency and the expectation of increased drug residence time on the ocular surface.
Membrane Anchoring Improves Potency, and Durability
Human Chemerin Receptor
Human Chemerin Receptor
* Adapted from Doyle J et al, J. Biol. Chem. 2014
- Lipidated drug candidate OK-101 showed higher potency against human chemerin receptor than the corresponding non-lipidated OK-101.
- Signaling of lipidated OK-101 persisted despite serial washes, whereas activity of the non-lipidated OK-101 was markedly diminished.
Validation of OK-101 in Pre-clinical Dry Eye Mouse Model
- Animals induced with scopolamine to generate acute dry eye disease (DED) showed a dramatic, statistically significant increase in corneal permeability relative to naïve non-stressed animals.
- Cyclosporine, the positive control in the DED study, showed a statistically significant reduction in corneal permeability (p ≤ 0.001) in scopolamine-induced DED animals.
- OK-101’s effect in reducing DED-induced corneal permeability was virtually identical to that of the cyclosporine positive control and close to the baseline corneal permeability observed in non-stressed control animals.
- OK-101 demonstrated a similar reduction of DED-induced corneal permeability (p ≤ 0.001).
OK-101 increased mucin secreting goblet cells and reduced inflammatory CD4+ T cells
- Dry eye disease (DED) typically leads to a loss of goblet cell density as was observed following induction of DED in mice administered no drug (control vehicle).
- Topical administration of OK-101 significantly rescued the DED-induced loss of goblet cells in DED animals.
- OK-101 also demonstrated a statistically significant (p ≤ 0.01) reduction in dry-eye-induced enhancement of inflammatory CD4+ T-cells. The levels of CD4+ T cells observed in OK-101 treated animals were equivalent to the CD4+ T cell level observed in naïve untreated animals.
Ocular Pain Reducing Activity of OK-101
A significant proportion of dry eye patients suffer from “neuropathic pain” with moderate to greater pain intensity.
*Ciliary Nerve Ligation Model
*Collaboration with Dr. Pedram Hamrah, Tufts Medical Center, Boston (Kenyon et al (2020) IOVS, Vol.61, 4085
OK-101 reduced corneal pain response similar to gabapentin (GBP), a commonly used drug for neuropathic pain.
- Neuropathic corneal pain is a severe, chronic and debilitating disease with no commercially approved topical treatments currently available for this condition.
- OK-101 suppresses neuropathic corneal pain in a mouse model of neuropathic corneal pain.
- OK-101 was topically administered to mice in contrast to the positive control gabapentin which was administered via intraperitoneal injection.
- Pain relief was evaluated by an eye-wipe count, and OK-101 was shown to reduce corneal pain similar to that of gabapentin, a commonly used oral drug for neuropathic pain.
- OK-101 had no effect on corneal epithelial integrity compared to gabapentin or BSS.