Periodic Reporting for period 1 - RESTORE VISION (Novel advanced and repurposed therapeutics for vision restoration in a group of severe rare ocular surface diseases: from validation to first clinical investigations)
Reporting period: 2023-05-01 to 2024-10-31
In Europe, approximately 30 million people suffer from blindness and visual impairment. Rare Eye Diseases (REDs) are a major cause of visual impairment and blindness affecting patients of all ages. Currently, many REDs have few treatments available which are often ineffective and cause significant side effects. To tackle this medical need, RESTORE VISION will create and test new treatments for 7 REDs affecting the cornea and ocular surface affecting over 500k patients in Europe. Onset and progression of these REDs is characterised by overlapping physiological mechanisms: defective corneal wound healing, nerve deterioration, issues with stem cell function and abnormal vessel growth. RESTORE VISION aims to improve eye health by better understanding rare disease mechanisms of action, using rare disease models to test novel and repurposed compounds, applying topical drugs in preclinical models of 7 REDs and conducting pioneering first-in-human studies to ensure their safety and effectiveness. New therapeutics with significant potential will be evaluated for the first time. Our pioneering ‘streams’ approach is based on the repurposing of existing drugs and the development of new compounds all with solid preliminary data showing remarkable effects in restoring the cell physiology, immune, avascular, neural and signalling environment in the cornea. This innovative approach aims to short circuit lengthy and complex regulatory and drug development processes, ensuring rapid translation into the clinic.
To investigate therapeutic targets in human samples and mechanism of action in RED models a clinical ethics protocol was initially prepared by OSR and further defined by the other clinical partners, INS and UKK, following local regulations. Following the OSR Ethics approval the clinical study in Italy has initiated, thirteen study participants have been enrolled to date and the biological samples were collected and stored in the OSR Biobank. Local Ethics approvals are expected at the other 2 centres in INS and UKK by Q2/25. Partner INS leads on studies to develop eye drop or periocular formulations and to test the RESTORE VISION compounds for in vitro and in vivo toxicity. Review of approved ophthalmic excipients resulted in a recently published scientific manuscript. Collaboration with our subcontracting partner FAREVA enabled the development of preservative-free formulations for Spironolactone, Aprepitant, and Losartan, addressing challenges such as improving Spironolactone viscosity and overcoming Aprepitant solubility issues. For the in vivo toxicity studies, ethics committee approval has been obtained. INS conducted in vitro assays in various cell lines and proceeded with preliminary toxicity studies to screen the RESTORE VISION drugs. In vitro and In vivo models for REDs have been established at the different partner sites and new and repurposed drugs are being evaluated for therapeutic activity in RED models. MSC-EVs have been shown to enhance corneal epithelial wound healing. Application of Prima-1Met significantly inhibited corneal opacification in a pre-clinical model for EEC. Duloxetine has been tested in an Aniridia mouse model. Despite positive pre-clinical results in a 7 day model, therapeutic efficacy has not been observed with a longer treatment regime in an advanced stage of the disease with the drug concentration tested, and more pre-clinical work needs to be performed with testing of higher dosages and in an earlier stage of disease. Olisens has shown therapeutic efficacy in several pre-clinical mouse models. Additional therapeutic efficacy data have been received for topical and systemic application of Spironolactone. In OSR novel pre-clinical data for target expression for Aprepitant and Fosaprepitant indicate a potential time frame treatment window. The possible mechanism of action has already been investigated for most of the RESTORE VISION drugs. For the most promising advanced therapeutic drug candidates (stream 2a drugs), clinical studies have been designed and further promising candidates from preclinical testing (stream 2b drugs) were identified and defined at the M18 Interim results meeting on 04/12/24. In UKK and OSR clinical trial applications are anticipated in Q2/25, with applications in INS to follow regulatory advice. A project Regulatory Roadmap was developed, which identified preliminary questions to be addressed prior to an orphan drug designation (ODD) application and documented the current regulatory status of each of the RESTORE VISION drugs. Exploitation pathways will be crystallised during the course of the project but an IPR expert is already working with partner KOL to discuss IPR activities. Optimal exploitation pathways and licensing opportunities will be discussed with KOL planning a series of exploitation workshops later in the project to include all relevant parties.
RESTORE VISION’s ground-breaking research advances beyond the state-of-the-art by validating novel drug targets for 7 REDs and identifying mechanisms of action, generating new drug formulations for novel and repurposed drugs, building a novel in vitro and in vivo preclinical RED testing platforms that have never been used before in REDs, evaluating new molecules that have never been tested or used in humans and conducting multiple first-in-human trials. In the first 18 months we have made significant concrete steps already towards project impacts. Successful development of novel or repurposed drugs for REDs will achieve impact upon selected targeted stakeholder groups (e.g. patients, clinicians, research community) in addition to having an overall scientific, economic and societal impact. This work will have major implications for the lives of RED patients. For many of the REDs addressed in this project, there exist no current therapies. The cost-effective treatment strategies proposed here will contribute directly to medical treatment becoming available for many RED patients for the first time, leading to increased quality of life. This is particularly profound given that some of the REDs in RESTORE VISION are congenital and progressive, resulting in lifelong and increasing complications for RED patients.