Intravitreal UBX1325 Shows Efficacy in Diabetic Retinopathy, DME, with Dante Pieramici, MD

Clinical trials to date have indicated the favorable safety profile and long lasting efficacy of UBX1325 (foselutoclax), an intravitreal injection targeting cellular senescence, in slowing the progression of diabetic macular edema (DME) and diabetic retinopathy (DR).

New data presented at the 43rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, came from 2 distinct phase 2 and 2b clinical trials, titled BEHOLD and ASPIRE, respectively. Investigators tested UBX1325, a novel senolytic small molecule inhibitor of anti-apoptotic protein BCL-xL, in limiting the impact of DME and DR.1

Prior studies have indicated the efficacy of UBX1325 in treating neovascular age-related macular degeneration (nAMD). These trials indicated UBX1325’s ability to recover outer retinal function within 8 weeks of the trial’s start point. This prevents senescent cells from disrupting the blood-retinal barrier or increasing reactive oxygen production.2

For enrollment in BEHOLD, patients were required to be ≥18 years old, have nonproliferative DR and DME, have center-involved DME with central subfield thickness (CST) ≥325 to 900 µm, and have best-corrected visual acuity (BCVA) in the study eye (most affected) of 70-30 ETDRS letters (equivalent to 20/40 to 20/250 on the Snellen chart). Patients were excluded if they had concurrent disease in the study eye or structural damage other than DME which could compromise BCVA or prevent improvement. Additionally, patients with significant media opacities like cataract were omitted.1

The first step of the trials, BEHOLD, was a phase 2 proof-of-concept, double-masked, sham-controlled, multicenter trial. It enrolled 65 patients, all of whom received a single intravitreal dose of 10µg UBX1325. Pieramici and colleagues established a primary safety objective based on ocular and systemic treatment emergent adverse effects (TEAEs) through 48 weeks and a primary efficacy endpoint based on mean change from baseline in BCVA for UBX1325 versus sham at week 24. Follow-up assessments were conducted through week 48.1

The ASPIRE trial, a phase 2b, multicenter trial, utilized aflibercept as an active comparator. A total of 52 subjects were included, receiving intravitreal injections of either 10µg UBX1325 or 2mg aflibercept. Patients were dosed every 8 weeks. The primary endpoint is change in BCVA from baseline to week 24, which will indicate noninferiority. Follow-up assessments will be conducted through week 36 to monitor the effect’s durability.1

BEHOLD saw UBX1325 well tolerated with few TEAEs while substantially improving and maintaining BCVA. The difference between UBX1325 and sham in mean BCVA change to week 48 was +5.6 ETDRS letters (95% CI, -1.5 to 12.7). Patients in the UBX1325 arm also stabilized or improved central subfield thickness.1

Investigators found that 53% of patients receiving UBX1325 did not require anti-VEGF rescue at any point, compared to 22% in the sham arm. Additionally, 30% of UBX1325-treated subjects showed 2-step improvements in diabetic retinopathy severity score (DRSS) at week 48.1

HCPLive sat down with lead presenter Dante Pieramici, MD, California Retina Research Foundation to discuss the studies, their results, and the implications of this new genetic therapy for common ocular diseases. Pieramici discussed the relevance of cellular senescence and the reason this trial focused on this metric.

“Senescence is one of the hallmarks of aging,” Pieramici told HCPLive. “But it also seems to play a role in retinal diseases such as diabetic retinopathy. There’s a lot of preclinical evidence in animal models that in models of retinopathy, cellular senescence occurs, the cells become senescent, they stop dividing. These are vascular cells, and they start producing secretory factors such as cytokines that can negatively impact the cells surrounding them.”

Pieramici also spoke to the potential next steps for UBX1325 and its uniqueness in the medical field.

“So, this is a very unique mechanism of action,” Pieramici said. “It’s actually going to help get rid of the cells that are sick, that are probably causing damage to the cells in their vicinity and then allowing replacement with more healthy cells. And so, I think it’s a completely different mechanism of action, but one that probably can be supplemented by using anti-VEGF agents as well.”

Editor's Note: Pieramici reports the following disclosures: NGM, Gemini, Neurotech, 4DMT, Oculus, Boehringer, and others.

References

1. Pieramici D, Sapieha P, Bhisitkul R, Mallinckrodt F, Klier S, et al. Senolytic Candidate UBX1325 for Diabetic Macular Edema: The BEHOLD Phase 2 and ASPIRE Phase 2b Trials. Abstract presented at the 43rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, July 30-August 2, 2025.

2. Macha N, Yu M, Sapieha P, et al. Multifocal Electroretinography Changes after UBX1325 (Foselutoclax) Treatment in Neovascular Age-Related Macular Degeneration. J Clin Med. 2024;13(18):5540. Published 2024 Sep 19. doi:10.3390/jcm13185540