UNITY Biotechnology CEO on recent trial results and why he is confident that the fundamental hypothesis behind senolytics has merit.
Back in March, senotherapeutic drug developer UNITY Biotechnology reported topline results from the Phase 2b ASPIRE trial evaluating its lead compound UBX1325 in patients with diabetic macular edema (DME). While the trial met many of its objectives, its failure to meet the primary endpoint saw the company’s stock fall some 30% on the news.
But should the recent trial results be seen as a setback, or hailed for demonstrating progress towards a new treatment paradigm for age-related disease and decline?
Longevity.Technology: UNITY is developing drugs that selectively eliminate or modulate senescent cells to combat age-related diseases. Senescent cells are damaged or aged cells that stop dividing but resist cell death, accumulating in the body and promoting aging and chronic disease. Senotherapeutics – the drugs that target these cells – represent what is still a nascent, emerging area within longevity biotech, and UNITY is among only a handful of companies to have conducted human trials. We caught up with UNITY CEO Anirvan Ghosh to get his thoughts on the trial results and what they mean for the company moving forward.
Reflecting on the missed primary endpoint and its implications, Ghosh frames the trial as a meaningful milestone despite the statistical shortfall.
“This is the first time we’re evaluating our lead program against aflibercept, which is the standard of care in the field in a DME patient population,” he said. “We are not aware of any other molecule in the world that has shown monotherapy superiority to aflibercept.”
Supporting the senolytic hypothesis
According to Ghosh, the study had two main goals: to confirm whether the vision improvements seen in the BEHOLD study were real and reproducible, and to determine whether the ASPIRE results could support a path to a pivotal trial and ultimately approval.
“We saw qualitatively similar vision improvements in the UBX arm in ASPIRE as we had seen in BEHOLD,” he says. “That alone is an important fact to absorb because this is the first time this novel mechanism of action – a senolytic mechanism – has been taken into a well-controlled human study for a second time.”
Ghosh points out that the consistency between its trials supports the foundational hypothesis at the core of UNITY’s therapeutic approach.
“It provides very strong evidence that the fundamental senotherapeutic hypothesis has merit,” he says. “We’ve shown that targeting senescent cells can lead to improved outcomes.”
Of course, Ghosh acknowledges that showing improvement alone is not sufficient in a field where the standard of care is already very effective, but he emphasizes the technicalities that prevented the study from hitting its primary endpoint.
“Our primary endpoint was the BCVA average of week 20 and 24, but even at week 24, we met non-inferiority, so it’s a very, very narrow technical definition,” he explains. “Having run a lot of trials, when a study doesn’t work, it’s rarely just one small measure falling short while everything else looks good. But that’s exactly what happened in our case.”
Navigating uncharted territory
Importantly, from the perspective of what UNITY does next, the results also highlighted a subgroup – patients with moderately aggressive DME – in which UBX1325 appeared to outperform aflibercept. The company is now evaluating whether this could represent a viable patient population for a more targeted late-stage trial.
“You could imagine a scenario, like with a cholesterol drug, where you see benefit in a specific range of patients but not others,” says Ghosh. “So we have some work to do to see if this could be viable in this indication.”
Addressing whether the market potentially had unrealistic expectations for senolytics, Ghosh acknowledges the early excitement surrounding the field but cautions that development in this area is inherently complex.
“We are navigating uncharted territory,” he says. “There was a huge amount of excitement – partly because senescence is implicated in so many diseases, and partly because there was a hope that one senolytic could work broadly across tissues. One thing we’ve learned is that different tissues have different senescent cell types – I do not believe there will be one senolytic drug that is going to work everywhere.”
While the senolytics field still holds promise, Ghosh expects that progress will be uneven and slower than initially hoped.
“At this point, we have not hit the mark, and hence we see the broad reactions in the market,” he says. “But my hope for the field would be that we learn from this – to better pick the right indications, design the right studies, and continue the path forward.”
The road ahead
UNITY expects to release complete 36-week data from the ASPIRE trial this quarter, which Ghosh say will guide decisions about subsequent studies. The company is considering either a pivotal study focused on the subpopulation of patients with moderately aggressive DME, or a bridging study designed to better understand the drug’s mechanism.
“There’s no way to visualize senescent cells in the eye – we don’t have a good way to measure what’s happening molecularly when you give a senolytic,” explains Ghosh. “So one idea is to take aqueous humor samples from the eye and analyze them by proteomics to see changes in inflammatory markers, which is a key prediction of the senolytic hypothesis.”
Beyond UBX1325, UNITY has other ophthalmology programs in development, including a late-preclinical VEGF/Tie2 bispecific program targeting vascular integrity, a biological pathway that degrades with age and is implicated in several retinal conditions.
“The program is not a senolytic, but it intersects with age-related biology,” says Ghosh. “We paused it to focus on our lead program, but we believe direct activation of the Tie2 receptor might yield a stronger outcome compared to existing approaches.”
Whether UNITY advances this program internally or through partnerships has yet to be determined. The company has previously opted for the partnership option, notably in its neurodegenerative disease program, where it inked a deal with Jocasta Neuroscience, a company developing therapies based on the modulation of alpha-Klotho levels in the blood.
“They have generated quite a bit of preclinical evidence,” says Ghosh, although UNITY no longer has a direct role in that program beyond milestone- and royalty-based arrangements.
Slow progress in longevity
When it comes to the broader state of longevity biotech, Ghosh observes that while UNITY’s programs are among the most clinically advanced in the field, progress across the sector has generally been slow.
“Calico and Altos have raised a lot of money and have been around for a long time, but I haven’t seen any clinical data from them yet,” he said. “This tells you that it’s not a quick and easy game.”
However, Ghosh stresses that the fundamental biology – whether involving senescence, telomeres, or any other aging-related mechanisms – is not in question.
“These are not going away – they are fundamental biological mechanisms,” he says. “The challenge is finding practical ways to target them, and sometimes, a new technology comes along – like CRISPR for genetic mutations – that makes it possible.”
As the field of aging biology matures, UNITY’s experience underscores both the promise and the hurdles of pioneering new therapeutic paradigms.
“I believe that the work we are conducting, along with others, will lead to a new class of therapeutics,” says Ghosh. “But we have to be prepared for a long road, with careful science and iterative progress.”
Images courtesy of UNITY Biosciences.
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