Navigating the maze: Establishing novel endpoints for IRD trials

The development of therapies targeting currently untreatable inherited retinal diseases (IRDs) is a research priority for ophthalmic innovation. Functionally devastating, IRDs are estimated to cost more $15 billion per year in the United States and Canada.¹ With upward of 100 distinct diseases under the IRD umbrella, these conditions show significant variability in phenotype and prognosis. Up to three-quarters of patients have identifiable genetic defects that could hypothetically be targeted by gene therapy.² To date, however, there is only 1 such approved treatment.

The genetic heterogeneity of IRDs along with their generally slow progression and inherently small patient populations make measuring the benefits of treatment—and then translating those into clinical trial endpoints—a major challenge. Typical outcome measures such as central visual acuity and ocular coherence tomography imaging of the macula may not be adequate. Alternative, novel outcome measures are necessary to assess loss of peripheral vision, color vision, night vision, light and contrast sensitivity, and changes to retinal structure.

The rise of functional endpoints: Why mobility matters

IRDs dramatically impair patients' ability to perform activities of daily life. Their unique nature has propelled functional outcomes measured by mobility or maze-based endpoints to the forefront.

The breakthrough case was Spark Therapeutics’ Luxturna for RPE65-mediated Leber congenital amaurosis (LCA). Here, the Multi-Luminance Mobility Test (MLMT), a real-world maze performed under varying light conditions, provided compelling evidence of how treatment improved patients’ functional vision, ultimately setting a new global standard for regulatory approval.³

The MLMT, developed by researchers at the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania, and later licensed to Spark Therapeutics, was specifically engineered to capture meaningful improvements in daily function—not just retinal sensitivity. Unlike visual acuity tests that measure clarity at a single fixation point, MLMT tracks a patient’s ability to navigate a course dotted with obstacles under light conditions ranging from near-darkness (1 lux) to well-lit environments (400 lux).

This design suited the natural history of RPE65-mediated disease, where significant vision loss manifests as reduced light sensitivity and legal blindness by adolescence.⁴ A thorough peer-reviewed validation study cemented MLMT as a robust measurement tool, ensuring the data would be acceptable to regulators and the scientific community.

The challenge of IRD heterogeneity

The heterogeneity of IRDs render drug development particularly complex. Even within a single mutation—such as RPE65—patients can vary widely in the severity and pattern of degeneration. This diversity affects the suitability of any assessment tool: one size rarely fits all. While MLMT was tailored for diseases characterized by declining light sensitivity, other IRDs might require alternative approaches.

The Luminance Dependent Navigation Assessment (LDNA), used by Ocugen in the company's Phase 3 clinical trial for its gene therapy with a broad retinitis pigmentosa (RP) indication, is one example of this evolution.⁵ The LDNA is a more sensitive and specific assessment tool, demonstrating uniform correlation between light intensity and lux levels. It is designed to optimize sensitivity and specificity for the targeted condition by employing a 10-level, logarithmically spaced scale, allowing finer discrimination of change across the full spectrum of disease progression. Importantly, LDNA designed for patients with early-to-advanced cases of RP has undergone validation, demonstrating high reliability with subjects showing minimal variability in their ability to successfully navigate the courses and the time required.

According to Ora Clinical, its specialized mobility assessment endpoint, the Visual Navigation Course (VNC), has been presented to and accepted by the FDA as an integral endpoint in the United States for relevant clinical trials.^6,7 It is highly adaptable to various patterns of vision loss, such as central, light perception, or peripheral vision issues, and can be tailored for specific disease characteristics.

Ray Therapeutics is using a multi-luminance mobility measurement in its safety study of RTx-015 gene therapy in RP or choroideremia patients.⁸ The company is also sponsoring an observational study to assess endpoints and measurement in these patients.⁹

The evolution of maze testing

Physical mazes offer immediacy and realism, as patients are confronted with real-world obstacles and variable lighting. They allow for direct observation and patient feedback, which can help in their adaptation to diverse phenotypes seen in IRD populations. However, physical maze assessments may not be practical for all trial centers. They are logistically burdensome, require meticulous certification of light levels, and cannot easily simulate every real-world scenario. Young children may excel at navigation due to their enhanced flexibility, while adults may struggle, introducing psychosocial confounders into the measure.

The advent of virtual reality (VR) mazes—such as UPenn's VR-O&M¹⁰ and Street Lab's MOST¹¹—has introduced a new layer of flexibility and scalability. These tests can be deployed broadly without physical infrastructure and potentially standardize obstacle presentation and lighting for reproducibility.

Still, VR mazes introduce their own challenges: young children may struggle with headset interfaces, they can cause motion-sickness and headaches, and the underlying technology has yet to fully replicate the richness of real-world navigation. Currently, VR tools lack substantial validation, although that will likely change as the technology evolves and is employed in more trials.

Regulatory perspectives and the search for meaningful change

As functional endpoints gain prominence, regulatory bodies like the FDA have begun to set expectations around what constitutes clinically meaningful improvement. Yet many uncertainties remain when it comes to disease stabilization, which may mean regulators will need to show increased flexibility. This is especially true of conditions associated with slower progression, like RP.

Low luminance visual acuity (LLVA) has been recognized by the FDA as a viable primary endpoint in pivotal trials, with its clinical significance viewed as analogous to the 15-letter gain on the ETDRS chart for best-corrected visual acuity (BCVA). At the same time, the use of LLVA remains debated, given the heterogeneity of RP across early and advanced stages and the uncertainty over whether smaller changes—such as a 5-letter gain—carry the same clinical relevance as the established 15-letter threshold.

Taken together, these considerations highlight the need for a flexible, multimodal approach—one that combines LLVA with complementary measures such as FST, patient-reported outcomes, and novel assessments like LDNA—to more comprehensively capture therapeutic benefit in RP trials.

One highlight of physical maze assessment as evidenced by Luxturna's approval and the MLMT experience is its intuitive impact: any observer can appreciate how a patient is able to navigate the course. This ease of interpretation helps bridge gaps with regulators, payers, clinicians, and most importantly patients themselves, in a simple and meaningful way that transcends the complexity of the underlying test protocol.

The pitfalls

In designing appropriate mobility and maze assessments in varied IRD presentations, researchers must confront the ceiling effect. Many patients quickly “max out” the scale making further improvements difficult to demonstrate. Moreover, in gene-agnostic therapies, or trials addressing ultra-rare mutations, endpoints must balance broad applicability with specificity. It is rare to find a “universal” test.

There are also examples of trials in which mobility testing was not successful. Nanoscope's RP gene therapy MCO-010 failed to meet its initial primary endpoint of mean change from baseline in Multi-Luminance Y-Mobility Test (MLYMT) scores at 52 weeks. (It later met a new primary endpoint of BCVA after a protocol change approved by regulators.)¹²

Similarly, Janssen's gene therapy for X-linked RP did not meet its primary endpoint using a Vision-guided Mobility Assessment (VMA) maze.¹³

Simplicity is the holy grail. If less labor-intensive endpoints—such as LLVA and FST—could reliably correlate with meaningful mobility improvements, trials would both accelerate and broaden. While some non-US regulatory agencies have accepted correlations between MLMT and FST, the FDA has so far declined to follow suit for the primary outcome measure. Patient-reported outcomes are emerging as important endpoints, especially in ultra-rare or late-stage diseases where other measurements lose value.

Looking forward, the destiny of IRD trials may lie in fully customizable, virtual mobility assessments that can be tailored to the disease, genotype, and even individual patient severity. This would further align appropriate endpoints with the therapy's mechanism of action and crucially, the real deficits that matter most to patients in their daily lives. Large, well-structured natural history studies will remain essential to demonstrate that intervention meaningfully alters the disease trajectory for each mutation.

Conclusion

All stakeholders—industry sponsors, academic researchers, regulators, payers, and patient advocacy groups—must remain agile, receptive to new tools, and open to evolving definitions of "treatment success." Early and frequent engagement with regulatory agencies and payers is critical, as is introducing the patient voice into endpoint selection. As the technology improves and emerging datasets support virtual or hybrid approaches, the field will converge on solutions that balance scientific rigor, patient-centricity, and feasibility.

Ultimately, data driven innovation will guide the future and success of IRD trials. For now, maze-based mobility assessments remain at the center of IRD drug development, but the future promises more precise tools, scalable and patients-centric measures paving the way for transformative treatments for patients in need.

Daniel C. Chung, DO, MA

dchung@beacontx.com

Chung is Chief Medical Officer of Beacon Therapeutics. He is an experienced clinical/medical leader with a demonstrated history of working in the biotechnology industry. Chung is skilled in ocular gene therapy development in pre-clinical animal models, translational research, and clinical development. extensive background and expertise in inherited retinal diseases and ophthalmology.

Huma Qamar, MD

huma@ocugen.com

Qamar is Chief Medical Officer at Ocugen, Inc. She has more than 21 years of work experience in clinical medicine, surgery, vaccines, cell and gene therapy, DME, pharmaceutical, health law, oncology research, patient centered outcomes research, Phase 1 trials, women's health, sarcoma, melanoma, hematology, CAR-T19, and much more.

Murthy Chavali, PhD

murthy.chavali@ocugen.com

Chavali is Director of Clinical Development at Ocugen, Inc.He is an accomplished leader in drug discovery, research and development with over 20 years of experience in academic and pharmaceutical industry. Chavali's expertise lies in successfully building, advancing and managing drug development pipelines by leading novel target identification and validation leading to clinical development for a variety of modalities (gene editing, oligonucleotides, GTx, Biologics and small molecules).

David J. Tanzer, MD

david.tanzer@lexitas.com

Tanzer is Chief Medical Officer at Lexitas Pharma Services. He has over 20 years of broad-based leadership experience spanning private sector companies (Lexitas, OcuTerra Therapeutics, Novartis, Johnson & Johnson Vision, Abbott Medical Optics), non-profits, academic, and military organizations. Tanzer's specialties include R&D, med affairs, safety, commercialization, compliance, and QA within the medical/healthcare field.

References

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7. Ora Clinical. Retina, Glaucoma, Refractive & CED. https://www.oraclinical.com/wp-content/uploads/2024/04/Ora_FactSheet_Posterior_Segment_042624_digital.pdf

8. Study to Evaluate Safety of RTx-015 Injection in Retinitis Pigmentosa or Choroideremia Patients (ENVISION). https://clinicaltrials.gov/study/NCT06460844

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