This article was originally published in a sponsored newsletter.
For this month’s Retina Minute, I have the pleasure of interviewing a dear friend, Dr. Victor Gonzalez.
Dr. Gonzalez, recently at the American Society of Retina Specialists meeting in Stockholm, you presented some interesting data on a new potential compound to treat diabetic macular edema (DME). Can you talk about this new compound and the study?
Of course. As you know, the pathogenesis of DME is complex, and most current medications target either anti-vascular endothelial growth factor (VEGF) or some of the inflammatory cascades. Endothelial damage and cell loss is an important component of what we see in diabetes. We think hyperglycemia activates the traditional pathways, leading to oxidative stress and endothelial cell damage. Eventually, we see damage resulting in loss of circulation, hypoxia, and neovascularization. The compound of interest is an oral compound, called CUO6, from Curacle. It is a potent endothelial dysfunction blocker, and the hope is that it can stabilize the cells and the tight junctions to normalize endothelial cells, resulting in inhibition of inflammation, improvements in perfusion, and ultimately improvement in vision in these patients. There is early but strong evidence that CUO6 may also have a neuroprotective effect.
The medication was evaluated in a phase 2a, open-label, parallel group, multi-center study. The treatment was for a 12-week period and the patients were randomized to a 100 mg pill, a 200 mg pill, or a 300 mg pill, once per day. The patients who we typically enroll in our cystoid macular edema trials were enrolled here, except the best-corrected visual acuity (BCVA) in this group ranged from 20/25 to 20/200, or 34 to 83 letters, and patients had to have a minimum diabetic retinopathy severity score greater than 35. A total of 66 patients were enrolled and were evenly balanced among the three dosage groups. The endpoints evaluated were change in BCVA from baseline, change in central subfield thickness (CST), and safety; the anti-VEGF washout was 3 months.
I can tell you that 50% of the patients were treatment naïve, so we had a good group. The subjects had good vision and only mild CST thickening. Patients’ mean BCVA was approximately 70 at baseline, and the three groups gained 1.9, 2.5, and 2.2 letters, respectively. When we looked at a pre-specified group of patients whose visual acuity was less than 69 letters, we found that there was a dose-related improvement in visual acuity ranging from 4.3-letter gains for the lowest dose to 5.8-letter gains from baseline in the higher dose. We also found that there was stability of CST during the 12-week period. There was nothing statistically significant in terms of improvement.
The advisory board members evaluated each patient’s OCTs and graded them into five groups: better, slightly better, stable, slightly worse, or worse. They found that there was a numerically favorable improvement for the higher doses that was not necessarily a CST improvement; it was more of a macular volume improvement. In other words, we found anatomical changes that tended to be favorable to the higher doses of the oral drug. Not everybody got this improvement, but there certainly was a trend and a suggestion that there were some benefits.
This drug has also been demonstrated to have other metabolic impacts on biomarkers in the blood, mainly glucose and inflammatory. In this case, we looked at glucose levels and tissue necrosis factor levels from baseline to week 12, and we found a numerical improvement in the higher doses, suggesting that there may also be a biological effect reflected from a decrease in the glucose levels and inflammatory factors.
There were no systemic adverse events or ocular events, so the drug is relatively safe. The next steps for CUO6 will be a 6-month phase 2b trial that will include a control, which was a limitation of the phase 2a trial. Curacle has improved some of the formulation delivery to try to get higher levels of the medication with lower doses.
Was there any control of the hemoglobin A1C in this population, and were the results stratified by differences in the potential changes in hemoglobin A1C during the trial?
No, that is part of what will be studied in the phase 2b trial.
Were patient demographics well-balanced between men and women, and between Caucasians and Hispanics?
Believe it or not, in this case, more than 60% of patients were men.
Given CUO6 is an oral medication, was there any stratification based on BMI?
In this study, no.
You mentioned that the macular volume seemed to be a better predictor of how the drug affected the eyes at 12 weeks. Was there a statistically significant improvement in macular volume or was it just the trends?
There was a trend, but no statistically significant difference.
What did the phase 1 trial show you?
Phase 1 showed similar results to what we got here. It did include a dose escalation, which suggested an improvement in vision at higher doses, but that study had a small number of patients. It is quite early in the process for both the phase 1 and phase 2 data so far.
This is great preliminary data. Assuming this medicine makes it all the way to approval, how will you use it in your diabetic patients with DME?
I think the benefit for these patients will be even before we get to that level. We are studying CUO6 for DME, but there is consideration of moving it earlier to address compliance issues. As we know, injections can be a burden for patients, whether that is because they are afraid of them, or because they are unable to come in monthly, bimonthly, or even every 3 months for treatment. If we can use this pill and have similar or better results than our anti-VEGFs, what better opportunity is there?
Dr. Gonzalez, this is fascinating data. When we think of diabetes and ocular complications, shots come to mind, but in terms of increasing patient compliance and potentially treating patients at earlier stages, this seems to have great potential. I am excited to see how the next level goes and how phase 3 is formulated. Hopefully CUO6 could eventually make its way into our clinics.
I agree. I think this medication could be beneficial from a compliance standpoint and perhaps even more of a preventive one if we can show that it has an impact earlier in the disease process.
