A recent study published in Nature Medicine assessed the efficacy of a novel therapy that targets cellular senescence in patients with advanced diabetic macular edema (DME) who did not benefit from anti-vascular endothelial growth factor (anti-VEGF) therapy.
Give me some background first.
At various stages of diabetic retinopathy (DR)—a vision-threatening complication of diabetes—compromised vascular endothelial barrier function can lead to DME.
A previous study from the research team showed that sustained hyperglycemia induces DNA damage to vascular endothelial cells, resulting in cell senescence (i.e., cells that stop multiplying but don’t die) and micro-inflammation that further cause the reduced barrier function associated with DME.
Therefore, investigators sought to understand how senescent cells contribute to DME to develop a novel senolytic therapy (i.e., intervention that eliminates senescent cells) for the long-term treatment of DME.
What about current treatments for DME?
While anti-VEGF therapies are one of the current standards of care for DME, these treatments require frequent intravitreal injection, are suboptimal in a large proportion of patients, and the efficacy can diminish over time.
Corticosteroids and grid/focal laser therapy are other interventions for DME; however, they are associated with increased intraocular pressure (IOP) and cataracts as well as irreparable damage to the retina, respectively.
Consequently, there is an unmet need for safe, long-lasting, and disease-modifying therapies for DME patients.
Now talk about the study.
After performing pharmacological elimination of senescent cells in a mouse model of DME, investigators noted reduced diabetes-induced retinal vascular leakage and preserved retinal function.
As a result, the research team conducted a phase 1 single-ascending-dose safety study (NCT04537884) of UBX1325 (foselutoclax).
What is UBX1325?
UBX1325 is a senolytic small-molecule inhibitor of BCL-xL, which is a mitochondrial protein responsible for preventing cell apoptosis.
Intravitreal injection of UBX1325 is intended to remove senescent endothelial cells, leading to reduced local inflammation, improved function of the blood-retina barrier, and, as a result, improved visual function in diabetic retinas.
The novel drug was developed by scientists at UNITY Biotechnology in collaboration with the Maisonneuve-Rosemont Hospital Research Center from the Université de Montréal in Montréal, Quebec, Canada.
Findings?
The primary objective of assessment of safety and tolerability of UBX1325 was achieved.
Of note, the exploratory phase 1 efficacy data suggested that one injection of UBX1325 resulted in improvements in vision for at least 6 months.
Additionally, results from the mouse model also indicated that inhibition of BCL-xL may provide benefits broadly across retinal vascular diseases.
Expert opinion?
According to the study authors, “Therapeutic clearance of senescent cells can potentially remove an underlying source of pathogenesis and thus allow healthy endothelial cells to regenerate and remodel retinal vasculature, ultimately leading to long-term disease modification.”
Take home.
These findings suggest that therapeutic targeting of senescent cells in a diabetic retina with a BCL-xL inhibitor (i.e., UBX1325) may provide a long-term, disease-modifying intervention for DME.
Further, as the accumulation of senescent cells has been reported in various geriatric and metabolic diseases, senolytic drugs have the potential to become treatments for a spectrum of age-related conditions.
Next steps?
UNITY Biotechnology is advancing UBX1325 in the phase 2b ASPIRE trial (NCT06011798).
ASPIRE is a randomized, double-masked, active-controlled study; data is expected to be released in the fourth quarter of 2024.