Oral Apx3330 Reduces The Drss Worsening After 24-Weeks Of Daily Treatment: Efficacy And Safety Results Of The Zeta-1 Phase 2 Trial In Diabetic Retinopathy

The purpose of this study was to evaluate the safety and efficacy of APX3330, an oral, novel, small molecule inhibitor of Ref-1, in patients with diabetic retinopathy (DR). Ref-1 is a transcription factor regulator of both angiogenic and inflammatory signaling pathways relevant to diabetic eye disease. In addition to assessing the safety and tolerability profile of APX3330, the ZETA-1 Phase 2 trial aimed to investigate whether early intervention can help prevent the progression of diabetic retinopathy and improve patient outcomes. 

ETA-1 (NCT04692688) was a randomized, placebo-controlled, double-masked Phase 2 trial evaluating the safety and efficacy of APX3330 in treating diabetic retinopathy conducted at 25 study locations in the United States.

Subjects were randomized 1:1 to receive either APX3330 (total 600 mg/day) or placebo twice daily for 24 weeks. Eligible subjects had diabetic retinopathy severity scale (DRSS) scores of 47, 53, or 61 in the study eye, with a best corrected visual acuity (BCVA) of ≥20 and absence of center-involved (CI) diabetic macular edema (DME), with no treatment for DR or DME 6 months prior. The fellow eye criteria included any baseline DRSS score and CI-DME. The primary efficacy endpoint was % of subjects with a ≥ 2 step DRSS improvement in the study eye at week 24 compared to baseline. Secondary endpoints included change in monocular and binocular DRSS, central subfield thickness (CST), and BCVA. Safety measures were also assessed. 

ZETA-1 trial enrolled 103 DR subjects with 90% NPDR (baseline DRSS of 47 or 53); mean baseline CST was 270 µm. The primary endpoint was not met with 8% of study eyes showing ≥ 2 step DRSS improvement in each treatment group. Consistent with its mechanism of action of bringing VEGF and inflammation to physiologic levels, APX3330 demonstrated a statistically significant reduction in binocular ≥ 3 step worsening after 24 weeks, with 16% of placebo subjects worsening compared to 0% of APX3330 subjects (p=0.04). Numerically more placebo vs. APX subjects lost ≥5 BCVA letters (19% vs. 5%; p=0.07). Across treatment arms, 211 adverse events were reported in 64 (62%) subjects. Most were mild in severity and considered unrelated to study medication. 

The ZETA-1 Phase 2 trial of APX3330 demonstrated a statistically significant prevention of DR progression as measured by ≥ 3 step binocular DRSS worsening compared to placebo and a favorable safety and tolerability profile. The safety profile in diabetic patients is consistent with that observed in hundreds of patients of hepatitis, cancer, and healthy. APX3330 may represent a promising oral treatment option for preventing risk of disease progression in NPDR patients who otherwise are monitored and untreated. As a next step, the sponsor plans to meet with the US FDA to confirm the primary endpoints and overall design of the Phase 3 registration trials.