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Aging and Lifespan

Unity Biotechnology and Senescent Cell Therapy

Let’s have a look at the case of Unity Biotechnology, because this is a story that won’t get so many headlines. Unity has been investigating a really interesting but high-risk idea. It’s in the anti-aging field, so those two adjectives sort of apply by definition, and it’s the hypothesis that one of the problems is the accumulation of senescent cells. Those are old cells that are not yet dead, but not so alive, either – they’ve lost the ability to divide, and problem other abilities as well, but they’re still just hanging around. In fact, they seem to be doing worse than that – senescent cells secrete various inflammation signals and other molecules that actually seem to impair the function (and even the survival) of the cells around them. They’ve been implicated in a whole list of degenerative diseases, and there have been several studies in animal models that show beneficial effects of outright elimination of such cells on overall health and even lifespan as a whole (see those last few links for references).

Their lead candidate is UBX0101, which is a small-molecule inhibitor of the MDM2/p53 interaction (I’ve been unable to find a structure). That’s a protein-protein target that has received a lot of attention over the years, and compounds that affect it have been reported to disrupt the whole senescent-cell secretion phenotype. It’s a complicated story – compounds that inhibit the MDM2 interaction often do so by binding to p53 and stabilizing it. That also tends to mean activating it as well, because MDM2 is sort of the default braking system for p53, which is at the center of a great big gigantic web of cellular activity. It’s involved in tumor suppression (by monitoring for DNA damage), the cell cycle itself, apoptosis (another option if the damage is too severe), and more, and it certainly seems to have a big role in the done-with-that-cell-cycle-business phenotype of senescent cells. As that last link will show, though, such MDM2 inhibitors were first characterized as caused normal cells to become senescent themselves, but closer examination seems to indicate that this was a reversible effect once you stopped dosing cells with the compounds, and that their effect on natural senescent cells was something else entirely.

So Unity had done a Phase I trial with their compound in patients with osteoarthritis of the knee, which showed that it was well tolerated and actually seemed to show the sort of biomarker response that you’d want to see. Today they reported their Phase II data: nothing. No response at all versus placebo in any arm of the study. The compound’s development has been halted, and Unity’s stock has taken a dreadful beating this morning on the NASDAQ.

There are several things to take away from this. None of them are new, but we all could use to be reminded of them (and people outside the field definitely need to be!) First off, Phase I results are not Phase II results, because they are not designed to read out on efficacy. We all need to keep that in mind during these coronavirus days – we simply *do not have* the most important results for all the vaccine candidates that are in the clinic now, and trying to read the Phase I tea leaves can only take you so far. There is no substitute for a well-designed Phase II study, and every new drug has got to pass through one before you can say anything real about its use in human disease. It’s also worth remembering that Phase III results rarely look better than the Phase II ones – if anything, Phase III tends to expose limitations while it’s confirming that the good parts of the Phase II work were actually valid (if in fact it does that second part at all!) This particular drug is obviously not going to get there, but keep that in mind next time something barely clears a Phase II and then goes on further.

Another take-away is that anti-aging work is really, really hard. Gegen den Tod ist kein Krautlein gewachsen, or if you’d rather take that dose in Latin hexameter, contra vim mortis non crescit herba in hortis. In other words, there is no herb against death. (I came across that one not by poring over collections of Latin sayings, but by spending my youth reading science fiction stories). I continue to think that combating aging is a very exciting area for therapeutic intervention, with potential effects on both overall health and lifespan, but it is an area that’s very likely to hand us a lot of unexpected reverses. Like this one.

There are a lot of places where things could have broken down. From the micro to the macro, they include: maybe this compound isn’t the right one to affect MDM2/p53, but it’s still a valid target. Or maybe that particular interaction isn’t a valid target for senescent cell therapy, for reasons yet to be worked out. Perhaps there’s something about osteoarthritis itself that makes it a less attractive test bed for this approach. Or it could be that senescent cell therapy in humans is just not going to work at all. The only way to understand these things is to do more work, apply more brainpower, and spend a lot more money. The hard way, in other words.

52 comments on “Unity Biotechnology and Senescent Cell Therapy”

  1. electrochemist says:

    Senescent cells: “I’m not dead yet! I’m feeling better! I think I’ll go for a walk…”

    1. Ken says:

      You’re not fooling anyone, you know.

      1. bf says:

        I can’t take ‘im like that! It’s against regulations….
        Can you hang around a couple of minutes? He won’t be long…

    2. Knight of Camelot says:

      It’s straight out of Monty Python. “Bring out your dead!”

    3. Tony Warren says:

      He’s only mostly dead.

      To add another bad reference to the comment.

    4. mymagoogle says:

      Chocolate coating makes it go down easier.

  2. John Wayne says:

    Somebody has to keep trying this, or most of the scifi I’ve read won’t happen.

    1. loupgarous says:

      Ad astra per aspera, in other words. They don’t usually hand out Nobels for discovering Great Truths scrawled on the back of the phone book.

      1. Derek Freyberg says:

        As the Royal Air Force has it, “Per ardua ad astra”; or as one of the British writers (might have been Orwell) more snarkily put it, “Per ardua ad aspidistra”.

        1. Peter Kenny says:

          Great autobiographies that never were: I aim for the stars but sometimes I miss and hit London instead (Wernher von Braun)

          1. John Wayne says:

            LOL

            (too soon?)

  3. Christophe L Verlinde says:

    In the following paper, Nat Med. 2017 Jun; 23(6): 775–781, UBX0101 is referenced to 2 publications about ABT-263 aka Navitoclax.

  4. cancer_man says:

    Resveratrol 4 ever!

    1. matt says:

      resveritol is only slightly mimicking oleic acid….
      olive oil is 10 to 100 times more effective..
      Dr. Sinclair

      1. Lu says:

        That old guy at Harvard that thinks he ain’t?
        My daughter says he’s gross.
        But what does she know, she’s only 19.

  5. Simon Auclair the Great and Terrible says:

    Put the pop in apoptosis

    1. Marko says:

      I think certain forms of dementia may be due to runaway cornpoptosis.

      1. loupgarous says:

        Well played, sir.

  6. Barry says:

    There is no signal in all of cancer genomics than the mutations/deletions/blocked expression of p53. Vogelstein has reported these in virtually all the colorectal cancer isolates his team have examined. But what to do with that knowledge remains problematic. McCormick proposed oncolytic viruses that selectively infect and lyse cells that are p53 defective. That approach has not yet been disproven. Rescuing p53 function by keeping (somewhat) broken p53s in the cytosol longer is a hard problem w/o proven benefit.

    1. Barry says:

      Aargh.
      “There is no clearer signal in all of cancer genomics”, not “There is no signal in all of cancer genomics”
      sorry

  7. anon the II says:

    This is kind of a perpendicular question. You said that you couldn’t find a structure of UBX0101. I’ve been looking for the structure of LYTAK1. I’ve found 12 papers on its use and nobody knows it’s structure. Not even people at Lilly from which is supposed came.

    Should we just put a stop to publications on molecules for which there is no published structure? One of the hallmarks of science is that it should be reproducible. If you can’t reproduce it, maybe it shouldn’t be published.

    By the way, if you do an image search on UBX0101, you come up with something called navitoclax (https://en.wikipedia.org/wiki/Navitoclax) which has effects similar to those you’re describing. And it’s big enough to block protein-protein interactions.

    1. david tyvoll says:

      Do you know for sure that it came originally from Lilly? Confluence patented such structures (US20150203499), in paticular on page 150 compound 195. A pyrrolopyrimidine that hits TAK1 at 13 nM.

      1. anon the II says:

        Thanks, I’ll look this up.

        But no, I don’t know that it came from Lilly except that all of the papers say it came from Eli Lilly. But maybe it’s more complicated than that. Maybe it didn’t originate at Lilly. Thanks for the lead.

  8. Jacker says:

    of Scifi, any newish recommendations for books, short stories, movies, etc ?

    1. passionlessDrone says:

      The Three Body Problem is outstanding!

      As far as short stories, I recently read Exhalation and several were quite good.

      1. Dr. Manhattan says:

        Agree with you on the Three Body Problem trilogy.

        And Ted Chiang is an incredibly inventive author. In addition to the book Exhalation, his book Arrival also has a number of his stories.

        1. Metaphysician says:

          I give a hearty recommendation to the movie version of Arrival, too. It’s what I call ‘benign Lovecraftianism’: just because the cosmic truths aren’t evil and destructive, doesn’t mean learning them won’t drive you crazy ( or look an awful lot like that from the outside! ).

          1. John wayne says:

            Recently published scifi books I recommend:
            – We are Legion (We are Bob), Dennis E. Taylor (3 books out, 4th about to hit)
            – All Systems Red, Martha Wells
            – Spin, Robert Charles Wilson (not that recent)

            I also read The Three Body Problem and I enjoyed it. I was a little disappointed in the ending because that sort of thing has been done a lot in other SciFi stories.

            If you want global recommendations for scifi or my science fantasy picks please ask.

  9. Armand says:

    UBX0101= Nutlin 3a

  10. Dr. Manhattan says:

    “Gegen den Tod ist kein Krautlein gewachsen”. You weren’t the only one spending your youth in a State of Blish.

    I’ll go warm up the Dillon-Wagoner gravitron polarity generator…

    1. Paul says:

      Wow, the spin-dizzies helped push me into electronic engineering. I’m glad to see the anti-agathics pushed others into drug discovery.

  11. David Edwards says:

    Just popping in to say hello to another James Blish fan. 🙂

  12. Marko says:

    A good example of a journalist using non-scientific terminology to communicate more effectively to the wider public about Covid-19 :

    https://twitter.com/DrEricDing/status/1295465896480210944/photo/1

  13. Klagenfurt says:

    Earth to Homo sapiens sapiens: I’m not done with evolution yet, extending your reproductive lifespan makes me even less competitive in this galaxy game.
    #antiantiaging

  14. aairfccha says:

    Semi-OT: Is there anything new in the field of Telomerase gene therapy?

  15. David says:

    Did Unity make any comments about why THEY think their compound didn’t do it’s magic? Data on secondary outcome measures, PD biomarkers?

  16. Sok Puppette says:

    Look, I’m getting old over here while you pharma people slack off and get fat off old drugs and academic research while wasting time on these outdated trials. Don’t you have a computer? Just have it generate random molecules, then use AI to pick out the good ones. You can run your tests in molecular simulation and make the one that works using automated nanofluidics. Do I have to think of everything?

    … and did I miss anything? 🙂

    1. bf says:

      That sounds like “Groundhog Day“, scientifically. Or, in other words “all around the world, same song” by Digital Underground….. I know a lot of people won’t know that last one but I’m still putting it out there:-)

      1. EJ says:

        There is an idea to exploit the Novikov self consistency principle for computation. The idea is to set up a machine that sends the result of a computation back through time, where only the answer to the problem in question is temporally consistent.

        Basically, give Bill Murray some homework, and the looping doesn’t stop until he gets the answer right.

  17. loupgarous says:

    Ah, yes.
    The “let’s apply software development techniques to Big Pharma Moonshot” idea.
    It had years to work, and yCombinator’s put its equity where their mouth is (to their credit) but we’re still waiting.
    I’d say “thanks for the chuckles, but both major US political parties are busy writing new riffs on “Made in America”. What, $800 million in US loans for repurposing Kodak as a vertically integrated API and finished generic drug provider? No one who’s familiar with Kodak’s existing assets says they evoke “pharma”. Phlow’s closer to the Pharma mark, but let’s see some results, please.

    The other party’s candidate’s on record as saying we just need some more Moonshots in health care and cancer. Since my cancer’s in my liver, I’ll pass on the Moonshot known to exist for human consumption. Sure, it’s a botanical, but that’s as close to Pharma as it gets.

    1. Wheels17 says:

      Kodak has a synthetic chemistry department with a long history of production quantity manufacturing of complex organic chemicals at high purity (take a peek at photographic coupler molecules, EP0349331A2 for example). They also have a significant infrastructure for handling organic solvents for closed loop recycling. I can’t judge whether that will/would translate well into the pharma space, and the mess associated with the stock may mean we’ll never know, but it might have worked.

  18. anon says:

    Unity Biotech needs to find some big pharma sucker (alas Sirtis) plenty fast to buy it before the investors figure out that some of the original science may not be reproducible:

    https://forbetterscience.com/2020/07/17/jan-van-deursens-bullying-lab-members-speak-out/

    JvD is a founder in the company, and a lot of stuff in his academic lab cannot be easily reproduced (the article though is about his bullying of trainees, which mentions irreproducibility of data)

  19. idiotraptor says:

    I just read the story at the link above. Wow, JvD certainly sound like an petulant and infantile flaming A-hole. He sound like a candidate for a position in the Trump administration.

  20. Picky, picky, picky says:

    “and problem other abilities” => “and probably other abilities”

  21. SoCal2Boston says:

    Unity definitely calls UBX-0101 an MDM2/p53 inhibitor, but there are multiple references to this compound being navitoclax (ABT-263) which was developed as a BCLxL inhibitor. Does anybody have clarity on this and what the mechanism actually is?

    1. Visitor says:

      As mentioned above “Christophe L Verlinde says: 17 August, 2020 at 1:06 pm
      In the following paper, Nat Med. 2017 Jun; 23(6): 775–781, UBX0101 is referenced to 2 publications about ABT-263 aka Navitoclax.”

      UBX-0101 was misleadingly briefly referenced as being navitoclax in the original Nat. Med. paper without any further details, mdm2 and p53 are not even mentioned in the manuscript. Hence the confusion (on purpose? what else would explain that unbelievable mistake?). Details emerged later in patent applications. Although it doesn’t change anything from the clinical trial point of view, how Nat. Med. allowed this is beyond comprehension.

  22. TallDave says:

    that is a shame

    “Another take-away is that anti-aging work is really, really hard”

    yep, nature has wound us up to run 50-100 years, and the mechanisms for targeting senescence that allow us to do so are so exceedingly complex that just tinkering with an infinitesimal gear here and there may never do much good

    some days it feels like we might as well be trying to turn ash back into a well-worn Zelazny paperback

    as our ability to model protein improves we may find better solutions, particularly re mitochondria

    1. confused says:

      A largely uneducated comment…

      If you plot body mass vs. lifespan for mammals, humans are well above the usual line; AFAIK, the only mammals that live longer than humans are much larger than us (e.g. bowhead whale).

      I wonder if this is so hard partially because humans are already pushing the limits on lifespan? (For a mammal’s system, anyway; giant tortoises live longer, but their metabolism is a lot slower, so maybe not more “metabolic time”).

      1. TallDave says:

        lol so the mechanisms for dealing with cellular senescence are *not* exceedingly complex? please inform the Nobel committee of your research

  23. Karl Pfleger says:

    More coverage with broader context commentary from an (excellent) aging-specific blog: https://www.fightaging.org/archives/2020/08/unity-biotechnology-fails-phase-ii-trial-of-localized-senolytics-for-knee-osteoarthritis/

    For other anti-aging treatments that are “in the pipeline” see LEAF (Life Extension Advocacy Foundation)’s Rejuvenation Roadmap: https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/
    It includes 10 others currently in the cellular senescence category.

    Overlapping but different from the above, for a list of startups pursuing anti-aging in various ways, see http://agingbiotech.info/companies/
    On a non-mobile browser, sorting by the clinical stage column also gives a picture of what’s in the pipeline. After sorting by any column, one can also restrict so to see only companies doing things related to senescent cells by clicking the triangle of horizontal lines in the Google Sheets filter view interface and selecting only the senescence values for that column. There are about a dozen other companies pursuing therapeutics in this area plus a few doing diagnostics.

  24. Mo says:

    If this worked on animal trials then why aren’t they selling it to people that want to extend the lifespan of their pets and prizewinning horses?

  25. eub says:

    “the sort of biomarker response that you’d want to see”

    Worth a systematic underlining every time anybody uses a biomarker in lieu of final endpoint: your biomarker is only as good as your bio-, and your bio- ain’t shit or you wouldn’t be farting around in Phase I right now.

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