Unity Biotechnology Fails Phase II Trial of Localized Senolytics for Knee Osteoarthritis

UNITY Biotechnology is the largest of the handful of biotech startups working on senolytics, therapies capable of selectively destroying a sizable fraction of the senescent cells that accumulate in old tissues. The company entered clinical trials with a first generation senolytic drug quite early in the development of this presently small industry, with so far only the Mayo Clinic and Betterhumans also running trials in humans. This week, UNITY announced the failure of a phase II study for knee osteoarthritis, an outcome that was half expected by some observers and competitors, but which will no doubt prove to be a burden for senolytic companies seeking to raise funds for further development.

UNITY Biotechnology Announces 12-week data from UBX0101 Phase 2 Clinical Study in Patients with Painful Osteoarthritis of the Knee

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to extend healthspan by slowing, halting or reversing diseases of aging, today announced the 12-week results from the Phase 2 study of UBX0101, a p53/MDM2 interaction inhibitor, in patients with moderate-to-severe painful osteoarthritis (OA) of the knee. There was no statistically significant difference between any arm of UBX0101 and placebo at the 12-week endpoint for change from baseline in WOMAC-A, an established measurement of pain in OA. Given these results, UNITY does not anticipate progressing UBX0101 into pivotal studies and will narrow the company's near-term focus to its ongoing ophthalmologic and neurologic disease programs.

"Developing novel treatments that selectively eliminate or modulate senescent cells is at the heart of what we do, and we have generated valuable data that will enable us to learn from this study and inform future studies in diseases of aging. While these are not the results we had hoped for, the evidence that senescent cells contribute to diseases of aging remains compelling, and we are excited to advance UBX1325 for retinal diseases, which inhibits Bcl-xL, a distinct senolytic target. Diabetic macular edema and diabetic retinopathy are attractive not only because of the strength of underlying biology, but also because of the sensitive, quantitative, and objective clinical assessments available. The burden of senescent cells in various diseases of aging is increasingly evident, which together with our research gives us great conviction in our science and the future of our pipeline."

It has been a topic for discussion - sometimes quite pointed discussion - in the industry that UNITY adopted a single dose localized injection approach for their delivery of senolytics, delivering their drug to the knee joint directly. Many people have thought that this was a poor choice. On the one hand this means much lower amounts of the drug in question can be used, which is a desirable characteristic when the drug is a toxic chemotherapeutic compound. On the other hand, it is far from clear that the harm done by senescent cells is local to a significant enough degree for this strategy to work. These cells secrete inflammatory and other signals, and much of that is carried throughout the body. If one destroys only half of the senescent cells in the knee joint, does that in fact both meaningfully and reliably alter the character of inflammatory damage, given what is going on in the rest of the body?

There are a few reasons as to why this attempt could have failed. Firstly, the small molecule drug used may just not work reliably enough in humans in comparison to mice. It would be far from the first time that has happened, if so: promising phase I data can evaporate in phase II, just because more and different patients are involved. Mayo Clinic data from the use of the dasatinib and quercetin senolytic combination in patients with idiopathic pulmonary fibrosis suggests that the results, in terms of destruction of senescent cells, are similar in humans and mice, but that is not the drug being used by UNITY, and it targets a different set of mechanisms to induce apoptosis in senescent cells.

Secondly, as noted above, local administration may be a poor strategy if the goal is to reduce inflammatory burden, given that senescent cells throughout the body are capable of contributing to that burden. Maybe it works in some people, but it will be unreliable given the wide variation in status of the systemic inflammatory burden. Unreliability is always a good possibility when trying to explain early success leading to later failure in clinical trials. The Mayo Clinic and Betterhumans trials of the dasatinib and quercetin combination used oral administration, and thus the drug goes everywhere in the body, globally reducing senescent cell counts and the inflammatory signaling that they generate.

Thirdly, the specific mechanism targeted by UNITY may not be as useful as hoped. It is inhibition of the interaction between p53 and MDM, and has the look of something that suppresses or alters the activity of senescent cells as much as destroys them. This can appear good if measuring specific markers of senescent cell signaling, but it might not actually be as helpful as hoped if the cells are still there, and still undertaking activities that are not being measured. The complexity of cell signaling is another point at which mice and humans might differ enough to make a particular type of signaling suppression more effective in one species than another.

Overall, the animal data, and other human data, for the use of senolytics to reverse age-related pathology is compelling. Very compelling. It is unfortunate that the first attempt at bringing an approach to the clinic failed, but numerous other groups are out there working on the problem, and most of them have what look to be better approaches to the challenge. We'll see how the next few trials progress.

Comments

The big problem with dasatinib is that it is off patent, so Unity can't invest tens of millions getting through phase 3 trials, only to see doctors prescribe cheap dasatinib "off label" for other conditions when in fact they are treating knee osteoarthritis taking away Unity's profits.

I hope that Betterhumans or the Mayo clinic can get some philanthropic funding to carry out a stage 2 d+q trial for knee osteoarthritis. Some anonymous donor gave40 million to the metformin trial. It would have been a much better use of 40 million to fund a d+q trial in knee osteoarthritis or idiopathic pulmonary fibrosis.

Posted by: jimofoz at August 18th, 2020 6:38 PM

The phase I trial had pretty unimpressive results on the WOMAC-A score too imo: an insignificant effect in the wrong direction for the low dose group and a barely any larger effect for the high dose group. So I would have said this result was right in line with it. The only result in phase I that I would have called meaningful was the 0-10 pain scale rating (NRS), which did show a dose dependent effect in the right direction. I assume that must have also evaporated, since they're giving up on the drug?

https://www.globenewswire.com/news-release/2019/06/18/1870153/0/en/UNITY-Biotechnology-Reports-Promising-Topline-Data-from-Phase-1-First-in-human-Study-of-UBX0101-in-Patients-with-Osteoarthritis-of-the-Knee.html

Posted by: nshepperd at August 18th, 2020 6:39 PM

Treating the symptoms of aging without a real change in the rest of the body is the wrong direction. The disease is aging and osteoarthritis is just the symptom of it and focusing on the symptoms is a waste of resources and funds. Its like trying to extinguish only a particular kind of a tree in a forest fire while the rest of the trees around them are burning.

Posted by: golden axe at August 18th, 2020 8:00 PM

Golden Axe, focusing on knee arthritis was just a way to get it through the FDA process more quickly.Approval for a general ant-aging drug will never happen..until aging is classified as a disease.

Posted by: august33 at August 18th, 2020 9:20 PM

@golden axe
We don't know yet how to fix the root causes, especially in general. Osteoarthritis has a big contributing part from inflammation which hinders the regeneration. Then there might be a depletion of stem cells which are needed to repair the constant wear and tear on the knee. There might be deficiencies on supplying blood and nutritions. There might be distorted signaling. What is remarkable is that feet joints suffer much less degeneration then the knee even if they bear even more load. There are so many things we don't know . And the joints are a simple problem. We have decent prostheses for knees and other joints. However, fixing more subtle tissues is still out of reach. While the trial results were to be expected it is a big disappointment for the whole Senolytic concept. Just a few years back Osteoarthritis wild look like a low hanging fruit and a quick win. There's infinie inflammation. Sometimes painkillers and anti-inflammatory drugs alone help improving the knees. So a silver bullet to reduce inflammation is an apparent solution.

Of course, UBX might be doing it wrong even if Senolytics coukd help here. Their compound might be a crappy Senolytic, the protocol might wrong (might need slower release our multiple injections) or simply Osteoarthritis might have noting to do with senescent cells in the knee. While not plausible the root cause might be due to wrong immune reaction or some something else.

What can be done is a meta study of people treated with dasatinib who happen to have comorbididty like Osteoarthritis or other senecent cells suspects.

Posted by: Cuberat at August 18th, 2020 10:02 PM

The UBX IPO price set their market value at about a billion dollars, that always seemed high to me for a company with only speculative products. Now that their market value is below $200,000,000 the risk reward profile is much more attractive to me. I bought 31,000 shares at about $3.21 today

Posted by: JohnD at August 19th, 2020 12:42 PM

@Cuberat
What I am saying is that you need to heal the entire body or most of it and not just one spot in the body. The problem probably didn't started in the knee and It isn't necessarily easier to heal a disease by focusing on the symptoms or one spot related to the disease like the knee. There is a problem in the rest of the body and if you develop a senolytic drug you should make it work for the rest of the body and not just in the knee because you have better chances of getting better results(whether it is in treating the symptoms or aging in general) if you succeed.

I read about partial cellular reprogramming technology developed by turn.bio(and Salk Institute) in order to reverse multiple types of aging damage in the cell. It apparently had some success in mice https://www.cell.com/fulltext/S0092-8674(16)31664-6 (I think this study was done by Salk and I don't know if what they are doing is exactly what turn.bio doing)
and it can be a start for real anti-aging therapies that will solve problems like Osteoarthritis.

Posted by: golden axe at August 19th, 2020 12:58 PM

This is indeed to be regretted. You hit the nail when you made the comparison with the dotcom-crisis. We can't afford another blow to the field. A message to risk-adverse investors who intend to withdraw would be confronting them with the numbers: the loss of lives if this field is set back another 10 years. 150.000 deaths a day x 365 x 10 = half a billion humans lives! There can be no return to the old paradigm. The dark ages of medicine must end! I hope you will succeed with your company, cancer and heart disease virtually erradicated.
Best Regards,

Posted by: Braekmans Herman at August 20th, 2020 3:12 AM

It's been commented here numerous times, before any senolytics trials were even in progress that senolytics should not be a monotherapy. Mice (well lab mice,anyway) have ludicrous regenerative capacity compared to humans due to super long telomeres. You can't just delete a bunch of old cells in people and expect it to work. Atleast this trial was only for knees so they didn't kill anyone.

Posted by: Mark at August 20th, 2020 4:51 AM

As Aubrey said at our conference last week, some people are overeacting (including the absolute moron calling for Ned to go to jail who posted on here) to these dissapointing results from UNITY. There are going to be bumps in the road but eventually there will be progress. Ned is going to be taking a lot of flak right now and as Aubrey said:

"This is a guy I regard highly and a very important person in the field, we need to defend this guy and support him at this point, when he is going to be taking many bullets"

The takehome here is there will be setbacks because biology is hard, but we should not start playing the blame game and turning on each other. We have to be resiliant and roll with the punches, support those working on the science, and avoid badmouthing them and each other.

We will get Aubreys talk up ASAP where he speaks about UNITY and the movement in general.

Posted by: Steve Hill at August 24th, 2020 8:33 AM

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