Aiming to Redefine Diabetic Retinopathy Treatment and Development

Diabetic retinopathy (DR) remains one of the most common and preventable causes of vision loss among working-age adults in the United States.^1,2 Impacting millions of individuals, DR represents a continuum of disease driven by chronic hyperglycemia and vascular compromise in the retina.^3,4 Despite decades of progress in diabetes management and the availability of effective retinal therapies, early detection and proactive treatment of DR remains strikingly low.⁵

Within the DR disease spectrum, non-proliferative diabetic retinopathy (NPDR) represents the earliest and most prevalent stage, affecting about 1 out of every 4 people with diabetes.⁶ Yet, despite the availability of therapies capable of altering disease progression, approximately 1% of eligible NPDR patients receive pharmaceutical treatment today.⁷

This disconnect between clinical potential and real-world practice underscores a fundamental gap in how the disease is managed. Low treatment rates with pharmaceutical treatments reflect the burdens faced by patients managing multiple comorbidities, work demands, and complex treatment regimens – all of which emphasize the need for approaches that bridge early DR care to active NPDR treatment.⁴

Ocular Therapeutix (“Ocular”) is aiming to address these challenges head-on with the goal of redefining how patients are treated, and how success is measured, across the DR continuum.

Despite Available Therapies, Uptake in DR Remains Limited

In the past two decades, the introduction of anti-VEGF therapy has revolutionized care across retinal diseases, such as wet age-related macular degeneration (AMD).⁸ However, the same success and adoption have not been replicated across the DR continuum.⁷ Despite the use of anti-VEGF therapy for center-involved diabetic macular edema (DME), the increase in DME incidence suggests that earlier intervention, particularly during earlier NPDR stages, may be under-utilized.^9-11

There are several potential reasons for this. First, diabetes itself poses a substantial and complex burden of disease management and treatment.¹² Patients often have many physician appointments and are still working. Furthermore, management of DR with anti-VEGF agents requires fixed and frequent intravitreal injections, which adds to the burden of competing health priorities faced by patients and care partners.^4,13 Compounding the issue, NPDR patients are typically working adults, making the injection frequency burdensome and often unsustainable due to the challenge of missed work and lost wages.^2,4 For patients and care partners, travel to retina specialists alone increases the logistical and emotional strain, further contributing to poor adherence or delayed care.⁴

Compounding these barriers is the fact that many patients with NPDR or even early proliferative disease do not experience noticeable changes in their central vision.¹⁴ For both patients and physicians, this lends to more of a “watch and wait” approach, even though the disease process is likely progressing at the microvascular level.¹⁵

As a result, panretinal laser photocoagulation (PRP), first developed in the 1970s, is still the most recommended management in specific situations in DR patients to prevent disease progression. While laser therapy can prevent severe vision loss, it can also result in irreversible damage to peripheral retinal tissue and potential reductions in night or color vision.^13,16,17 The field continues to seek alternatives that combine efficacy with improved safety, durability, and convenience.

Measurement Challenges: Rethinking the DRSS Scale

For decades, the Diabetic Retinopathy Severity Scale (DRSS) has served as the gold standard for objectively quantifying disease progression and evaluating treatment efficacy in DR clinical trials. Originally developed for use in the landmark Early Treatment Diabetic Retinopathy Study (ETDRS), the DRSS remains widely used in clinical research.¹⁸ However, its utility is not reflective of how DR is evaluated in day-to-day practice by retina specialists.

DRSS provides a structured method to assess pathological changes in the context of a clinical trial; however, it is not an approach typically used in retina practices since it is difficult to quickly grade a patient’s score by busy retina specialists. Furthermore, historically the DRSS has been used to evaluate either the improvement or regression of disease, which has historically had inherent limitations even in clinical research that can obscure meaningful patient outcomes:

• Binary endpoints: Traditional DRSS research analyses often rely on defining success as a two-step of either improvement or worsening on the DRSS, not both. This approach discards valuable data from patients who show stability, which, in a progressive disease like DR, may represent a significant therapeutic benefit.¹⁸
• Limited sensitivity: By focusing on preselected binary thresholds, the DRSS framework can fail to capture subtle but clinically relevant improvements or preventive effects that don’t meet rigid criteria.
• Clinical disconnect: Retina specialists rarely use the DRSS in daily practice, preferring qualitative assessment or simplified versions of the DRSS. As a result, regulatory endpoints may not directly align with the way clinicians understand and manage DR progression.

To fully appreciate the impact of future therapies, particularly sustainable, long-lasting treatments designed to make disease management more feasible for patients, a more comprehensive, data-rich analytical approach is needed.⁴

Redefining Treatment: Ocular’s Innovative Approach

Ocular is pursuing this challenge from two fronts: reimagining therapeutic design and rethinking treatment offering.

At the center of this effort is OTX-TKI (also known as AXPAXLI™), an investigational axitinib hydrogel administered by intravitreal injection, with the goal to dramatically improve durability and long-term outcomes for patients. Designed for once- or twice-yearly dosing, OTX-TKI aims to address one of the major barriers to care – the burden and unsustainability of frequent injections for working adults.^2,4

HELIOS-1 was a Phase 1 study of OTK-TKI in patients with moderate-to-severe NPDR without center-involved DME and provided early, compelling proof-of-concept, supporting advancement into pivotal Phase 3 development.

This design of the Phase 3 clinical program with OTX-TKI aims to improve long-term outcomes and treat the full spectrum of diabetic retinal disease.*

Redefining Development: The Ordinal DRSS Analysis

Ocular is also aiming to reshape how clinical outcomes and endpoints are measured in DR. The Company’s complementary HELIOS registrational trials leverage a novel ordinal analysis of the DRSS, designed to capture the full spectrum of patient response.

Unlike the traditional “improved versus worsened” model, the ordinal DRSS analysis considers both direction and magnitude of change across the entire continuum of DR severity. This provides a patient-centric view of potential treatment impact that also aligns with clinical practice.

This innovation offers several key advantages:

• Captures the totality of treatment effect: By analyzing incremental changes in either direction as well as no change (i.e., stable disease), the approach recognizes the full range of patient responses.
• Reflects clinical practice: Physicians aim not only to improve disease status but also to halt progression, an outcome equally valuable in long-term management.
• Enhances sensitivity for regulatory and clinical interpretation: The ordinal endpoint increases statistical power and provides a more nuanced understanding of drug performance over time.

During the design of its global registrational program for OTX-TKI in DR, Ocular collaborated with the U.S. Food and Drug Administration (FDA) to ensure regulatory alignment and confirmation that the ordinal DRSS endpoint delivers a robust and clinically meaningful measure of patient outcomes through a Special Protocol Agreement (SPA).

Ultimately, this led to the design of the HELIOS Clinical Program, representing complementary global clinical trials using this ordinal DRSS analysis as a primary endpoint.

These results will aim to support a broad label across diabetic retinopathy, from early, non-proliferative disease to more advanced stages.

Redefining Unmet Needs and Outcomes in DR

DR is a complex, multifaceted disease – addressing it effectively will require innovation on multiple fronts. Importantly, the unmet need in DR is not due to a lack of options, it is a therapeutic mismatch between what is possible and what is practical with available treatments. Current regimens require considerable effort from patients already navigating chronic disease management.

Ocular’s approach with OTX-TKI seeks to bridge this gap between clinical trial experience with real-world practice where frequency of injections is often not sustainable for patients managing multiple comorbidities and competing health priorities.

If successful, this approach has the potential to redefine how DR is broadly managed – promoting earlier intervention, offering a more sustainable treatment paradigm, and supporting improved long-term disease control.

Moreover, integrating a durable treatment like OTX-TKI with a more sensitive analytic endpoint in DRSS has the potential to reshape not only treatment protocols but also how success is defined in DR research.

The ordinal DRSS endpoint represents an evolution toward data contextualization, capturing incremental gradations of disease change and aligning with how retina specialists view progression and stability in practice. By reflecting both the prevention of worsening and the achievement of improvement, Ocular’s approach resonates with the dual goals of modern diabetic eye care – preservation and protection.

As the HELIOS program advances, Ocular envisions a future in DR that goes beyond a potential new therapy, but also offers a new lens through which to view progress – one that could redefine both how we treat and assess DR and how we measure success moving forward.

*As of publication in January 2026, all investigational product candidates are currently undergoing clinical evaluation. This content is not intended to convey any conclusion of safety or efficacy, and there is no guarantee that any product candidate will successfully complete development or gain FDA approval or other regulatory authority approval.

References:

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