Development of a selective PI3K-Akt-activating neurotrophic small molecule drug, MT-002, for the healing of corneal wounds in Neurotrophic Keratitis.

Calista is developing topical MT-002, a selective PI3K-Akt activator that safely restores normal wound healing in a clinically predictive animal model of Neurotrophic Keratitis (NK). NK causes progressive corneal damage that can lead to corneal perforation, ulceration and blindness. NK is caused by a loss of nerve sensation from the brain to the eye, decreasing growth factor release that stimulates wound healing. Growth factor drugs promote wound healing in NK, and rNGF (Oxervate) was approved in 2017/18, but there are several problems that MT-002 solves. The PI3K-Akt pathway is activated by all growth factors that stimulate normal wound healing. Innovatively, MT-002 binds selectively to PI3K intracellularly, activating the Akt pathway. MT-002 doses induce sustained elevations in p-Akt for up to 2 days. In a NK mouse model, we topically dosed MT-002 eye drops to corneal wounds. MT-002 safely restored normal healing equivalent to rNGF. MT-002 showed no adverse safety effects in a 7-day ascending dose rabbit study. MT-002 improves on rNGF because it is safe, effective, inexpensive, stable at Room Temperature and can be dosed twice daily. This proposal will complete our in vivo testing of MT-002 with an animal model of NK that provides clinically predictive results using MT- 002 clinical dose, formulation and administration schedule. Corneal wound healing is a primary outcome in both this pre-clinical study and clinical trials, providing a measure that allows for clear decisions on efficacy. Aim 1: Synthesis of MT-002, a peptide PI3K-Akt activator with stability, bioavailability and efficacy. In order to undertake in vivo studies of Aim 2, Calista will require one large scale batch synthesis of MT-002. Deliverable 1: Synthesis of 100 mg of MT-002 peptide with andgt;95% purity and identification of peptide manufacture issues, if any, for follow-up to guide follow-on preclinical and clinical studies manufacturing. Milestone 1: Decision to proceed to Aim 2 efficacy studies. (3 mons; mons 0-3) Aim 2: MT-002 corneal wound healing efficacy in the rat trigeminal nerve model. (9 mons, mons 3-12) We will test MT-002 using the clinically predictive ‘Nishida’ model where NK is modelled by thermocoagulation of the trigeminal nerve. Clinical trials were successful in therapies that used this model. This will be undertaken in collaboration with corneal wound healing expert, Dr Rajiv Mohan at the University of Missouri. Deliverable 2: MT-002 restoring normal wound healing rates at 1-4 days post-debridement. Milestone 2: Decision to solicit a Pre-IND meeting with FDA and proceed with exploratory IND studies and any needed follow-up PK or PD characterization. Success in this proposal will complete proof of concept efficacy data with a clinically predictive model, dose form, and frequency of administration to justify IND studies in a 2-year Phase 2 SBIR proposal and/or investment. We anticipate that clinical Phase 1 safety and PK trials will be completed in 1 year, Phase 2a efficacy studies in another 1 year and we will partner for pivotal Phase 2b studies during another 2 years.Narrative Neurotrophic Keratitis is a disease that results in progressive corneal damage that can lead to corneal perforation, ulceration and blindness. Calista Therapeutics has discovered a new treatment that can restore normal wound healing. A successful therapy will have a high impact on patient health and reduce rates of blindness.