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Nivien’s Shot

Have you ever heard of Nivien Therapeutics? Unless you follow the oncology world pretty closely, probably not. But they are – well, were – a startup out of Harvard that was working on a promising approach to overcoming chemotherapy resistance in pancreatic cancer. Now that’s what we call an “unmet medical need”, considering the steepness and swiftness of the death rates from resistant pancreatic tumors, and Nivien’s approach was a new one. They were targeting the Hippo pathway, which is normally a regulator of organ size during development. It was first discovered in Drosophila, and as is often the case the fruit flies led to an even more complicated situation in humans and other mammals on further research. The YAP/TAZ/TEAD transcription factors are involved in both the Hippo pathway and in many tumor types, though, which suggested that there could be an application in oncology. More specifically, it appeared that the YAP pathway itself might be one of the regulators of a general drug resistance pathway in tumor cells and that this had therapeutic potential.

Well, did it? Here’s an essay on Medium from founder Nathaniel Brooks Horwitz, and here’s an epitaph from John LaMattina at Forbes. Those, and my switch to the past tense in the above paragraph, will give you the short answer: it turns out that inhibition of this pathway is (A) possible but (B) not enough to be useful for cancer patients. I would not like to try to count the number of times I have experienced something similar over my career. Those have been within the structure of larger companies with more things going, so they didn’t wind up costing everyone their job as can happen with a startup, but it is a very common story on any scale. John LaMattina makes the same point, and he is also most definitely in a position to know from personal experience as well. Most ideas for new drugs, and new modes of action for drugs, don’t work out. Nivien didn’t even get to human trials themselves, with their famous 90% failure rate, but anyone who’s done this work will tell you that preclinical failure rates are no joke, either.

And both Horwitz and LaMattina are right that hardly anyone outside the industry seems to know this. That’s been one of the purposes of this blog from the beginning, to get across what it’s really like to do drug research (and to get across just how difficult and tricky it can be). The two opposite errors in talking about this work are to despair of anything and to hype everything, and you have to walk between those. The despair part is illustrated by my often-used example of not turning into the guy in the conference room who sits in the back and says “Yeah, that’s not gonna work” to every idea. You’re right 95% of the time, but to what end? And as for the hype part, here’s Horwitz:

It’s easy to accidentally generate the impression of an imminent win. Often, new biotechnologies really are revolutionary. Many companies, however, generate this impression intentionally, even when undeserved.

Raising money, recruiting people and building a movement around your mission almost demands irrational optimism, especially in failure-riddled drug development.

There is an allure and a danger to believing in something like this, giving it your all, and seeking to convince others to do the same while knowing the chances of success are lean. No one wants to commit to a marginal endeavor.

But employees want transparency. Investors want a fair bet. And patients, who know more than anyone, want honesty. They are not one-liners for your PR machines or slides for your pitch decks. Now, reading the latest and greatest biotech PR, I’m furious when I see overstated results and oversold potential.

That’s exactly the territory. Realism would demand that you make clear that you are very likely to fail, but that will not bring you any resources to even get that far. But the kinds of stories that some investors (and some journalists, and some patients) might want to hear the most are not the true ones, and that’s not good, either. Unfortunately, the field is absolutely drenched with that oversold potential, and there’s probably no way to keep that from happening, humans being what they are.

Horwitz’s essay is an honest look at just what it’s like to work out on the cutting edge of the business – new company, new mode of action, new chemical matter, new employees, new funding – and the story he tells is how most of those stories go. Just not quite all. And it’s that “not quite all” that keeps this whole business rolling. . .

34 comments on “Nivien’s Shot”

  1. mallam says:

    And the dance of searching for new trans formative medicines continues. From novel scientific discoveries to concept of application to possible treatment to search for funding to actual implementation, testing, evaluation, more failures than successes. And yet there are enough potential positives for all involved, scientists, MDs, patients, investors, (from within company, individuals, VCs, family & friends ) to be motivated to continue pushing the giant rock uphill.

  2. RandomWok says:

    Drug Discovery and Development in our age has left the realm of sober, subdued conference room discussions and entered the world of Hollywood hucksterism and the old “wildcatter” bluster from early oil exploration days. Most of these new startups are headed up by finance types, and one wonders how much of the hype is born from that unholy nexus between market players (who earn big commissions anyway) and unscrupulous academics pushing for their payout with irreproductble “breakthroughs” in biology and therapeutics. If the hype stops, real estate prices will plunge in the Boston area.

    1. Eric says:

      I’ve been in the field for 20 years and it’s always been this way. When was it not driven by investor hype? (no snark intended, it’s an honest question – was it truly different in the 70s or 80s?)

      1. Emjeff says:

        I doubt it; were people any different in the 70s and 80s?

        1. Isidore says:

          No, they were not, but the stakes were lower. I think the whole thing got much worse with the hype around sequencing the human genome a couple of decades ago. Since then everyone has tried to one-up everyone else with a vengeance.

        2. Dr CNS says:

          Of course they were!
          Are you saying nothing has changed in human culture in the last 40 years?

          1. cancer_man says:

            Just the amount of cocaine in their bodies.

      2. Anon mickey says:

        Bayh-Dole (1980) empowering universities was passed in the early 80’s given the cynicism expressed about universities above, I would bet that had a significant impact on universities pursuing drug development.

  3. Edward Taussig says:

    Has there ever been a successful attempt at developing a drug to overcome resistance? It’s the graveyard of cancer drug development. It’s also a moving target, as newer drugs obviate some of the need to enhance older drugs.
    Someday there may be a clinically successful, and perhaps even a commercially successful drug to overcome resistance, but it’s not way to invest 🙂

    1. Barry says:

      depends on how broadly you define “resistance” of course. Augmentin made $billions by overcoming resistance (to beta lactams)

    2. Nesprin says:

      Yes- I’d argue that synthetic lethality is a paradigm for overcoming resistance. For ER+ breast cancer (which I know best), CDK4/6 inhibitors help overcome resistance to fulvestrant and for Her2+ trastuzumab+ lapatinab works better than either alone.

      At the moment there’s probably 50 ongoing trials testing an immunooncology drug+ a chemotherapeutic agent.

    3. hn says:

      With imatinib resistance in chronic myelogenous leukemia, second generation kinase inhibitors were developed that are active. The resistance came from mutations in the target Abl kinase.

    4. Lambchops says:

      Indeed, similar story for TKIs in EGFR and ALK NSCLC. Subsequent generations of TKIs are often developed with an eye to being active against common resistance mutations. Though as Edward pointed out it’s often the case that a superior next generation drug means that the original resistance mechanism may no longer be in play in the treatment pathway. Hence you end up with some debate over optimal sequencing of drugs (is it better to use your best second generation inhibitor first-line or is a combination of two other drugs which might overcome a resistance mechanism better).

      Though obviously it’s a lot more complicated than that depending on AE profiles etc. Long story short – targeting resistance mechanisms can work and is often a worthwhile endeavour.

    5. Gustavo says:

      Depends on the type of resistance you are talking about.
      Others on this thread have focused on a precision medicine approach (i.e. inhibiting a driver & then inhibiting another specific pathway that confers resistance). This may work.
      Resistance to cytotoxic chemotherapy, on the other hand, has many mechanisms (pumping out drug, activating DNA repair, blocking apoptosis even when DNA is damaged, etc.). Blocking this type of resistance might be more difficult.

  4. Hap says:

    As long as investors respond well to the hype song (or don’t respond well to its converse), there’s no incentive for companies to stop singing it. Honesty seems to have gone out of favor, and that is unlikely ever to end well.

  5. Druid says:

    I would not advise a scientist who has made a career in academia to strike out into a start-up based on their discovery unless they really wanted to give up their PI position to be an entrepreneur. Publishing new discoveries in papers before patent filing still happens, and it is near impossible to continue to publish while finishing the invention stage and going into development without giving the bigger players a start. The only exceptions are the medics who are involved too late for real harm. Overestimating the “value” of a discovery or invention is the first mistake made by academics and underestimating the time and money required to prove safety the second. Believing that regulations only apply to big pharma is the third.
    Unlike betting on horses, where every race has a winner, there are no guarantees in drug R&D, but when successful, the sense of satisfaction is very rewarding, so we keep trying.
    “I got the horse right here, the name is Paul Revere … can do, can do, …”

  6. Isidore says:

    “Between the idea
    And the reality
    Between the motion
    And the act
    Falls the Shadow”
    T.S. Eliot

  7. Barry says:

    Nivien should be praised for killing a dead-end approach before the expense of Clinical Trials. The whole industry would be more productive if this lesson were applied more broadly. But in reality, science is pursued by humans, and egos and careers get attached to projects. No one gets that promotion for making the right call when that call is to end a project.

    1. ScientistSailor says:

      Hear, Hear! A fine example of ‘Truth-Seeking’ behavior, rather than the usual ‘Progress-Seeking’ behavior many in the field demonstrate.

    2. nonchemist says:

      I suppose this is the plus side of (relative) outsiders going into the drug development business. Sometimes you have the “we’ll cure cancer and aging in five weeks, tops” Silicon Valley types, but here you’ve got smart, hard-working people who could give their data a sober look and cut their costs at an opportune time, instead of going with the post-hoc subgroup route that could have tempted more established companies.

      Kudos to them, and best of luck in their future endeavors.

  8. Niklas B says:

    Great post, as an industry outsider I love these kinds of insights. While the technical terms may differ, the VC/Hype phenomenon appears much the same.

  9. An Old Chemist says:

    It seems that the future of the cancer drugs will be biologic drugs, like immunotherapy drugs Keytruda, Opdivo, and Yervoy plus CAR-T drugs like the ones of Kite pharma/Gilead and Novartis. These drugs have not shown any signs of resistance. The only hurdle is that these work well only in a small percentage of patients. Merck is currently conducting 800 clinical trials of Keytruda in 30 different cancer types. CRISPR and gene therapies can add to the list of these biologic drugs. The days of small molecule drugs for disease management seem to be numbered for the life-threatening diseases.

    1. sgcox says:

      I am not so sure. From 2018 FDA new drug approvals, Fig.1
      https://www.forbes.com/sites/bernardmunos/2019/01/14/2018-new-drugs-approvals-an-all-time-record-and-a-watershed/#29a7a04c332d
      For cancer indications, ~13 are small molecules and only 3 are biologics, 2 antibodies and one E.coli enzyme (!)

      1. sgcox says:

        correction, 4 or 5 antibodies for cancer, very hard to read small font.

    2. Ari says:

      “These drugs have not shown any signs of resistance.” Sadly, this is not so.

    3. Lambchops says:

      Not strictly true, small molecules will still have a place in combination therapies (and may potentially help to alleviate the poor response rates sometimes seen with psychotherapies). And in some cases a targeted small molecule is still more effective than an immunotherapeutic approach (eg ALK or EGFR positive metastatic NSCLC). Or away from oncology think the Vertex drugs for cystic fibrosis (I’m no expert in the area but I believe that while gene therapy has promise, it’s still a long way off).

      Certainly biologicd and gene therapies are becoming more common and this is a good thing but the days of small molecules are far from numbered.

      1. Lambchops says:

        Psychotherapies is meant to say “immunotherapies” – autocorrect out of control there!

    4. Barry says:

      CAR-Ts to my knowledge have never worked against a solid tumor. That’s a big exception. Checkpoint inhibitors (against CTLA4, or PD1, or PD1-L) have been successful against a variety of solid tumors, but fundamentally, they’re disinhibiting killer-T cells against indiscriminately. The side effect will be auto-immune attack in many cases. That’s a tolerable side-effect when you’re dying of a resistant cancer, but may preclude these agents ever getting approved as first-line therapy.

    5. KK says:

      Actually not so fast with biologicals and CAR-T therapies. Resistance is beginning to emerge and you can see it in CD-19 CAR-Ts. While subset of data is small, patients that relapse happen to have cancer cells that no longer express CD19 and so are resistant to further treatment from CD19 CAR-Ts. Companies are now moving towards combo approaches in these therapeutic modalities, like creating CD19-BCMA dual targeting CAR-Ts. And like commentor had said, these cell therapies can not target solid rumors. For antibodies, you still have the issue that they can only hit surface cell targets which aren’t that many compared to targets in the cell where there are prob few thousand. In that realm small molecules still remain king and will always have a place in drug development.

  10. Fffhhhhhhh says:

    Toxic blog post, as usual. Why don’t you actually do the world a favor and infuse some positivity into discussions. We all get the “ let’s all be condescending and critical science smart guys “. ,……Old hat, uninspiring, silly, arrogant, small. And, it’s been so overused by big shot profs, that no one lends any credibility to people that act like that.

    1. Nick K says:

      The truth always hurts.

  11. Anonymous says:

    An abundance of random thoughts on this topic.
    o From La Mattina: “The enthusiastic team worked extremely hard putting in 90 hour weeks …” That is hardly unique. As just one example, it reminded me of the early days of Vertex with researchers sleeping at the lab, etc. (read Billion Dollar Molecule). It still took more than 10 years (and millions of dollars) to make their own first drug. (I think Vertex licensed a Japanese drug to generate sales before they made one of their own in-house. Too much history! I can’t remember everything!)
    o There are so many “brand new” approaches to cancer treatment. I have not checked out this site (link in handle) in detail, but it looks like someone interviewing scientists each with the next great idea. Note that the most recent video interviews are from 6 years ago. Which ones have been funded? I don’t know.
    o There are a lot of very good new ideas to battle cancer but not enough capital to fund them all. To badly paraphrase an editorial in Technology Review from many years ago, “The US does not have a PhD shortage. The US does not have a shortage of good ideas or entrepreneurs. There is no “innovation shortage” in the US. There IS a shortage of investment to support the huge number of good ideas that sprout in the US.”
    o I think an element of jealousy arises when some researchers with more or better data than others scramble for even one research dollar while a couple of undergrad whippersnappers can get VCs to pour money into something more speculative. Each investor has their own risk/reward sweet spot. Anything other than honest presentation of the risks and the potential rewards skews the actual investment decisions.
    o Horvitz mentions “irrational optimism” (cf., Milton Friedman “irrational exuberance”) and the abandonment of the program when honest evaluation of the data did not justify continued effort and I applaud him for that. Too often, I have seen “irrational optimism” exceed the data by so much as to be what I consider to be fraud. As scientists, it would be scientific fraud to argue for a program based on reliable data (from good experiments) that signals a bad outcome OR to rely on bad, sometimes deliberate or knowingly bad data (experiments or assays not properly performed or interpreted) that supports the “optimistic” position. To knowingly present investors or others with such ill founded optimism could be criminal fraud (albeit often defended as “a forward looking statement”).
    o (The first patents, WO2018119418 and US 62/439022, list Horwitz and Shah as inventors. I haven’t read them in their entirety, but how can Kirschner and Gujral not be on those patents?)
    o More NIH funded academic research on Hippo may yield better understanding to someday allow the resurrection of an improved, more well informed biotech effort. Of course, we will hear how “The folks at Nivian were right all along! They just needed more time, more money, and more resources.” There are many other dead programs in the same boat. Many “dead” programs can be resurrected by new data and new insights.
    o Despite this failure, Horvitz and Shah now have great VC contacts and great CVs. I will guess that they will have successful futures in biotech.
    o I have more random thoughts on this general topic, for another time.

  12. Nile says:

    Coming from here, in the world of finance, I do not believe that there is a place for single-product startups in early-stage drug development.

    I regard the venture capitalists and equity funds who support them as vampires, knowing full well that 90% of their victims will bleed out and die while they, themselves, are well-capitalised and well able to live with the much, much lower probability of failure in their entire portfolio.

    Also: don’t be too sure that the financial benefits of the 5-10% of their succeses are equitably distributed between the innovator, who has most to lose, and the investor who has taken very little risk to their accumulated wealth.

  13. Spencer says:

    Are some pre-clinical models better than others? I’ve been watching Kitov Pharmaceuticals NT-219 with great interest. They used a double autologous PDX model and tested their small molecule drug in treatment resistant in combination with various drugs on the market (keytruda among many others). Their data showed a synergistic effect in that neither drug alone provided much bennefit but together they saw significant reduction in tumor burden. The data does look compelling but what is hard to know is if this will translate better than other pre-clinical trials. anyone have a thought on this approach?

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