Safety and Efficacy of Senolytic UBX1325 in Diabetic Macular Edema.

Background: We tested the ability of a single intravitreal injection of foselutoclax (hereafter UBX1325), a novel senolytic small molecule inhibitor of antiapoptotic protein B-cell lymphoma-extra large, to mitigate the impact of diabetic macular edema.

Methods: Patients with diabetic macular edema with prior suboptimal response to anti-vascular endothelial growth factor treatment were randomly assigned (1:1) to either a single intravitreal injection of 10 μg of UBX1325 or sham and were followed for up to 48 weeks. The primary trial objective was to evaluate the safety and side-effect profile of UBX1325 as assessed by ocular and systemic treatment-emergent adverse events (TEAEs). Our secondary objective was to probe efficacy, defined as mean changes from baseline for UBX1325 versus sham in best corrected visual acuity measured in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (range, 0-100 letters, higher scores indicate better vision) and retinal structure.

Results: Between June 2021 and April 2022, 65 participants (32.3% women) were randomly assigned to either UBX1325 (n=32) or sham (n=33). There were four TEAEs of Grade 3 or greater in the sham group, of which three were considered serious, while there were five in the UBX1325 group of Grade 3 or greater and considered serious. There were no apparent between-group differences with respect to vital signs, electrocardiograms, or routine blood chemistries. For the secondary outcome of efficacy, the difference between UBX1325 and sham in mean change to week 48 in best corrected visual acuity was 5.6 more ETDRS letters (95% confidence interval, -1.5 to 12.7).

Conclusions: In this sham-controlled trial there were no TEAEs that led to discontinuation of treatment with UBX1325 compared with sham. There were trends suggestive of potential efficacy; larger trials are needed to further evaluate these findings. (Funded by UNITY Biotechnology; ClinicalTrials.gov number, NCT04857996.).