ASRS 2023: ZETA-1 phase 2 trial efficacy results for APX3330 with David Lally, MD

David Lally, MD, spoke with our team about the ZETA-1 phase 2 trial efficacy results for APX3330, a novel, oral ref-1 inhibitor for the treatment of diabetic retinopathy at the 2023 ASRS annual meeting.

Video Transcript

Editor's note - This transcript has been edited for clarity.

David Lally, MD:

My name is David Lally and I am a practicing physician at New England Retina Consultants in Springfield, Massachusetts. Diabetic retinopathy is the most common cause of blindness among working-age adults. Currently, the majority of these patients are not being treated, as patients are typically asymptomatic, and they are reluctant for frequent eye injections.

The current treatment paradigm for the majority of physicians is to wait and monitor nonproliferative diabetic retinopathy disease with anti-VEGF, or steroid injections, or laser treatment reserved for those patients who develop proliferative diabetic disease or develop diabetic macular edema. Developing an alternative route of administration orally could reduce the treatment burden for our patients and allow us to intervene earlier in the stages of diabetic retinopathy and APX3330 is a first-in-class, novel medication that inhibits Ref-1, which is a transcription factor regulator. By inhibiting Ref-1, you block activation of both HIF-1alpha and NF-kappaB, leading to down regulation of inflammation and VEGF.

This drug was well studied previously, initially in patients with hepatitis and solid tumors, and the safety profile was good in those trials. The ZETA-1 trial is a Phase 2 randomized, multi centered, placebo-controlled trial that investigated APX3330 for the treatment of diabetic retinopathy. Subjects with moderately severe to severe NPDR or PDR were randomized in a 1 to 1 fashion to receive either APX3330 at the 600 milligram dose daily or placebo daily for 24 weeks. The primary outcome measure was the percent of subjects that had a 2-step or greater improvement on their DRSS scores at week 24. In this trial, there was 103 subjects that were randomized across 25 US sites. Now, APX3330 did not meet its primary endpoint, and the percent of subjects that had 2 or greater steps improvement on DRSS scores. However, in Phase 2 trials, we are often learning about a drugs potential efficacy in a disease for the first time, and those other signals beyond the primary endpoint can sometimes redirect development plans into Phase 3.

The ZETA-1 trial may be one of these instances because what we saw when we looked at the change in binocular DRSS scores over 24 weeks, was that none of the APX treated patients developed a binocular 3-step or worse DRSS progression scores. That's in comparison to the placebo arm, where 16% of those subjects did develop 3-step or greater DRSS worsening on binocular scores. So APEX3330 may be showing us an ability to stabilize diabetic retinopathy disease, as opposed to improving it. Now, the FDA has previously remarked that they may consider the prevention of diabetic retinopathy worsening as a potential valid primary endpoint. There is an end of Phase 2 meeting planned with the FDA to discuss this primary outcome measure later this year. Thank you.