Mixed Results With Senolytic Agent for Retinal Disease

SEATTLE -- A drug targeting senescent cells in diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) produced mixed outcomes in two separate clinical trials.

The 48-week results from the placebo-controlled BEHOLD study showed that UBX-1325 significantly improved best-corrected visual acuity (BCVA) by 6.2 letters in patients with DME, but did not differ significantly from the sham group, whose BCVA remained stable. On the other hand, UBX-1325 did not demonstrate noninferiority versus aflibercept (Eylea) after 24 weeks of follow-up in the ENVISION study of patients with nAMD (wet AMD).

In both trials, UBX-1325 significantly reduced the need for supplemental or rescue medication, as reported here at the American Society of Retina Specialists meeting.

"In the phase II BEHOLD trial, a single injection [of UBX-1325] improved visual acuity at 48 weeks, led to 50% of patients achieving a rescue-free interval at least until 48 weeks, maintained retinal structure and anatomy, and had a generally favorable safety and tolerability profile with no intraocular inflammation," said Arshad Khanani, MD, of Sierra Eye Associates and the University of Nevada in Reno.

Patients with more unfavorable baseline characteristics appeared to derive the most benefit from UBX-1325, he added.

The rationale for development of UBX-1325 came from recognition that senescent cells -- stressed, non-dividing, but still metabolically active cells -- accumulate in areas of disease activity and drive pathology, said Khanani. UBX-1325 is a BcL-XL inhibitor that selectively eliminates senescent cells, reduces inflammation and vascular leakage, and in preclinical models, appears to affect disease modification by means of vascular remodeling.

The BEHOLD trial involved patients with active DME, defined by need for at least two intravitreal injections within the previous 6 months, residual retinal fluid (≥300 µm), and a BCVA ≤73 letters. Actual baseline characteristics included a median of 4.1 intravitreal injections, retinal thickness of 439 µm, and BCVA of 61.4 letters.

Patients were randomized to a single intravitreal injection of UBX-1325 for sham injection and followed for 48 weeks. The primary outcomes were safety and tolerability, change in BCVA from baseline, durability of response, retinal fluid and central subfield thickness (CSFT), and proportion of patients in the UBX-1325 arm requiring at least two supplemental treatments. Criteria for rescue treatment consisted of a decrease of 10 letters or more in BCVA or a CSFT increase ≥75 µm.

Data analysis included 65 randomized patients. The UBX-1325 group had a median age of 64, HbA1c of 8.0%, diabetes duration of 17 years, DME duration of 3.5 years, BCVA of 61 letters, and CSFT of 425 µm.

The results showed significant improvement in BCVA from baseline to 48 weeks in the UBX-1325 group (P<0.05). That compared with an increase of less than one letter in the sham group. CSFT declined slightly in the UBX-1325 arm (-13.7 µm) and increased in the sham group (24.2 µm).

More than half (53%) of patients in the UBX-1325 arm required no rescue medication at 48 weeks as compared with 22% of patients randomized to sham injections (P=0.0159). Khanani said 50% of patients in the sham group required two or more rescue treatments, as compared with 37.5% in the UBX-1325 group.

Treatment-emergent adverse events (TEAEs) occurred in a similar number of patients in the two groups. In the UBX-1325 arm, six patients had a treatment-related TEAE, five had a grade ≥3 TEAE, and five had a serious TEAE. No intraocular inflammation, endophthalmitis, retinal artery occlusion, or vasculitis occurred in either group.

A prespecified subgroup analysis showed that patients with worse baseline BCVA, worse CSFT, lower HbA1c, and higher Diabetic Retinopathy Severity Scale scores exhibited trends toward greater improvement in BCVA.

UBX-1325 produced mixed results in the 24-week ENVISION study. The trial missed the primary endpoint of change in BCVA versus the aflibercept control group, but 52% of patients treated with the senolytic agent required no rescue anti-VEGF treatment during the 24 weeks of follow-up, reported Raj Maturi, MD, of the Midwest Eye Institute and Retina Partners Midwest in Indianapolis.

The study involved 51 patients with nAMD. They had received an average of four anti-VEGF injections in the previous 6 months, had a baseline mean BCVA of 60 letters, CSFT of about 370 µm. They were randomized to intravitreal UBX-1325 or aflibercept. Patients in the UBX-1325 group received a single aflibercept injection 4 weeks after the study medication.

After 24 weeks of follow-up, the UBX-1325 group had a mean reduction in BCVA of less than one letter, reflecting stable vision. Unexpectedly, patients in the aflibercept arm had a gain of 3.5 letters, which accounted for the investigational therapy's failure to achieve noninferiority, said Maturi. CSFT did not improve with UBX-1325. The drug was well tolerated, and no patient developed intraocular inflammation.

A post hoc analysis suggested that UBX-1325 performed better among patients with a nAMD duration greater than 2 years and presumably with a greater accumulation of senescent cells.

Maturi speculated that a single dose of aflibercept after UBX-1325 might not have been sufficient to achieve an anti-VEGF plateau. A second stage of the ENVISION trial is evaluating the senolytic agent in combination with anti-VEGF therapy.