Advancing Retinal Disease Therapies: Aligning Clinical Endpoints with Patient Priorities

The last day of the 24th Congress of the European Society of Retina Specialists (EURETINA 2024) saw experts discussing the clinical endpoints, performance related outcomes, standardization, new measures and current challenges in therapeutic research for inherited retinal diseases. 

Achieving meaningful clinical endpoints

First speaker Prof. Bart Leroy (Belgium) discussed the differing priorities in treating inherited retinal diseases (IRDs). 

While patients focus on slowing degeneration and improving vision, industry seeks “a return on investment,” and regulators want “real-world evidence of improvements in daily living.” He noted that patient concerns, like light perception and stability, often don’t align with regulatory measures. “There is a delta between what regulators say and what patients may say,” he said.

According to Dr. Leroy, a key challenge in developing IRD treatments is finding meaningful endpoints that are accepted by regulators like the FDA and EMA. This is complicated by the fact that “IRDs are very different in retinal structures and functions affected, visual function in early and late stages of the disease, interpatient variability of visual function, and intrapatient variability of visual function between eyes and/or between visits,” he said. 

To achieve meaningful endpoints for inherited retinal diseases (IRDs), there is a need for data from detailed longitudinal natural history studies. 

These studies should compare treatment effects with tailored outcome measures based on the most important visual activities of daily living (e.g., object recognition, reading, mobility), capturing patient experiences in a quantifiable way and adapting to age. Additionally, repeating baseline testing before commencing trials is crucial to limit later learning effects, he emphasized.

Developing performance-based outcome relevant to patient daily living

Subsequently, Dr. Colas Authie (France) discussed the importance of performance-based outcomes in evaluating patient capabilities through the MOST VR (Streetlab Vision; Paris, France) mobility test. 

He explained that the MOST VR test assessed the impact of vision impairment in rod-cone dystrophies on mobility, aiming to validate a novel mobility outcome for clinical studies. 

Using a virtual reality headset and motion capture devices, patients navigate a maze, encountering obstacles along the way. This test is designed for various age levels and is mirrored in a physical mobility course. A key innovation is a continuous performance score used to evaluate performance across age groups, eliminating noise from a potentially potent signal.

A study* that Dr. Authie did on the MOST VR test confirmed that both virtual and physical courses had the same difficulty. He noted that comparing physical and virtual mobility courses highlighted clear performance distinctions among patients and controls, demonstrating strong correlation and suggesting the virtual test can replace traditional methods. This test has been deployed in multiple global clinical studies, reflecting real-life patient challenges, he noted. 

In conclusion, Dr. Authie highlighted the necessity of validating results against physical tests to address the real-life challenges patients encounter. “I think that the approach of trying to validate against a physical test is really important,” he said.

Strengthening collaboration in rare disease research

Meanwhile, Dr. Helene Dollfus (France) emphasized the challenges and importance of addressing rare diseases like IRDs. “There are more than 6,000 low-prevalence and complex rare diseases, representing 40 million EU patients,” she noted.

“One of the philosophies of the European Reference Networks (ERN) is that not one member state alone can solve all the problems for all the rare diseases. So, the mission of the ERN is really to share care and cure and it’s a patient-centered project,” she elaborated. 

Dr. Dollfus noted that a key mission of the ERN is to promote research and innovation for all patients, and develop clinical trials and access to therapies, highlighting that ERN-EYE is dedicated to cover over 1000 rare eye diseases. 

“One main objective is really to facilitate the inclusion of patients in clinical trials and give access to innovation to as many people as possible,” she emphasized.

Introducing a new program under the Innovative Health Initiative aimed at improving clinical trials for rare diseases, Dr. Dollfus stated, “The objective is to deliver more effective tools to be holistic and inclusive.” 

This initiative, which involves the Rare Eye Disease Network (RNI), seeks to develop statistical methodologies tailored for small populations. The RNI will focus on three IRDs to enhance “epidemiological research and patient identification for clinical trials,” she said.

Another initiative, the ERICA project, aims to improve data collection across ERNs, facilitating “free access to this whole repository of all the PROMs accessible for rare diseases.”

Dr. Dollfus also emphasized collaboration among four ERNs dedicated to epilepsy, rare bone diseases, rare blood diseases and rare eye diseases. “We share all the same challenges,” she noted, highlighting the need to identify robust endpoints and develop natural history studies in the quest for improving the lives of patients with these maladies.

The urgent need for vision preservation and patient-centered care

Advanced therapies have immense potential in treating both inherited and age-related retinal diseases like age-related macular degeneration, geographic atrophy and diabetes-related eye conditions. 

These diseases create a substantial unmet need not only medically but also societally, impacting patients, caregivers and families. Avril Daly, from Retina International (Ireland), highlighted the urgency of addressing these conditions during her talk, noting, “These conditions have a very high unmet medical need, and a high unmet need in general in terms of societal perspective.”

Ms. Daly explained that current health assessments often fail to align with what patients truly value, especially in the preservation of vision. “Outcome measures do not always consider what is most valued to us as patients,” she said. 

The focus should shift towards early intervention, which can slow or prevent the progression of retinal diseases, thus improving quality of life. “There is very limited consideration to the value of vision preservation and the slowing of visual loss, which is incredibly important and life-altering when we can keep our vision,” she said.

Ms. Daly further stressed the socioeconomic toll that IRDs place on individuals and society, including limited access to education, employment and essential support systems. “The socio-economic burden of IRDs, in addition to their impact on well-being and mental health, has been felt by patients in a very real way,” she remarked.

In conclusion, she emphasized the need for healthcare systems to prioritize prevention and to recognize the value of slowing disease progression. 

“Preserving vision, even what you as sighted individuals may consider to be a very late stage, matters. It has a meaningful impact,” Ms. Daly stated, urging a stronger focus on patient-reported outcomes and lived experiences in the development of future therapies.

Editor’s Note: Reporting for this story took place at the 24th Congress of the European Society of Retina Specialists (EURETINA 2024), held from 19-22 September in Barcelona, Spain.

*Authié CN, Poujade M, Talebi A, et al. Development and Validation of a Novel Mobility Test for Rod-Cone Dystrophies: From Reality to Virtual Reality. Am J Ophthalmol. 2024;258:43-54.