Unity Biotech: Alternative to Anti-VEGF Shows Safety, Efficacy in Diabetic Macular Edema

 

• A single intravitreal injection of UBX1325 (foselutoclax) was shown to be safe in patients with diabetic macular edema.
• The drug also showed potential efficacy in patients who failed to optimally respond to anti-VEGF treatment.
• Results of a phase IIb trial comparing UBX1325 to anti-VEGF therapy are expected later this year.

A single intravitreal injection of UBX1325 (foselutoclax), a novel senolytic small molecule inhibitor, had a tolerable safety profile and "trends suggestive of potential efficacy" in patients with diabetic macular edema (DME) who failed to optimally respond to anti-vascular endothelial growth factor (VEGF) treatment, a phase II sham-controlled trial showed.

Among 65 patients followed for up to 48 weeks, five grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in the UBX1325 group, all of which were considered serious, while four TEAEs occurred in the sham group, three of which were considered serious, reported Przemyslaw Sapieha, PhD, of UNITY Biotechnology in San Francisco, and colleagues in NEJM Evidenceopens in a new tab or window.

In regard to efficacy, a secondary outcome, the difference between UBX1325 and sham in mean change to week 48 in best-corrected visual acuity was 5.6 more Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (95% CI -1.5 to 12.7).

The drug "seems to have a safer profile than anti-VEGF, and it led to sustained improvements in vision lasting up to a year," Sapieha told MedPage Today.

He pointed out that frequent anti-VEGF injections into the eye can be a significant burden, and many patients with DME are of working age. In addition, anti-VEGF agents can cost thousands of dollars per injectionopens in a new tab or window, and patients may need monthly treatments.

UBX1325 works by eliminating cells that become dysfunctional in DME and produce inflammatory factors, Sapieha said, adding that the mean vision improvements in the study are clinically significant, equal to a line of vision, and subgroups with less severe cases gained 10-15 letters.

A small pilot study previously showedopens in a new tab or window that UBX1325 achieved sustained improvement in visual acuity in patients with DME or neovascular age-related macular degeneration.

While anti-VEGF agents have become a standard therapy, Emily Y. Chew, MD, of the National Eye Institute, noted in an accompanying editorialopens in a new tab or window that they're "far from a perfect treatment."

"For example, in one trialopens in a new tab or window, while ranibizumab [Lucentis] 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," Chew wrote. "Furthermore, a secondary analysisopens in a new tab or window 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."

Chew said that the "relatively small" new trial shows 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."

She said that the loss to follow-up rate was higher than anticipated, possibly because patients in the sham arm sought treatment elsewhere. "Thus, it may have been more appropriate and a fairer comparator to have an active anti-VEGF treatment as the comparator with foselutoclax," she wrote.

Results of a phase IIb trial comparing UBX1325 to anti-VEGF therapy are expected later this year.

From June 2021 to April 2022, Sapieha and colleagues randomized 65 participants with DME and prior suboptimal response to anti-VEGF treatment to either UBX1325 (n=32) or sham (n=33). Mean age was 62.5, 67.7% were men, and 75.4% were white.

Participants received an average of four anti-VEGF injections in the 6 months prior to trial enrollment, with the last injection ranging from 3 to 6 weeks prior to randomization.

As for study limitations, the researchers highlighted the dropout rate of 25% by week 48 and noted that "other definitions of suboptimal response" to anti-VEGF agents could lead to different results. "Moreover, the patient population best suited to UBX1325 is still being explored and alterations to the patient population could also influence response," they wrote.

isclosures

The study was supported by UNITY Biotechnology.

Sapieha is chief scientist with UNITY Biotechnology. Some co-authors disclosed employment and consulting relationships with the company, and some had other disclosures.

Chew disclosed relationships with Merck, NGM Bio, Genentech, 4DMT, and Bionic Sight.

Primary Source

NEJM Evidence

Source Reference: opens in a new tab or windowKlier S, et al "Safety and efficacy of senolytic UBX1325 in diabetic macular edema" NEJM Evid 2025; DOI: 10.1056/EVIDoa2400009.

Secondary Source

NEJM Evidence

Source Reference: opens in a new tab or windowChew EY "Foselutoclax (UBX1325) for diabetic macular edema -- a potential novel therapy?" NEJM Evid 2025; DOI: 10.1056/EVIDe2500004.

https://www.medpagetoday.com/ophthalmology/generalophthalmology/115290