麻豆传媒

NEW YORK CITY -- An investigational drug targeting senescent cells achieved sustained improvement in visual acuity in patients with diabetic macular edema (DME) or neovascular age-related macular degeneration (AMD), a small pilot study showed.

After single doses of UBX1325, four of eight evaluable patients with advanced DME had at least 10 letters of improvement in best corrected visual acuity (BCVA) at 24 weeks, and five of eight had improvement of at least five letters. Nine evaluable patients with AMD had sustained improvement of three to four letters at 24 weeks.

Retinal thickness decreased in both groups, but the improvement did not persist during 6 months of follow-up. All patients had prolonged periods without rescue medication that blocks vascular endothelial growth factor (VEGF), and some patients in both groups required no rescue treatment, reported Raj Maturi, MD, of the Midwest Eye Institute in Indianapolis, during the American Society of Retina Specialists meeting.

"UBX1325 demonstrated safety, tolerability, and disease-relevant activity after just a single injection in a phase I study that lasted six months," he said. "The effect was rapid on vision within two weeks. It's an entirely new mechanism of action, and given its long duration, probably quite favorable pharmacodynamics."

During a discussion that followed the presentation, the drug's therapeutic potential beyond ophthalmic conditions emerged quickly.

"The idea of blocking senescence has tremendous implications for the entire body," said Abdhish Bhavsar, MD, of Retina Consultants of Minnesota in Minneapolis. "What other organ systems or what other applications in the eye are you imagining yourself right now?"

Without hesitating, Maturi mentioned heart disease.

"A lot of people die from heart disease," he said. "If you just kind of decrease or lessen the burden and allow normal tissue to grow, there might be some long lives that can happen at that point. Obviously, we're only looking at the eye because that's kind of what we're trained in, but the implications are neat."

UBX1325 is a product of an emerging therapeutic paradigm known as senolytics, treatment that eliminates senescent cells to allow restoration of healthy tissue. In the case of retinal diseases DME and AMD, targeting senescent cells and neutralizing factors that drive senescence has potential to eliminate the root cause of disease progression, said Maturi.

Senescence occurs as a result of cellular stress, caused by factors such as reactive oxygen species, he continued. As senescent cells accumulate, they produce cytokines, chemokines, and VEGF, which then recruit macrophages, CD4 lymphocytes, and fibroblasts into tissue. The process leads to development of fibrosis and other end-stage disease factors associated with AMD and DME, in this case.

"What if we could introduce a senolytic therapy that selectively eliminates just the senescent cells?" said Maturi. "Maybe it's a chance to get normal tissue back and potentially improve retinal function."

In preclinical studies, UBX1325 bound to its target Bcl-xL at a normal rate but did not induce apoptosis in animals that did not have an accumulation of senescent cells. When senescent cells were present, UBX1325 binding induced them, and only them, to undergo apoptosis.

In mice, intravitreal injection of UBX1325 led to clearance of neovascularization similar to what would be expected with anti-VEGF treatment. Unlike anti-VEGF therapy, UBX1325 also reduced the avascular area within the retina.

"We suspect that vascular remodeling and re-engagement occurs, so there is actually less dead tissue as compared to vehicle," said Maturi.

The preclinical data provided the basis for a phase I dose-escalation trial with a primary focus on safety. Investigators enrolled 24 patients, 12 each with advanced DME or previously treated AMD. Initially, eligible patients had BCVA of 20/80, subsequently modified to allow enrollment of patients with BCVA of 20/40 or worse.

In all cases, anti-VEGF therapy was considered no longer beneficial, and patients had not received an anti-VEGF agent or corticosteroids within 3 months prior to enrollment. Patients with DME had ≥350 µm of fluid and patients with AMD had evidence of sub- or intraretinal fluid accumulation.

In the DME cohort a single dose of UBX1325 led to rapid improvement in BCVA of 5-10 letters, usually within the first 2 weeks. The improvement was maintained in a majority of patients at 24 weeks. Central subfield thickness (CST) also declined rapidly but gradually returned to baseline levels during follow-up. Six patients required no rescue anti-VEGF treatment; two required rescue treatment after about 8 and 16 weeks, respectively.

Patients with AMD had rapid but more modest improvement in BCVA, topping out at about 4-5 letters. The improvement fluctuated during follow-up but was generally maintained to 24 weeks. In contrast to the DME cohort, CST declined gradually, reaching a maximum of about 25% at 12 weeks and then remained stable to 24 weeks. Three patients received no rescue medication, four received rescue treatment after about 12 weeks, and two received rescue therapy at 22 weeks.

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