Unity Biotechnology announces positive data in phase 2 BEHOLD study of UBX1325 in patients with DME

The study provided evidence of safety, visual acuity improvement and structural stability in a difficult-to-treat patient population.

Unity Biotechnology Inc. today announced 12- and 18-week data from its Phase 2 BEHOLD study of UBX1325, a senolytic Bcl-xL inhibitor, in patients with diabetic macular edema (DME).

During a conference call held today, Unity officials detailed Phase 2 BEHOLD DME study (NCT04857996) 12- and 18-week data.

“We have achieved a strong proof of concept for UBX 1325,” said Anirvan Ghosh, PhD, CEO of Unity Biotechnology, during the conference call. “We believe a senolytic approach can be key to the treatment of a number of other diseases.”

According to the company, UBX1325 is an investigational compound being studied for age-related diseases of the eye, including diabetic macular edema (DME), age-related macular degeneration (AMD), and diabetic retinopathy (DR) that is not approved for any use in any country. UBX1325 is a potent small molecule inhibitor of Bcl-xL, a member of the Bcl-2 family of apoptosis regulating proteins. UBX1325 is designed to inhibit the function of proteins that senescent cells rely on for survival.

In a Phase 1 clinical study in advanced wet AMD and DME, UBX1325 showed a favorable safety profile and improvements in visual acuity sustained through 24 weeks following a single intravitreal injection. In preclinical studies, UNITY has demonstrated that targeting Bcl-xL with UBX1325 preferentially eliminated senescent cells from diseased tissue while sparing cells in healthy tissue.

At 18 weeks after a single UBX1325 injection, the mean change in BCVA of UBX1325-treated subjects was an increase of 6.1 ETDRS letters, representing an improvement of +5.0 ETDRS letters compared to sham-treated subjects (p = 0.0368). In addition, patients treated with UBX1325 maintained CST compared to sham-treated patients who demonstrated progressive worsening of CST (i.e., increased retinal thickness) through 18 weeks.

The separation of UBX1325-treated patients from sham-treated patients at 18 weeks in measures of both visual function and retinal structure following a single UBX1325 injection suggests that one dose could have a durable therapeutic effect. The current standard of care for DME with the leading anti-VEGF therapeutic requires 3-5 monthly loading doses followed by every 8-week dosing, imposing a significant treatment burden on patients.

Ghosh pointed out that the 12- and 18-week BEHOLD results proved to be impressive considering that UBX1325 was given as a single injection in a patient population in which anti-VEGF treatment was no longer providing optimal benefit.

“The vision gains observed are greater than what has been previously reported with the standard of care in similar patient populations, and the durability of effect suggests that UBX1325 could address the large unmet need for longer-lasting, disease-modifying treatments for patients with DME,” he -These data represent an important and exciting step in validating the senolytic therapeutic concept that is core to Unity’s platform.”

The study provided evidence of safety, visual acuity improvement and structural stability in a difficult-to-treat patient population.

Overall Safety

UBX1325 demonstrated a favorable safety and tolerability profile with no cases of intraocular inflammation, retinal vein occlusion, endophthalmitis, or vasculitis.

At 12 weeks, a primary analysis set of 65 patients, patients enrolled in BEHOLD were receiving regular anti-VEGF treatment prior to enrollment into the study (mean rate of approximately 4 injections in the preceding 6 months) with the last anti-VEGF injection occurring 3 – 6 weeks prior to randomization.

Moreover, the patients treated with a single injection of UBX1325 had a mean improvement in BCVA of +4.7 ETDRS letters from baseline compared to +1.3 ETDRS letters in sham-treated patients (p = 0.1148).

Patients treated with UBX1325 had a mean change in CST of -1.4 μm from baseline compared to +40.3 μm in sham-treated patients (p=0.0747). 

At 18-weeks, a primary analysis set of 54 patients, patients treated with UBX1325 had a mean improvement in BCVA of +6.1 ETDRS letters from baseline compared to +1.1 EDTRS letters in sham-treated patients (p = 0.0368). Patients treated with UBX1325 had a mean change in CST of +3.2 μm from baseline compared to +53.5 μm in sham-treated patients (p = 0.0719) 

Based on pre-defined proof-of-concept criteria of alpha=0.15, the study demonstrated a statistically significant treatment effect for both BCVA and CST at both 12 and 18 weeks.

Arshad M. Khanani, MD, MA, FASRS, director of clinical research at Sierra Eye Associates, Reno, Nevada, pointed out that a 6.1-letter gain from baseline in DME patients who had been actively receiving anti-VEGF treatment and had vision loss with persistent fluid is a clinically meaningful outcome.

“The results are particularly noteworthy considering that there is a progressive improvement in vision through 18 weeks after a single injection of UBX1325,” Khanani said. “A treatment based on a new mechanism of action that shows a meaningful and sustained improvement in BCVA and stability of CST while also reducing the frequency of injections would be of huge value for patients with DME.”

In outlining the data during the conference call, Robert Bhisitkul, MD, PhD, professor of ophthalmology at University of California San Francisco, noted that the study is a multi-center, randomly assigned, double-masked, sham-controlled study designed to evaluate the safety, tolerability, efficacy and durability of a single 10 mcg dose of UBX1325 in patients with DME evaluated though 24 weeks.

“In the study, we enrolled 65 patients being actively treated with anti-VEGF immediately prior to the start of the study,” he explained.

Those patients had a visual acuity deficit (73 ETDRS letters, approximately 20/40, or worse) and residual retinal fluid (CST ≥ 300 μm). Patients have the option of rolling over to a 48-week long term extension and a majority of patients who have completed their 24-week visit have opted to remain in the study.

Jamie Dananberg, MD, chief medical officer of Unity, pointed out that on the wave of the positive proof-of-concept data, the company believes UBX1325 could represent a much-needed alternative to all other currently available treatments for DME, including the standard of care anti-VEGF therapy.

“The 12- and 18-week results indicate that a single injection of UBX1325 resulted in significantly greater letter gains and stabilization of retinal structure than the sham treatment, but also likely altered the disease trajectory of these patients who had been on anti-VEGF treatment,” he concluded. “We are greatly encouraged by these findings and look forward to our upcoming 24-week BEHOLD (DME) and 16-week ENVISION (wet AMD) study readouts in the months ahead.”

Bhisitkul noted that while the two studies share some similarities, they are very different.

“AMD is a more aggressive and rapidly progressing disease,” he said. “We have seen some extension and support of the Phase 1 data in the Phase 2 data. Hopefully, we will see the same thing in Behold.”