Foselutoclax (UBX1325) for Diabetic Macular Edema — A Potential Novel Therapy?

Diabetic macular edema, a manifestation of diabetic retinopathy that impairs central vision, is a leading cause of vision loss in working-age adults.^1,2 In the United States, 9.6 million people have diabetic retinopathy; this is 26% of all patients with diabetes. Of those with diabetic retinopathy, 1.84 million have a form of vision-threatening diabetic retinopathy, which includes diabetic macular edema.³ The current Food and Drug Administration–approved treatment for diabetic retinopathy consists of intravitreous injection of anti–vascular endothelial growth factor (VEGF) antibodies for treatment.¹ These drugs are far from a perfect treatment. For example, in one trial, while ranibizumab treatment resulted in a mean gain of 10 letters on the visual acuity chart, only half of the trial population achieved this visual acuity gain.⁴ Furthermore, a secondary analysis of a trial of three different anti-VEGF drugs demonstrated persistent diabetic macular edema following monthly injections of these drugs for 6 months, ranging from 32 to 66%, while 16 to 29% of participants in the trials had reduced visual acuity accompanying this persistent edema.⁵

In this issue of NEJM Evidence, investigators report results of a phase 2, multicenter, randomized, double-masked, sham-controlled clinical trial on the safety of an intravitreous drug, foselutoclax (UBX1325), for the treatment of patients with diabetic macular edema.⁶ The biological basis for foselutoclax’s actions derives from experiments in cells that were cultured while exposed to levels of glucose in the culture medium consistent with diabetic hyperglycemia. In these experiments, a subset of vascular endothelial cells demonstrated cellular senescence, leading to a partial breakdown of the blood–retinal barrier, resulting in vascular leakage and microinflammation. Foselutoclax, a small molecule, as opposed to the antibodies currently used for diabetic macular edema, was developed to inhibit the function of the protein known as B-cell lymphoma-2, a protein that participates in the regulation of cell death. In mouse models, foselutoclax treatment reversed the vascular leakage associated with diabetic macular edema.⁷

The participants eligible for the trial were patients who did not respond to at least two anti-VEGF therapies that were given in the prior 6 months, for retinal thickening due to diabetic macular edema involving the central subfield zone. Patients were randomly assigned 1:1 to either a single intravitreous injection of 10 μg of UBX1325 or sham and were followed for a duration of 48 weeks. The primary outcome was to evaluate the ocular and systemic safety as well as treatment-emergent adverse events of foselutoclax. The secondary outcomes included the difference in the change in best-corrected visual acuity from baseline, the number of anti-VEGF rescue medication treatments given to the trial participants, and other macular edema–related measures evaluated over 12, 24, and 48 weeks.

While 65 participants were enrolled (n=32 for foselutoclax; n=33 for sham), 15 (23%) participants did not complete the trial at week 48 (n=8 for foselutoclax; n=7 for sham). Given the limited exposure to foselutoclax, the treatment appears to be safe. For the secondary outcomes, visual acuity gains were initially greater for foselutoclax, but this declined as the sham arm received rescue anti-VEGF medications during the trial. The median time to the first rescue in the sham arm was 17.5 weeks, while the median time for the foselutoclax arm was greater than 48 weeks; half of foselutoclax-treated participants did not receive rescue therapy.

The results of this relatively small trial show that intravitreous injection of foselutoclax was not associated with worrisome safety signals and the secondary outcomes suggest that foselutoclax may warrant further investigations to assess potential efficacy. The lost to follow-up rate for this phase 2 trial was higher than predicted. This may have resulted from the trial having a sham arm rather than the standard of care, i.e., anti-VEGF therapies. It seems reasonable to speculate that patients in the placebo arm may have left the trial to seek vision-saving treatment. Thus, it may have been more appropriate and a fairer comparator to have an active anti-VEGF treatment as the comparator with foselutoclax. Indeed, an ongoing phase 2b trial, (NCT06011798), is comparing foselutoclax with the administration of 2 mg of intravitreous aflibercept, an anti-VEGF treatment, every 8 weeks for a period of 6 months. We eagerly await the results of this phase 2b trial. Thus, the data from the trial reported herein teach us about the biology of diabetic macular edema and, at the same time, they may represent a potential novel therapy at a non-VEGF target.

In 2018, the treatment of diabetic retinopathy was estimated to cost $753 million for Medicare Part B,⁸ making this form of macular edema of major public health importance, as the number of persons with diabetes will likely increase as the population ages. The need for the development of additional therapies for diabetic macular edema is urgent, and further drug development for candidate molecules, such as foselutoclax, is a potential welcome addition to our current treatment strategies.