Senolytics, drugs that remove senescent cells from the body, are proving effective in clinical studies, showing the ability to restore damaged tissue to prior levels of function. While not the fabled fountain of youth, this approach appears to hold significant promise in the pursuit of reversing certain effects of aging and increasing individuals’ health spans.
Unity Biotechnology, one of only a few companies pioneering senolytics, currently focuses on ophthalmologic and neurologic diseases. Its aptly named Phase II BEHOLD study treated patients with diabetic macular edema (DME) for 24 weeks using a Bcl-xL inhibitor (UBX1325). Because senescent cells—but not healthy cells—need Bcl-xL to survive, starving the body of that protein eliminates the senescent cells without harming neighboring cells. Preclinical studies suggest the compound also limits retinal neovascularization and reduces vascular leakage, which are common symptoms of DME.
The trial was conducted among patients who had plateaued in response to anti–vascular endothelial growth factor (anti-VEGF) therapy, a common first-line therapy for DME. Their anti-VEGF therapy was halted, and Unity’s senolytic therapy was administered.
When the trial began in June 2022, participants “had fluid in the eye and visual deficits,” says neuroscientist Anirvan Ghosh, PhD, CEO of Unity Biotechnology. He adds that six months later, a “very significant majority of them do not need a second injection, and they all have gained vision well above where they started.” From the baseline measured at the beginning of the BEHOLD trial, participants’ vision had improved an average of two lines on an eye chart, an outcome that Ghosh asserts is “very meaningful.”
A Phase II study of UBX1325 among patients with wet age-related macular degeneration (AMD) is now underway, with results anticipated this spring.
Changing the standard of care
UBX1325, if approved, may shift the standard of care of anti-VEGF treatments. Those treatments involve large molecules and require multiple injections to ensure adequate quantities remain in the eye to exert a therapeutic effect. Anti-VEGF treatments also pose logistical problems. “A biologic is generally much more complex to create and store, so the whole supply chain for a biologic is more complicated than for a small molecule,” Ghosh notes. “In contrast, our therapy requires only a single injection of a small organic molecule.”
Once injected into the eye, UBX1325 clears in less than two weeks. “Within that period, it has done its job,” Ghosh remarks. The patients have no residual drug in their systems, thus substantially lessening drug-drug interaction risks.
The improvements documented so far suggest that removing senescent cells not only affects the disease process but may also bring the eye to a younger state. According to Ghosh, the company’s hypothesis is that if the drug is administered early in the disease process, patients should be able to go longer before this or other kinds of retinal diseases show up, because the health of the eye is improving.
Becoming comfortable with disruption
“The challenges [in developing UBX1325] really are not on the development side,” Ghosh says. “The practical issues, such as making the product, delivering it to patients, and ease of use, have been relatively easy. Even the regulatory approval pathway appears straightforward at this point.”
Ghosh suggests that for Unity, the major hurdle is the same one faced by any company with a disruptive therapy in a field with a well-established standard of care. To clear this hurdle, Unity is working to help physicians become comfortable with this very new approach to treatment and understand what this approach means to patients. Ghosh elaborates, “We work a lot with our key opinion leaders and investors, so they understand we’re not developing just another drug that is similar to or an improvement on an anti-VEGF.”
Finding evidence across systems
Ghosh joined Unity three years ago from Biogen, where he was senior vice president and head of research and early development. “We had to deal with a lot of intractable diseases that are associated with aging,” he recalls. As part of the journey to find innovative approaches to address the pathology of Alzheimer’s disease beyond amyloid beta plaques and tau tangles, “I came across senescent cells,” he emphasizes.
“When you’re in your 80s and beyond, your Alzheimer’s risk dramatically increases,” he relates. “One of the things that caught my attention was the evidence around the accumulation of senescent cells in the aging brain. I thought, ‘One of these days, that’s going to be a big story,’ so I was fascinated when the possibility of coming to Unity came up.
“Nobody fully understands this science, but what was compelling was the consistency of evidence across animals and across systems.”
In the context of aging among vertebrates, including humans, there is a large increase in the number of nondividing, metabolically active cells. These senescent cells are present normally, but in a stressed environment—such as an eye affected by diabetes or macular degeneration—their numbers increase. Removing that senescence burden in the hopes of improving disease trajectories is foundational to Unity, Ghosh emphasizes, adding that these therapies offer the possibility of normal, healthy aging rather than dysfunctional old age.
Moving from skepticism to enthusiasm
“Senolytics,” Ghosh says, “is a psychological thing for people to get their heads around.” The concept of slowing the aging process or potentially reversing its effects on tissue comes with a healthy degree of skepticism. “Until you see it, you just don’t think it can happen,” he admits.
The data Unity has released in the past few months may provide the objectivity that physicians need to convince them to participate in clinical trials. “Ophthalmologists love innovation,” Ghosh notes. “When you talk with them, their instinct is to think about the path for earlier intervention, to prevent the disease from occurring.” Preventing serious disease is, in Ghosh’s view, the future of senolytics.
“We have learned a lot about how to target senescent cells central to certain diseases of aging, and we are now finding indications that show transformative disease-modifying benefit,” he says. Rather than detecting a problem, watching it escalate, and treating the symptoms, it may be possible in the not-too-distant future to treat eye disease as soon as early red flags are identified, so that patients never start to lose their vision. “That future state is so different from the one we are living in,” Ghosh declares. “It’s so exciting.”
Unity’s next milestones include completing the 24-week Phase II ENVISION study for wet AMD in Q2 2023 and finishing its 48-week extension in Q4. At the beginning of Q3 2022, the company reported nearly $104 million available as cash, cash equivalents, and marketable securities. That’s enough to see it into 2024.