Oral APX3330 Receives FDA Nod for Phase 3 Endpoint in Diabetic Retinopathy


Ocuphire's end-of-phase 2 meeting with the FDA supports APX3330's phase 3 advancement, with 3-step worsening in binocular DRSS score as the primary endpoint.

Close-up of Eye | Image Credit: V2osk/Unsplash

Credit: V2osk/Unsplash

Ocuphire Pharma, Inc. has announced the successful outcome of an end-of-phase 2 meeting with the US Food and Drug Administration (FDA), supporting the advancement of oral APX3330 into phase 3 trials for the treatment of diabetic retinopathy.1

Announced on November 2, 2023, the agreement was in reference to the phase 3 primary endpoint of 3-step worsening on binocular diabetic retinopathy severity scale (DRSS) score. Per a recommendation from the FDA, the company will submit a Special Protocol Assessment to agree on the clinical trial protocol and statistical analysis plan for the phase 3 trials.

Pending FDA approval, APX3330 has the potential to be the first oral treatment option for approximately 8 million patients in the US with non-proliferative diabetic retinopathy. Current treatment options for patients with NPDR are for clinicians to monitor its progression every 4 to 6 months, depending on disease severity.

“Approved anti-vascular endothelial growth factor (VEGF) therapies are not widely utilized in NPDR patients because of the necessity for consistent intravitreal injections in asymptomatic patients,” said David Brown, MD, the co-chairman of the medical leadership board at Retina Consultants of America. “A safe convenient oral medication that could slow or prevent diabetic retinopathy would be a major advance in our fight against diabetic blindness.”

APX3330 is a first-in-class, small molecule, oral inhibitor of the transcription factor regulator reduction-oxidation effector factor-1 (Ref-1). Its novel dual mechanism of action blocks the downstream pathways regulated by Ref-1 to decrease abnormal activation of angiogenesis and inflammatory pathways implicated across ocular diseases including diabetic retinopathy, diabetic macular edema (DME), and age-related macular degeneration (AMD).

The end of the phase 2 meeting was directly supported by results from the completed randomized, double-masked, placebo-controlled, phase 2 ZETA-1 trial. The trial evaluated the efficacy and safety of oral APX3330 in patients with diabetic retinopathy. Results from ZETA-1 showed the primary endpoint was not met, with approximately 8% of eyes with diabetic retinopathy showing ≥2-step DRSS improvement.2

However, the data revealed a higher percentage of placebo-treated patients had ≥3-step worsening on binocular DRSS from baseline, compared to APX3330-treated patients at 24 weeks. Overall, the agent was well-tolerated, with favorable safety among this patient population.

Citing these data, the company indicated oral APX3330 has the potential to slow or prevent clinically meaningful progression of diabetic retinopathy, with ≥ 3-step worsening on binocular DRSS used as the phase 3 primary endpoint.1

“We are pleased to have FDA agreement on the primary endpoint for phase 3 pivotal trials of APX3330 which we believe is the most advanced oral therapy currently in development for diabetic retinopathy,” said George Magrath, MD, MBA, the chief executive officer of Ocuphire, in a statement.

In an interview at the 127th Annual American Academy of Ophthalmology (AAO) Meeting, Arshad Khanani, MD, the director of clinical research at Sierra Eye Associates, expressed his excitement about the FDA acceptance of ≥3-step DRSS worsening as the primary endpoint for the pivotal APX3330 phase trial.

“I am excited about non-invasive options for treatment of diabetic retinopathy,” Khanani said. “And I am excited to enroll patients in the pivotal trial in the near future.”


  1. Ocuphire Pharma announces successful end-of-phase 2 meeting with FDA for oral APX3330 in Diabetic retinopathy. Ocuphire Pharma, Inc. November 2, 2023. Accessed November 27, 2023. https://www.ocuphire.com/news-media/press-releases/detail/420/ocuphire-pharma-announces-successful-end-of-phase-2-meeting.
  2. Iapoce C. Phase 2 Zeta-1 trial suggests promise of APX3330 in diabetic retinopathy. HCP Live. June 27, 2023. Accessed November 27, 2023. https://www.hcplive.com/view/phase-2-zeta-1-trial-suggests-promise-apx3330-diabetic-retinopathy.
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