A key to gaining regulatory approval for an emerging retinal-disease therapy is quickly and accurately demonstrating that it saves or restores vision in a clinical trial. Though the goal sounds simple enough, proving that a potential treatment is working is actually difficult. That’s because commonly used measures of visual function — including visual acuity and visual fields — are not always reliable for evaluating vision changes in many people with inherited retinal conditions.
For example, visual acuity can remain stable for someone with retinitis pigmentosa (RP) for decades. While visual fields for people with RP contract over time, measuring the changes objectively is challenging; results for a given patient can vary significantly, even for the same patient on the same day.
The Foundation Fighting Blindness Clinical Research Institute (FFB-CRI) has taken a proactive role in leading the development of retinal-disease clinical-trial endpoints, including the organization of a workshop of industry leaders on November 9, 2016, to share knowledge and discuss strategies for outcome-measure validation and development.
More than two-dozen retinal-disease clinical-research experts presented at the daylong workshop on current and potential clinical-trial outcome measures that may enable therapy developers to improve study design and increase the chances for regulatory approval. Improved outcome measures will make clinical trials for degenerative retinal diseases — including age-related macular degeneration (AMD), the world’s leading cause of blindness in seniors, and inherited retinal conditions such as RP and Stargardt disease — less expensive to conduct and able to deliver more precise results. Improved endpoints would also help deliver effective treatments to patients sooner.
Meeting organizers also included the U.S. Food and Drug Administration (FDA), the National Eye Institute (NEI), and the Association for Research in Vision and Ophthalmology (ARVO). More than 150 industry professionals attended the event in Bethesda at the National Institutes of Health, while nearly 200 other attendees from around the world participated through a webcast.
“With several potential treatments in development for retinal conditions, many of which are in, or advancing into, human studies, the need for clinical trial outcome measures is paramount,” says Patricia Zilliox, PhD, FFB-CRI chief drug development officer. “We were very pleased to help organize this meeting to share critical information about endpoints, and advance them for use in human studies for vision-saving treatments.”
Several researchers funded by FFB-CRI presented data on promising clinical trial endpoints for inherited retinal conditions. They included David Birch, PhD, at the Retina Foundation of the Southwest, who reviewed patient studies of ellipsoid zone (EZ) area, a measure of viable photoreceptors obtained through optical coherence tomography (OCT) imaging. EZ Area is an outcome measure that closely correlates with vision changes and may help researchers quickly determine if an emerging therapy is saving vision for people with RP in a clinical study.
Hendrik Scholl, MD, at the University of Basel, showed that measuring fundus autofluorescence (FAF) may be effective for quickly and precisely evaluating disease progression and the vision-preserving effect of potential therapies in clinical trials for people with Stargardt disease. FAF correlates with the accumulation of lipofuscin, the damaging, vision-robbing waste products in the retinas of people with the condition. Dr. Scholl is the principal investigator for the FFB-CRI-funded ProgSTAR project, a natural history study for people with Stargardt disease.
Jacque Duncan, MD, at the University of California, San Francisco, and chairman of FFB’s Scientific Advisory Board, reviewed an innovative imaging system known as an adaptive optics scanning laser ophthalmoscope (AOSLO). The sophisticated technology, adapted from telescopes used in cosmology, can identify individual cone photoreceptors and measure the density of cones in a patient’s retina. AOSLO technology is in development and not yet widely implemented, but it is highly valued for its power to precisely detect disease progression and effects of therapies.
“Our goal is to advance these emerging outcome measures and technologies and make them available to companies and clinical researchers, so they can quickly and cost effectively conduct human studies,” says Dr. Zilliox. “Strong endpoints can motivate industry to launch clinical trials by giving them a clear path for validating the effectiveness of therapies and increasing the opportunity for gaining regulatory approval for them.”