Oral diabetic retinopathy treatment fails to meet primary endpoint in phase 2 trial

Charles C. Wykoff, MD, PhD

Diabetic retinopathy (DR) is a growing global challenge. Currently, most patients with nonproliferative diabetic retinopathy (NPDR) are not receiving ocular-specific interventions despite the availability of FDA-approved therapeutics that can be given by intravitreal injection. There is a large unmet need for less invasive therapeutics that can meaningfully slow the progression of DR. For example, a therapeutic that could decrease the rate of proliferative diabetic retinopathy (PDR) and/or diabetic macular edema development would be clinically valuable for millions of patients with NPDR.

Its important to appreciate that the 24-week randomized controlled phase 2 ZETA-1 prospective trial was intentionally designed to be a proof-of-concept study. One hundred three patients with NPDR or early PDR were randomized equally to either placebo or APX3330 (Ocuphire Pharma) taken orally twice daily. The primary endpoint was the proportion of subjects with a two or more step improvement on the diabetic retinopathy severity scale (DRSS) at week 24.

While the predefined primary endpoint was not met in ZETA-1, an important prespecified secondary endpoint was met with statistical significance — preventing progression of DR. Specifically, 16% compared with 0% of patients demonstrated worsening of their cumulative DRSS score by three or more steps across both eyes in the placebo and APX3330 arms, respectively.

Slowing disease progression is an important clinical goal. Most patients with NPDR have excellent visual acuity and visual function, many being essentially asymptomatic from an ocular perspective. Therefore, being able to maintain these patients at this stage of disease by meaningfully decreasing the rate of worsening of DR would be valuable to patients. From a safety perspective, I was encouraged to see no signals of concern, with actually a higher rate of treatment-emergent adverse events in the placebo arm compared with the APX3330-treated arm.

When utilizing pharmacotherapies delivered locally, for example through an intravitreal injection, the most appropriate endpoints to consider are changes in DR severity, either worsening or improving, within the study eye. It is through this approach that aflibercept and ranibizumab were FDA approved, based on their impressive ability to improve DRSS scores in a study eye. However, when utilizing a systemically administered therapeutic, such as APX3330 orally, because both eyes of the patient are exposed to the medication, the most robust way to assess outcomes is more wholistically, considering DR changes cumulatively across both eyes. Toward this end, if APX3330 can meaningfully reduce the proportion of patients who experience worsening of DR severity levels over time within a randomized placebo-controlled pivotal trial, I believe this could meaningly advance the space.