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Retinal Physician | Retina Minute

March 2023

Potential Wide Use for Ocuphire’s APX-3330: An Oral Drug to Prevent Diabetic Retinopathy Progression—Results of the Phase 2 ZETA-1 Trial

Peter K Kaiser, MD, and Michael Singer, MD

For this month’s Retina Minute, I have the pleasure of interviewing my dear friend, Peter K Kaiser, MD. Peter is the Chaney Family Endowed Chair in Ophthalmology Research, Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine and Cole Eye Institute.
Peter, recently at the Angiogenesis meeting, you presented data on the Phase 2 trial of APX-3330 from Ocuphire. Can you explain the study design?
The ZETA-1 study was a Phase 2 clinical study evaluating Ocuphire’s oral drug, APX-3330. APX-3330 works at a different target from those that many of us have heard of previously, called the reduction oxidation effector factor 1, or Ref-1. Ref-1 is upregulated in situations of hypoxia or inflammation, and it activates HIF-1α, which is upstream of vascular endothelial growth factors (VEGFs), so Ref-1 activation leads to an increase in VEGF production. Ref-1 also increases NF-κΒ, which leads to the formation of TNF-α and other growth factors that lead to inflammation. Ref-1 is basically a bad actor and APX-3330 is a small molecule that blocks it. More importantly, APX-3330 is a pill that has been extensively investigated in 11 clinical studies, both in hepatic inflammatory as well as advanced solid tumor indications, and showed good systemic safety. Because it works by reducing VEGF and inflammation, the idea was to target something that both factors are involved with, which led us to test it in patients with diabetic retinopathy (DR).
In the Phase 2 ZETA-1 study, patients had DR with a DR severity scale (DRSS) score of 47, 53, or 61 (moderate to severe non-proliferative diabetic retinopathy [NPDR] to early proliferative diabetic retinopathy), confirmed by a central reading center. Patients also had to be able to forego panretinal photocoagulation laser or anti-VEGF injections in the opinion of the investigator for more than 6 months and they had to have vision better than 60 letters (20/63 or better). Some of the key exclusion criteria were: Patients could not have center-involved diabetic macular edema (DME) because we did not want to have to give anti-VEGF which could affect DRSS outcomes. It was okay to need anti-VEGF in the fellow eye, but not in the study eye. Also in the study eye, patients could not have intravitreal injections of anti-VEGF or steroids for the previous 6 months to make sure that there was nothing affecting the DRSS score.
What was the primary endpoint and how long was the study?
This was a placebo-controlled Phase 2 study, so patients were randomized 1:1 to the APX-3330 b.i.d. pill vs a placebo pill. The primary endpoint was percentage of the subjects with a two-step or more improvement in DRSS at week 24, which was used in both the aflibercept (Eylea, Regeneron) and ranibizumab (Lucentis, Genentech) clinical study designs for their approval in DR.
With an oral drug, there are many systemic factors to control. Were patients balanced based on systemic considerations, such as body mass index and hemoglobin A1C in the trial?
Patients were all balanced at baseline based on systemic factors such as hemoglobin A1C, blood pressure, heart rate, and BMI between the groups.
What was the effect? If two eyes were involved, did they count one eye or both eyes?   
The primary outcome was not met, so there was no significant difference between the treated eyes and the placebo eyes at 24 weeks. Interestingly, there was a trend in which the drug worked in qualified fellow eyes (that is, patients whose fellow eye met the same inclusion criteria as the study eye). It was not statistically significant, but the fellow eyes did better than the study eyes.
It is important to understand that when the FDA evaluates systemic medications for DR, it actually prefers a binocular DRSS score in which you add the DRSS scores from each individual eye. In that case, it is no longer a two-step change that is significant; it is a three-step binocular change. So, you can either have a three-step improvement in binocular DRSS or prevention of a three-step worsening, and both would be approvable endpoints with a systemic drug. Obviously for local drugs with which we do intravitreal injections or eyedrops into one eye, the two-step change is accepted by the FDA.
How did both eyes do together? Did APX regress retinopathy? How did it do compared to the fellow eye in terms of prevention of progression of retinopathy?
When we looked at the binocular change in DRSS, there was a nice trend for improving three steps or more.  In the placebo group, 16% of patients worsened three steps or more, but none of the patients in the APX group did, which was statistically significant. Both these endpoints were pre-specified in the statistical analysis plan.
To put that into perspective, consider the RISE and RIDE studies in which approximately 30% of patients had a two-step worsening after 1 year in one eye, rather than binocular DRSS like the ZETA-1 results. We only have data at 52 weeks for RISE and RISE, but we would expect approximately 25 to 30% of patients receiving placebo to have this three-step worsening at the week 52 mark. RISE and RIDE were DME studies with sham controls, so they were one of the few studies in which we could see how patients did with sham, although some patients did get laser. The ZETA-1 result is exciting because the Phase 2 study met an approvable endpoint with an oral DR treatment.
This whole idea of using binocular DRSS scoring is new to us. Many people have told me that they have never heard of adding two eyes’ DRSS scores together before, but it is a known approvable outcome when testing a systemic drug that affects both eyes. Because several other oral medications are being evaluated in this space, we are going to see a lot more studies using this three-step either improvement or prevention of worsening in other analyses.
I want to elaborate on another positive data point from the study. We saw a trend in prevention of loss of vision, which you would expect if you are preventing worsening of DRSS. A five or more letter loss of vision occurred in approximately 20% of placebo patients and only 5% of the APX group. This result was not significant but had a strong trend with a p-value of 0.07.
How about in terms of DME? How did the two arms do in terms of development of DME during the 6-month period?
That is still being analyzed. We do not have all the data yet from the optical coherence tomography findings, but patients entering the study had to have less than 320μm of retinal thickness. At baseline, on average, the eyes started with approximately 270μm retinal thickness, so these patients started off with no DME. There were patients who had extra foveal macular edema and that is being analyzed to see how those patients did in the clinical study.
To your point, the current study was limited because there was not enough runway in terms of the 24-week timeframe. What is the next step for this potential drug?
When we perform a Phase 2 study, the goal is to be able to use the results of the Phase 2 to design pivotal Phase 3 studies. Ideally, you do not want to change anything about the study design between phases to maximize success. The three-step change in binocular DRSS was a prespecified secondary outcome, so it is reasonable to move it up to primary in Phase 3. The main difference between the studies would be that the primary outcome would have to be at 1 year because the FDA requires a 1-year outcome for DR studies.
If this drug got approved, how would you use it in your clinical practice?
This is one of those drugs for which safety is good. It has been tested in many clinical studies with patients who had liver problems and tumors, and the only safety issues that came out of those studies were mild skin rash and diarrhea. In this Phase 2 study, we had low rates of adverse events (AEs). There actually were higher AE rates in the placebo arm than in the APX arm, and almost all were mild to moderate. We had three patients in the APX arm with pruritus, two patients with rash, and one with diarrhea.
Ocular AEs were similar or higher in the placebo group than in the APX group, and most were things you would expect with DR: The development of diabetic retinal edema was higher in the placebo group, as were hemorrhages, exudates, floaters, vitreous hemorrhages, and the progression of retinopathy. There was nothing in the APX group that would stand out as concerning in any way, so the drug appeared safe.
Given this safety and assuming no difference in Phase 3, I would ask my patients who have hit the moderate stage of NPDR if they wanted to take this drug to prevent further worsening of their DR, especially because this pill could be added on top of other treatments. I also see a potential where APX-3330 will be prescribed by endocrinologists, diabetologists, or even primary care doctors if they see in the notes that patients have DR. To me, it is simple for patients to be able to take a pill that prevents progression. That is a no-brainer, as long as it is safe.
This drug obviously may have potential in terms of augmenting our treatment of the DR disease state.
Even though we have approved treatments for DR, they are not typically used in our practices simply because of the injection burden. In contrast, we could use APX-3330 in almost all my moderate or higher NPDR patients, presuming the safety is as good in Phase 3, so I am excited about it.
Peter, I always learn so much from you. As retina specialists, we are ecstatic about the possibility of having an oral treatment to prevent diabetic retinopathy progression because it could augment our intravitreal therapies and possibly increase compliance, leading to less vision-threatening disease. Thank you so much for sharing this data with us.
Thanks for having me, Michael.
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