BEHOLD Trial: UBX1325, a potential new therapeutic option for treating diabetic macular edema

Senescent cells accumulate in areas of disease activity in DME and wet age-related macular degeneration and release mediators that drive the pathology. UBX1325 seems to prevent that disease activity. (Image Credit: Adobe Stock/Kitreel)

Reviewed by David S. Boyer, MD

The phase 2 clinical trial of UBX1325 (Unity Biotechnology, Inc.) in patients with diabetic macular edema (DME) showed a significant and clinically meaningful improvement in visual acuity (VA) through week 48 of treatment, according to David Boyer, MD, Adjunct Clinical Professor of Ophthalmology, University of Southern California, Keck School of Medicine. He reported the results from the BEHOLD Study at the Clinical Trials at the Summit 2023, Park City, UT.

Boyer explained that senescent cells accumulate in areas of disease activity in DME and wet age-related macular degeneration and release mediators that drive the pathology. UBX1325 seems to prevent that disease activity.

Preclinical studies of UBX1325

A mouse model of oxygen-induced retinopathy that mimics preretinal neovascularization showed that 1 dose of UBX1325 led to 2 distinctive vascular phenotypes, he explained.

First, because neovascularization is rich in BCL-xL (B-cell lymphoma-extra large), no pathological vasculature was seen in the UBX1325-treated retinas. Second, and in contrast to anti-vascular endothelial growth factor (VEGF) therapies, regeneration of functional blood vessels occurred.

The mouse pups were exposed to 75% oxygen from day 7 to 12 of life and then exposed to 21% oxygen (room air); the vascular phenotypes were analyzed at day 17 of life.

The mouse model showed decrease neovascularization and a significant decrease in the avascular area. This is in contrast to anti-VEGF therapy, that despite a decrease in the neovascular area, no change is seen in the avascular area.

“The activity of UBX1325 will reduce retinal hypoxia and prevent the production of angiogenic factors that are central to disease progression such as VEGF. This may be the basis for disease modification,” Boyer said.

BEHOLD study

Individuals with DME were included who had undergone repeated anti-VEGF treatments (≥2 injections/6 months; actual, 4.1 injections in previous 6 months), had residual retinal fluid (≥300 µm; actual, 439.6 µm), and had a VA deficit of 73 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters or worse (actual, 61.4 ETDRS letters).

Patients received either a 10-microgram dose of UBX1325 or sham treatment.

The study endpoints were the safety and tolerability of UBX1325, best-corrected VA (BCVA) change from baseline, durability of the response, subretinal and intraretinal fluid, central subfield thickness (CST) changes, and the proportion of patients treated with UBX1325 who needed 2 or more rescue treatments.

The results showed a marked drop in the need for anti-VEGF rescue therapy by patients treated with UBX1325 beyond week 18 compared to sham-treated patients through 48 weeks. Specifically, the median time to the first rescue treatmentin the UBX arm exceeded 48 weeks (at least 30 weeks greater than the sham arm), 50% of UBX-treated patients went without rescue throughout the study, and about 80% of sham-treated patients required rescue before 48 weeks, he reported.

The UBX1325-treated patients had significant improvements in BCVA from baselineof 6.7 letters at 24 weeks (P=.0031) and 5.6 letters at 48 weeks (P<.05) (excluding data post-rescue), and at all time points, the UBX1325-treated patients had a significant BCVA improvement (P=.05) from baseline ) including data post-rescue, except for sham weeks 4 and 8 and UBX1325 week 8.

The results showed that 50% of UBX1325-treated patients gained at least 5 letters of vision through 48 weeks, with over 20% gaining at least 10 letters (excluding post-rescue data).

The CST remained stable in UBX1325-treated patients compared to worsening in sham patients at 48 weeks (excludingpost-rescue data).The retinal structure was maintainedin UBX1325-treated patients with a CST that was lower than baseline and was -37.9 µm compared to sham at 48 weeks.

UBX1325 also had a favorable overall safety and tolerability profile with no development of intraocular inflammation.

Dr. Boyer concluded, “UBX1325 may be an important future therapeutic option for patients with DME.”