Arshad Khanani, MD: 48-Week Results of BEHOLD Study on UBX1325 for DME

New data indicates the potential proof-of-concept for the safety, tolerability, and efficacy of UBX1325 in patients with diabetic macular edema (DME), who have residual visual acuity deficits and macular edema after ≥6 months of anti-vascular endothelial growth factor (VEGF) therapy.

The research, presented at the American Society of Retina Specialists (ASRS) 41st Annual Meeting in a late-breaking session, suggests the novel senolytic BCL-xL inhibitor may represent a future treatment option for patients with DME.

“Because we know that DME is a disease where you have many inflammatory cytokines and of course, VEGF is the primary driver of disease, we have Ang-2, we have IL-6” presenting investigator Arshad Khanani, MD, director of clinical research at Sierra Eye Associates, told HCPLive at ASRS 2023. “The idea is that we are not going after those individual cytokines, but we are rather getting rid of the cells that are producing those cytokines because the cells are sick.”

Evidence has implicated cellular senescence in the vascular pathology of DME, with pre-clinical mouse model data of retinopathy suggesting the potential therapeutic rationale for UBX1325. The phase 2 BEHOLD study investigates the safety and efficacy, as well as evidence of biological activity, of a single intravitreal injection of UBX1325 in patients with long-standing DME.

BEHOLD was a prospective, multicenter, randomized, double-masked trial of UBX1325 versus sham conducted in 23 sites across the United States and Canada. Enrolled patients were ≥18 years old with DME, BCVA 73 - 20 ETDRS letters, and residual retinal fluid, plus previous treatment with ≥2 anti-VEGF injections in the preceding 6 months (last anti-VEGF given 3–6 weeks prior to randomization). Overall, a total of 65 patients were randomized 1:1 to receive either a single injection of intravitreal UBX1325 10 µg or sham, with a 48-week follow-up period.

Patients could be rescued with anti_VEGF based on prespecified criteria or at the investigator’s discretion. Primary endpoints for the trial included ocular and systemic safety and tolerability of a single intravitreal injection of UBX1325. Secondary and exploratory endpoints included the change in BCVA, central subfield thickness, number of anti-VEGF rescue treatments received during the study period, retinal fluid, leakage, and capillary nonperfusion.

Upon analysis, the investigative team found UBX1325-treated patients had a significant improvement in BCVA of +6.2 ETDRS letters from baseline (P = .0037), suggesting a difference +5.6 ETDRS letters compared to sham (P = .1198) at 48 weeks. Almost 60% of patients treated with UBX1325 gained ≥5 letters from baseline compared to ≤20% of sham-treated patients.

Moreover, retinal structure was maintained in UBX1325-treated patients with a CST of –16.6 µm from baseline at 40 weeks, representing a treatment difference of –56.3 µm (P = .0479), as well as a CST of –13.7 µm from baseline at 48 weeks, representing a treatment difference of –37.9 µm (P = .2289). Data showed 53.1% of UBX1325-treated patients did not require anti-VEGF rescue for ≥48 weeks compared to only 21.9% of those in the sham arm (P = .0096). The analysis through 48 weeks indicated no events of intraocular inflammation, while adverse events occurring at higher rates versus sham were mostly attributable to intravitreal procedures.

“The next study, the ASPIRE study, will be looking at patients with UBX1325 compared to a standard of care control arm,” Khanani told HCPLive. “And obviously, you know, we are looking forward to participating in that trial because it's a novel mechanism of action. And we need to look into it further because of the positive data we have seen from the BEHOLD study."

Relevant disclosures for Dr. Khanani include 4DMT, Allergan, Bausch and Lomb, Genentech, Iveric Bio, Kodiak, Novartis, Opthea, Regenxbio, and Roche.