From phone to phenotype: Identifying novel digital biomarkers as functional endpoints for clinical trials in inherited retinal diseases

Inherited retinal diseases (IRDs) such as retinitis pigmentosa (RP) and choroideremia (CHM) are progressive genetic eye disorders which lead to visual impairment and blindness. IRDs are a leading cause of visual impairment among paediatric and working-age adult globally, affecting at least 1 in 3000 people. For most patients, no medical or surgical treatments exist, but a large number of clinical trials are underway. Over 350 gene mutations have been identified in the underlying pathology of IRDs, resulting in gene therapy becoming an increasingly active area of clinical research. Yet, clinical trials for IRDs face significant challenges, especially in meeting regulatory standards. These trials typically rely on visual acuity (VA) as a primary endpoint, a measure which does not accurately reflect meaningful improvements in real world vision. For example, in RP and CHM initial impairment of rod photoreceptors causes night blindness and peripheral visual field loss, followed by subsequent progressive cone involvement, which leads to loss of central vision; however, this occurs over many years, and so measuring changes in VA over short periods such as 1-2 years will not yield a demonstrable difference in a trial setting. This limitation makes it difficult for trials to demonstrate efficacy, causing many trials to fail. Innovative endpoints which provide more sensitive, functional measures may increase the likelihood of clinical success and regulatory approval. The aim of this study is to validate a novel device called ‘OverSight’, a smartphone app which tracks patterns in mobility, keystrokes, and other behaviours to provide insights into how visual impairment impacts daily functioning, this is termed digital phenotyping. Digital phenotyping refers to the use of smartphones and wearables to collect patient-generated health data (PGHD). Smartphones are increasingly being used to collect health information, and monitoring these interactions can provide a detailed picture regarding a person’s overall health status. Our work to date has demonstrated that PGHD collect via OverSight, such as walking speed and typing speed, can be used as surrogate measures of visual function. Specifically, these datastreams correlate with visual functioning and can be used to remotely monitor behaviour over time, thereby providing potential digital biomarkers which can be used as functional endpoints in clinical trials. Objectives: 1. Recruit 200 patients with IRDs and collect longitudinal data on behavioural patterns via OverSight. 2. Conduct baseline and 12-month follow-up structural imaging alongside app data collection to assess structural and functional correlations in disease staging. 3. Identify which OverSight datastreams represent candidates for digital disease biomarkers and functional trial endpoints. If successful, this project has significant potential for patient benefit. OverSight could revolutionise clinical trial design by assessing patient-relevant changes which current vision assessments may overlook. OverSight addresses current challenges in clinical trials by tracking outcomes which are meaningful to patients, complementing traditional clinical parameters. This approach could enhance trial sensitivity, making disease-related changes easier to detect and ultimately accelerating the clinical trial process.