Author: Arshad Khanani
Co-authors: Sharon Klier, Ben Xie, Lauren Masaki, Sara Huang, Jamie Dananberg
Abstract
Purpose: Cellular senescence is implicated in the vascular pathology of diabetic macular edema (DME).This study is testing the safety and efficacy of a novel, small molecule, Bcl-xL inhibitor senolytic agent in a Ph2 study in DME. Preclinical data in the OIR and STZ mouse models of retinopathy supports the role of senescence in the pathophysiology of DME and of UBX1325 as a potentialnovel therapeutic for this disease. In Ph1, patients receiving the higher doses of UBX1325 achieved an approximate 10 ETDRS letter gain within 2 weeks, an effect maintained for up to 24-weeks along with stability of retinal fluid.Setting: This study was a prospective, multi-center, randomized, double-masked study comparing a single injection of UBX1325 10µg vs. sham procedure. The study was conducted in 23 enrolling sites within the United States and Canada.
Methods: This Phase 2 study (www.clinicaltrials.gov NCT04857996) is underway and is currently active and fully enrolled. The study enrolled patients ?18 years of age with DME with best corrected visual acuity (BCVA) between 73 to 20 Early Treatment Diabetic Retinopathy Study (ETDRS)letters (equivalent to 20/40 to 20/400 on the Snellen scale) and residual intra-retinal or sub-retinal fluid despite having received at least 2 anti-VEGF antibody injections in the prior 6 months. A total of 65 patients were enrolled and randomized 1:1 to receive, 3 ñ 6 weeks after their last anti-VEGF treatment, either a single intravitreal injection of UBX1325 10µg or sham procedure. Patients will be followed for approximately 48 weeks with primary endpoint assessment occurring at 24 weeks and includes the change from baseline in BCVA, central subfield thickness (CST), the number of anti-VEGF rescue treatments received during the study period, presence of intra- or sub-retinal (IR/SR) fluid, leakage, and area(s) of non-perfusion by optical coherence tomography angiography (OCTA) and fluorescein angiography (FA), and safety and tolerability.
Results: An interim analysis is planned to occur at mid-year, the data of which will be presented from all patients enrolled in the study up through the 12-week time point. These data will be the first conference presentation of UBX1325 in a Phase 2 study in diabetic macular edema, representing a unique evaluation of the therapeutic potential in retinal disease of a senolytic agent. The data presented will include safety and tolerability of UBX1325, change from baseline in UBX1325 vs. sham-treated patients in BCVA (ETDRS letters), CST (by SD-OCT), change in area-under-the-curve of BCVA and CST, change in DRSS score, proportion of patients gaining ?5 and ?10 ETDRS letters, proportion of patients with macular fluid (by SD-OCT), proportion of patientsrequiring anti-VEGF rescue treatment, and exploratory analyses of extent of leakage (by FA) and non-perfusion (by FA and OCTA).
Conclusions: UBX1325 is a novel senolytic agent that is being investigated for the treatment of DME. These data represent the first clinical confirmation of preclinical data observing improvement in retinal function (ERG) and leakage in STZ mice and reduced neovascularization and ischemicarea in the oxygen-induced retinopathy mouse model. Such data represents the potential proof-of-concept for the safety and tolerability and the effect of a senolytic agent on visual function and on retinal structure, capillary leakage, and ischemia. As this mechanism of action is orthogonal to anti-VEGF therapy, UBX1325 could provide an important benefit as a stand-alone treatment, in combination regimen, or for use in patients who have a suboptimal response to current standard of care treatments for diabetic macular edema.
Financial Disclosure: Arshad Khanani : consultant and receives research funding from UNITY Biotechnology.All others - Employees of UNITY
