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More Thoughts on AbbVie’s Rova-T Implosion

I wrote a couple of months ago about the disappointing results that AbbVie had obtained with their cancer stem cell therapy “Rova-T” (rovalpituzumab tesirine) in small-cell lung cancer. This was the antibody-drug conjugate that they’d purchased from Stemcentryx – OK, let’s clarify that, they bought Stemcentryx out completely for nearly six billion dollars, largely to get their hands on this great new drug. As that March post says, though, the clinical results were deeply unimpressive. AbbVie stock took quite a hit on the news, even though there were already grounds for suspicion about just how the trial (TRINITY) would come out.

Now the company has done a more thorough presentation of the data at the American Society for Clinical Oncology (ASCO) meeting, and if anything, it’s even worse than it appeared in March. @zbiotech on Twitter is quoting a Leerink analysis (by Geoffrey Porges, I assume, who has been following this drug’s progress closely), and it’s not the tiniest bit encouraging. “The results shown in the presentation were even worse than we had feared. . .we can’t help but regard the ongoing trials as largely fruitless exercises“. That sort of thing.

Another problem for AbbVie is that it’s the adverse events that are sinking Rova-T, and those may be built into the other programs that they bought from Stemcentryx, since these apparently use the same cytotoxic payload. At the very least, it casts a real shadow over things. Going back and reading that last link, the 2016 press release announcing the deal, is a grim experience. It’s all about how this is a multibillion dollar opportunity, expected commercialization in 2018, compelling data in the earlier trials, etc.

But let’s go back to that Leerink analysis: “The TRINITY study provided yet another lesson in the perils of relying on single arm early trials without doing a randomized trial. . .” It certainly does that. Not everyone would have reached into their pocket for $5.8 billion on seeing the earlier Stemcentryx data (that figure on AbbVie), but you could have gotten a lot of people to agree that it looked promising. But “promising” or even “compelling” clinical data are only as solid as the clinical trials that generate them, and single-arm trials are just not solid enough to put that kind of money down on them with any real confidence. Sure, you’re going to win sometimes – but don’t pretend that you’re not gambling. And don’t get the idea that I’m speaking out against taking those kinds of risks in this business (sometimes you have to), but it would help to be a bit more honest about them.

It’s also worth thinking about this situation in light of that <sarcasm> amazing, life-saving Right to Try bill </sarcasm> that was just signed. This is exactly the sort of drug that comes under its purview. Early, early stage results, promising for a deadly disease. Give it to the poor desperate patients! But that’s no kindness: Rova-T turns out to be worse than the standard of care. You are not only not helping lung cancer patients with it, you are objectively doing them harm.

And this is what happens with the involvement of a huge, perfectly competent drug company that is willing to spend billions of dollars up front. What happens with smaller, shakier even-less-statistically powered approaches to deadly disease? Well, what do you think? And that doesn’t even take us to the bigger fear I have about the whole approach, that even worse outfits will configure themselves just to make money off the desperately ill, in completely legal fashion, without even bothering themselves about whether the marks customers patients have any chance of being helped or not. We’re not there yet, but we’ve opened the door to it. Haven’t we, Senator Johnson? There’s a man who apparently has no opinion whatsoever about the ability of the President to pardon himself – Hands in the air! Huge shrug! Who knows! – but he is confident that the FDA needs to get out of the way so that people can take drugs like Rova-T. Here we are.

19 comments on “More Thoughts on AbbVie’s Rova-T Implosion”

  1. johnnyboy says:

    In the future, all drugs will be famous for 15 minutes.

  2. George Papa-D Tenet says:

    Peter Thiel

    1. Tourettes of Chemistry says:

      Is this pertaining to Zero to One by PT? It would appear that One to Zero (the sequel) needs to be authored. That text is available as online as pdf it appears.

      In another setting far, far away, the Zero to One comparison Table was reviewed and a couple of comments added and a couple of comments not added. There is certainly more to the inherent and genreal complexity issues than captured here.

      What possible difference could 8 fewer protons and electrons make?

      Components Carbon Technologies (Life) Silicon Technologies (Lifeless)
      __________________________________________________________________________________________
      Subject Uncontrollable Organism – Dynamic Perfectly Determinate – Static

      Environment Natural, Poorly Understood at Depth Artificial, Well Understood at Depth

      Approach Random, Tends to Converge to Viability Engineered, Tends to Converge to
      over Time by Natural Selection – Task at Hand at Lowest Cost by
      Survival? Marketplace Selection – Survival?

      Regulation Heavily Regulated Essentially Unregulated

      Cost Expensive (>$1B per each novel drug) Cheap (pizza, beer–>iterate the clones)

      Team High-Salaried, Unaligned Lab Drones Committed Entrepreneurial Hackers
      ___________________________________________________________________________________________

      It might be characterized as a failure to communicate.

  3. Emjeff says:

    Time for the usual things to happen: the hard-working employees in Abbvie will get laid off, and the executives who did this deal will get big pay-outs. Wait for it…

    1. Anon says:

      It’s already happening (softly softly) in the UK, where the Humira loss of exclusivity will bite fairly soon.

      Strangely, a few of the head office UK leadership team have recently moved from affiliate roles to global ones. I cannot imagine why.

  4. Peter Kenny says:

    I couldn’t help thinking about another trial with the same name that was conducted in 1945, not too far from Socorro NM…

  5. UudonRock says:

    Love the correction on “marks” and “customers”.

  6. Peter S. Shenkin says:

    Well, the fact that a major pharma is willing to take such a risk (as others have as well) bespeaks the fact that drug development has become so hard that even a very risky opportunity looks better than the likelihood that in-house development (you know, by all those hardworking employees who will now lose their jobs) might come up with a significant new drug.

    But we knew that.

    On the bright side, @Derek, thank you for using “data” as a plural noun.

  7. Chrispy says:

    The pyrrolobenzodiazapines seem to be flaming out as warheads in ADCs. Seattle Genetics yanked their SGN-CD33A due to hepatotoxicity (including several deaths), which had a similar warhead. Was the problem with Rova-T off-target toxicity? Is DLL3 still a reasonable ADC target with something like a maytansinoid warhead? It looks like the CAR-T folks are still enthusiastic about CD33 as a target but not DLL3. Antibody-drug conjugates were supposed to be magic bullets; we would have more of them if it was nearly so simple.

  8. Blimey says:

    Yes, much better to go the route England has taken and remove the rights of the patient/guardian to seek alternative methods. That of course has a 100% success rate.

    1. Drew Smith says:

      @Blimey, that’s a BS take and you (should) know it. The legal issue was whether parents could impose treatment on a minor that were more likely to cause suffering than relief. Competent adults are still free to harm themselves with alternative therapies.

  9. loupgarous says:

    Agreed. I wish the drafters of the Right to Try bill (and its big fan in the White House) had been more honest about the implications for the right to try a medication without finding out how toxic it is.

    In this case and in the case of odanacatib, that would have been “pretty damn toxic”. In the case of any drug which has a known cytotoxic potential going in, you don’t base approval decisions on single-arm studies. Until now.

    By the way, this is also an example of the press being concerned about the wrong things. Trump’s not done anything obviously impeachable or treasonous, but the Democratic Party is still thumping a wild beat on that drug, and the press is still singing along.

    All the press would have had to do to save patients much potential pain and suffering AND get the dirt they want on Trump would have been… their jobs. Really scrutinize “Right to Try”. Ask people who treat those with bad, terminal prognoses if short-circuting the two clinical study phases likely to catch unsuspected drug toxicity and/or poorer outcomes than standard of care if they think they’d like that for, say, a loved one.

    That’s the sort of reporting that about 100 years ago resulted in the creation of FDA. The sort that the press could be much prouder of than what they’re doing now.

    1. Chemist says:

      “Wtf I hate the right to decide what I put in my body” – Retarded liberals like you

  10. loupgarous says:

    “on that drum…”

  11. jb says:

    Lowly bench scientists get chastised beyond belief for a p = .051 and writing ‘although not statistically significant, results trended…..”

    Yet if you run a study with a single arm you can convince someone to shell out $5bn for your idea. Amazing.

  12. MAEngineer says:

    All you need is a few executives to play out their roles as unwitting marks in order for companies to begin shelling out massive amounts of cash for incredibly risky things. Not everyone at a company (and especially not the company’s best scientists) has to believe that something is a good idea, just enough people in the right parts of an organization so that a company/investor collectively decides to get behind something crazy. Investors, board members, and the media that got behind Theranos are excellent examples of unwitting marks–read John Carreyrou’s Bad Blood to see how masterfully Elizabeth Holmes navigated around skeptics (in every stage of the company’s existence!) to preserve her company’s aura far past when the bubble should have burst. It’s all about convincing the right people that something is a good idea to keep the money flowing.

    1. rt says:

      So true. Happens all the time in large phama.

  13. T. says:

    David Carbone presented all the data as ASCO http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.8507
    and this looked a lot more positive than what was discussed above. For those who did not get the chance to see the presentation, here is the summary:

    The study focused on third line patients for whom there are no approved therapy. In fact, half of those patients do not receive treatment and have an overall survival of less than 1.5 month. The other half receive whatever the physician think will help them and have a median survival of 4.5 months and a best overall response rate of 18 to 21%.

    Also worth noting that Rova-T is targeted at DLL3. The relevant patient set was defined as those with at least 75% of their tumour cells expressing DLL3. For these 238 patients, the best overall response rate was 24%, and the median survival time was 5.6 months. Perhaps not the miraculous figures that one might want for $6 billion, but certainly clinically relevant, and better than what’s out there right now. A small but relevant proportion of these patients are still alive today thanks to the drug. As for tox, the study concluded that adverse events were generally manageable, certainly not the story painted up here. All in all, I don’t think that’s the last we’ll hear of Rova-T…

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