Most of the research relevant to the question of whether localized clearance of senescent cells can effectively treat age-related conditions has taken place in the context of osteoarthritis. While adding senescent cells to a joint is sufficient to provoke the onset of osteoarthritis, clearing senescent cells from only the joint region is not sufficient to produce significant patient benefits. The present consensus is that the senescent cells present in the rest of the body are producing a significant contribution by their signaling: those cells may be more distant, and their contributions thus more dilute, but there are a lot more of them.
UNITY Biotechnologies chose to pursue localized administration of senolytics in their initial phase 1 and phase 2 trials for both knee osteoarthritis and macular degeneration. Adopting a localized injection strategy is a time-worn approach intended to make things easier with regulators, as the much lower, localized dose means that there is a greatly reduced risk of side-effects. Unfortunately for UNITY investors, the outcome has been a demonstration, first in the knee, and now in the eye, that localized removal of senescent cells produces some benefit, but not as much as hoped, and not enough to show a clear advantage in human trials.
The conclusion adopted by the rest of the industry is that systemic, whole-body clearance of senescent cells is required to remove enough of the harmful effect of the senescence-associated secretory phenotype (SASP) on tissue function to produce meaningful gains for patients.
UNITY Biotechnology's lead asset, UBX1325, failed to show non-inferiority to Regeneron's anti-VEGF drug aflibercept in a Phase II wet age-related macular degeneration (wAMD) trial. This sent the biotech's shares tumbling 46% in premarket trading on Monday. The 24-week data are from the Part A portion of the proof-of-concept Envision study of UBX1325, a Bcl-xL inhibitor. The trial involved 51 patients with wAMD who received either two 10 mcg doses of UBX1325 at week zero and week four or anti-VEGF agent aflibercept 2 mg every eight weeks.
The trial used the Early Treatment Diabetic Retinopathy Study (ETDRS) to assess the therapies, which revealed an early and unexpected visual gain of 3.5 ETDRS letters with aflibercept, according to Unity. The 3.5-letter gain with aflibercept was mostly maintained for the study's duration. UBX1325 monotherapy, meanwhile, reduced letters by 0.8 from baseline.
Patients were already receiving aflibercept when they enrolled in the trial, but benefit from the therapy was not optimal, according to the press release. More than half (52%) of patients who received UBX1325 did not require anti-VEGF treatment throughout the 24 weeks of the trial, UNITY reported.
UNITY Biotechnology, Inc. ("UNITY"), a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced results from Part A of the Phase 2 ENVISION study of UBX1325 in patients with wet age-related macular degeneration (AMD) who were not achieving optimum benefit with their ongoing anti-VEGF therapy. UBX1325 treatment generally maintained visual acuity for 6 months (change of -0.8 ETDRS letters from baseline), with a majority of patients not requiring any anti-VEGF rescue. Patients in the every 8-week aflibercept arm had an early and unexpected gain of 3.5 letters at week 2 which was mostly maintained for the duration of the study. As a result of the strength on the control arm, the study did not meet the non-inferiority threshold compared to aflibercept through 24 weeks.
"Maintenance of visual acuity in hard-to-treat patients with active disease after withdrawal of their anti-VEGF therapy suggests that UBX1325 had an active treatment effect in wet AMD. We continue to be impressed with the durability of effect of UBX1325 in this patient population. Following a full analysis of ENVISION results, we will assess and optimize our resource allocation for future development of UBX1325. In the weeks ahead we will provide an update on Part B of the ENVISION study, and importantly, share 48-week data from the Phase 2 BEHOLD DME study. In DME, UBX1325 showed strong evidence of biologic activity and improvement in visual acuity - and, as a result, we plan to initiate a Phase 2b study in the second half of this year."