Phase 2 ZETA-1 Trial Suggests Promise of APX3330 in Diabetic Retinopathy


APX3330 showed statistically significant prevention of ≥3-step binocular DRSS worsening compared to placebo, but did not meet the study's primary endpoint.

Victor H. Gonzalez, MD | Credit: Gulf Coast Eye Institute

Victor H. Gonzalez, MD

Credit: Gulf Coast Eye Institute

New data suggest the primary endpoint of the phase 2 ZETA-1 trial was not met, with approximately 8% of eyes with diabetic retinopathy showing ≥2-step diabetic retinopathy severity scale (DRSS) improvement.1

However, the results, presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023), indicated APX3330 was associated with statistically significant reduction in binocular ≥3-step worsening after 24 weeks.

“APX3330 may represent a promising, non-invasive oral treatment option for preventing risk of disease progression in NPDR patients who otherwise are monitored and untreated,” wrote the investigative team, led by Victor H. Gonzalez, MD, the president/CEO and medical director of Gulf Coast Eye Institute.

Reduction-oxidation effector fctor-1 (Ref-1) is a novel target for retinal diseases, a transcription factor regulator of angiogenesis (vascular endothelial growth factor [VEGF]) and inflammation (NFkB). APX330 is a non-invasive, oral, novel, small molecule inhibitor of Ref-1, with a unique dual method of action that decreases abnormal angiogenesis and inflammation. The therapy was previously developed for hepatic inflammatory indications and solid tumors in 11 phase 1 and 2 trials; it has been extensively studied in ≥20 in-vitro and animal studies with favorable efficacy and safety.2

ZETA-1 was a multi-center, placebo-controlled, double-masked phase 2 trial in patients with diabetic retinopathy.1 A total of 103 patients at 25 investigational sites across the United States were randomized 1:1 to receive 600 mg APX3330 per day or placebo twice a day. Patients were ≥18 years of age, had DRSS 47, 53, or 61, and had Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity ≥60 letters; eyes with non-central DME were permitted.

Key exclusion criteria include optical coherence tomography (OCT) central subfield thickness (CST) >320 µm, center involved DME allowed in fellow eye, anti-VEGF treatment within past 6 months, and hemoglobin A1c ≥12.0%. Of the 103 patients with diabetic retinopathy, 90% had non-proliferative diabetic retinopathy (NPDR) with a baseline DRSS of 47 or 53.

Upon analysis, investigators found the primary endpoint was not met with 8% of study eyes showing ≥2-step DRSS improvement in each treatment group. Regarding a pre-specified, potential registration endpoint, APX3330 showed a statistically significant reduction in binocular ≥3-step worsening after 24 weeks, with 16% of the placebo group worsening compared to 0% of the APX3330 group.

The data showed 19% of placebo patients lost ≥5 BCVA letters compared to 5% of APX3330 patients (P = .07). Adverse events reported in ≥5 of study participants were pruritis, rash, and worsening of diabetic retinopathy or diabetic macular edema in the placebo group. However, no subjects withdrew from study due to rash or pruritis.

The investigative team noted the safety profile of APX3330 in diabetic patients was consistent with the profile observed in hundreds of healthy patients, as well as those with hepatitis or cancer.

“These phase 2 data support further evaluation of APX3330 in registration trials,” they wrote.


  1. Gonzalez VH, Brigell M, Su D, Patel R, Withers B, Kelly M, Haddad L, Pepose J, Kaiser P, Boyer D. Early Intervention for Diabetic Retinopathy (DR); Safety and Efficacy of Novel, Oral Therapeutic APX3330 in Patients with DR. Poster presentation at the 83rd Scientific Sessions of the American Diabetes Association. June 23 – 26, 2023.
  2. Kunzmann K. Investigative oral retina drug APX3330 shows favorable safety, Tolerability. HCP Live. October 9, 2021. Accessed June 27, 2023.

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