Positive interim data in Phase 2 BEHOLD trial investigating UBX1325 in DMO patients

Dr Arshad M. Khanani, clinical associate professor of Sierra Eye Associates, University of Nevada, Reno, Nevada, United States, announced 12-week interim results of BEHOLD, a proof-of-concept Phase 2a study investigating the candidate UBX1325, a novel senolytic approach for previously-treated patients with diabetic macular oedema (DMO) in the “Late Breakings” session at this year’s European Society of Retinal Specialists (EURETINA) Meeting on 2nd September in Hamburg, Germany.

Dr Khanani began his presentation by describing how senescent cells accumulate in areas of disease activity in DMO and wet AMD, releasing mediators (growth factors, pro-fibrotic factors and inflammatory factors) that drive the pathology of these two diseases.

UBX1325, which is in development by the company Unity Biotechnology, is a small-molecule inhibitor of Bcl-xL, a member of the Bcl-2 family of apoptosis-regulating proteins. According to the company, it is designed to inhibit the function of proteins that senescent cells rely on for survival.

Key inclusion criteria

The Phase 2a study was undertaken in previously-treated patients with DMO. Patients enrolled had to have 73-20 ETDRS letters, an OCT with residual retinal fluid central subfield thickness (CST) of at least 300μm and at least two injections of anti-VEGF therapy in the preceding 6 months with the last injection occurring 3-6 weeks prior to randomisation.

They were then randomised to receive either a single 10-μg injection of UBX1325 or a placebo injection. Patient demographics were well-balanced between both arms of the study.

Safety and efficacy data were analysed at 12 and 18 weeks following randomisation. Rescue criteria were an increase in CST of +75 μm from the lowest value and/or a decrease in best-corrected visual acuity (BCVA) of 10 ETDRS letters from the highest value.

Endpoints and methods

Safety and tolerability were one of the primary endpoints of the BEHOLD study, the others being visual acuity by BCVA, macular oedema as assessed on optical coherence tomography by CST and the proportion of patients receiving rescue.

There were 65 patients enrolled in the 12-week arm of the study and 54 patients in the 18-week arm. BCVA and CST analyses were performed by mixed model repeated measures (MMRM). This methodology takes post-rescue data into account so that the analyses reflect the treatment effect and not the effects of anti-VEGF rescue.

Improved BCVA

Patients treated with UBX1325 had a mean increase of 4.7 letters compared with 1.3 letters in the control group (P = 0.1148). At the 18-week time point, treated patients gained 6.1 letters, compared with 1.1 letters in the control group with (P = 0.0368). According to Dr Khanani, the improvements in BCVA were durable and robust across a range of disease severity.

Additionally, patients treated with UBX1325 maintained their retinal structure better than patients in the control group. UBX1325 was found to be well tolerated, had a favourable safety profile and showed no signs of intraocular inflammation.

Dr Khanani pointed out that the 6.1-letter game from baseline was a clinically meaningful outcome and better treatment based on a new mechanism of action that shows sustained improvement in BCVA and stability of CST whilst also reducing injection frequency would be of great value for DMO patients. He added that the candidate is currently being evaluated in a Phase 2 study, ENVISION, in nAMD patients, with data from this expected to be presented at “future meetings”.