APX3330 is an oral, novel, small-molecule inhibitor of Ref-1, in diabetic retinopathy (DR) patients. ZETA-1 was a multi-center, placebo-controlled, double-masked Phase 2 trial. Subjects were randomized 1:1 to receive APX3330 (total 600 mg/day) or placebo BID for 24 weeks. Eligible subjects had non-proliferative DR (NPDR) or mild proliferative DR, corresponding to DR severity scale (DRSS) scores of 47, 53, or 61 as confirmed by the Duke reading center. The primary efficacy endpoint was the % of subjects with ≥ 2-step DRSS improvement in the study eye at week 24 compared to baseline. Several key pre-specified endpoints were evaluated.

Results: ZETA-1 trial enrolled 103 DR subjects with 90% having NPDR with a baseline DRSS of 47 or 53. 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). 19% of placebo subjects lost ≥5 BCVA letters compared to 5% of APX3330 subjects (p=0.07). AEs that occurred in ≥5% of subjects were pruritis, rash, and worsening of DR or DME in the placebo group. No subjects withdrew due to rash or pruritis.


V. H. Gonzalez: Consultant; Alimera, Bausch + Lomb, Research Support; Adverum Biotechnologies, AbbVie Inc., Apellis, Genentech, Inc., IQVIA Inc., Iveric Bio, Regeneron. P. K. Kaiser: Consultant; Ocuphire, AbbVie Inc., Bausch + Lomb, Bayer Inc., Regeneron, Ocular Therapeutix, Novartis, REGENXBIO Inc. D. S. Boyer: Advisory Panel; 3Boehringer Ingelheim Canada Ltd. /Ltée, AbbVie Inc., Adverum Biotechnologies, Alexion Pharmaceuticals, Inc., Alkahest, Allergan, Amgen Inc., Apellis, Bausch + Lomb, Chengdu Pharmaceuticals, F. Hoffmann-La Roche Limited, Genentech, Inc., Iveric Bio, Gyroscope, Janssen Pharmaceuticals, Inc., Kodiak Pharmaceuticals, NGM Biopharmaceuticals, Oxurion, Novartis, ocuphire, Roche Pharmaceuticals, REGENXBIO Inc., Other Relationship; 4D Pharma PLC. M. G. Brigell: Consultant; Ocuphire Pharma, ONL Therapeutics. D. Su: None. R. Patel: Employee; Ocuphire Pharma. B. Withers: Employee; Ocuphire. M. Kelley: None. L. Haddad: None. M. Sooch: Board Member; Ocuphire Pharma, Employee; Ocuphire Pharma, Stock/Shareholder; Ocuphire Pharma. J. S. Pepose: Consultant; Acufocus, Bausch + Lomb, Brim Biotechnology, Johnson & Johnson Medical Devices Companies, Kala Pharmaceuticals, Mimetogen, Ocuphire Pharma, OKYO Pharma, Stuart Therapeutics, Thea Pharma.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.