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The Keytruda Story

This is a good history of Keytruda, the Merck immuno-oncology blockbuster, from David Shaywitz. Most big drugs have a tangled history, and this one is certainly not going to break tradition. As witness:

It was discovered accidentally, by biotech scientists looking for drugs that would tamp down the immune response in patients with autoimmune disease, and would stimulate, not block, PD1. Even after a potent PD1 inhibitor was identified and recognized as a potential cancer drug, the research program had to fight for funding through two mergers and acquisitions. After the program finally wound up at Merck, in 2009, it was considered such a low priority that it was shut down and placed on the out-license list. A term sheet (valuing the program at next to nothing) was reportedly in place, but pulled at the last minute, as promising results from competitor Bristol-Myers Squibb (BMS) motivated a reconsideration of the mechanism.

I remember telling one group leader at a former company, who was running another very odd and unexpected project, that if I were ever sitting in the audience at some dinner where he was getting a plaque and an award, I would throw my baked potato at him if he used the phrase “As we expected. . .” And he agreed that he would deserve some incoming spuds if that happened. In the case of Keytruda, the story goes back to 2003, and back not to Merck, and not to Schering-Plough, but to Organon, the long-gone drug division of Akzo Nobel. The story does not, at least at first, cover Merck with glory, although once they got moving, they did an excellent job. This is far from the only drug involved in a merger or takeover (in this case, two) that turned out to be much more important than the ostensible reason for the whole deal (which tells you something about our ability to do scientific and commercial forecasting).

It’s as much the story, though, of Bristol-Myers Squibb letting an opportunity get away from them with their own competing antibody, Opdivo, which had years of head start. As the article shows, even up until early last year, Merck looked like an also-ran, but Roger Perlmutter’s decision to resource Keytruda with everything possible turned out to be the right one. (Needless to say, if something unexpected had gone wrong, he would have surely been out the door, and presumably would have had plenty of company, too). But Keytruda really did work, the clinical decisions really were the right ones, and spending all that money and effort really has turned out to be the right decision. But there’s a lot of luck involved. If Merck had tried head and neck cancer patients earlier, for example, they would have run into trouble, since the antibody failed pretty conclusively in a recent trial. You can argue that that one was always going to be further down the list, but no one expected the numbers to be as bad as they were.

No, time and chance happeneth to them all. The Keytruda story is certainly about persistence, about risk-taking, and about a huge amount of hard work and tough decision-making. But while those are necessary, they’re not quite sufficient. No one likes to think about that, and it’s certainly a lot easier, in the wake of a success, to imagine that it was all due to clear-eyed foresight. But that’s almost never the case. Was Merck good, or were they lucky? They were both. And good for them.

16 comments on “The Keytruda Story”

  1. Dogbertd says:

    * I would throw my baked potato at him*

    Baked potato? I’d have thought you were a meat man. Fresh meat.

    1. Derek Lowe says:

      Ate the steak first, clearly.

    2. dearieme says:

      Naturally the meat man throws the tattie. Or the broccoli. But the aerodynamics of the spud is better.

    3. Paul says:

      Not hitting with the meat projectile would be a miss steak.

      1. Curious Wavefunction says:

        That’s why I always order the T bone. Then, after I eat the meat, I can at least throw the speaker a frickin bone.

  2. Anon says:

    As an ex-Merck I can tell you that the Ketruda story is true and has the hallmarks of Merck epitome. Ditto the same principles to Janumet/Januvia franchise as well (BMS was ahead of us in DPP 4). Enalapril (renin inhibitor) was inspired by early success of Squibb, then! I could go on and on. What Merck is (and was) good at is “sniffing” it out and throw 100+ people across the board and voila, we have a new product in the market! During those times when all these unfolded, I would wonder, is that how other companies operated? What ever happened to all those principles, vision etc? That said, I am happy for Merck and the scores of people still employed. I too had a great run with many friends!

    1. Chris says:

      Actually Novartis was way ahead of the pack with DPP-4. The industry did not even know about the program or is potential utility until senior management at Novartis decided to open up the research kimono, with the brilliant intention of “sharing risk”.

      Everyone came and saw and after they said DPP-4 what???? Merck when back and put over a 100 FTEs on the program and, along with some further bad decisions and shoddy work during development at Novartis, beat Novartis to the market.

  3. Barry says:

    With the glaring exception of the statins ( kudos to Roy Vagelos!) Merck has raised the come-from-behind after someone else found promise in a new field to an art. The image of a bicyclist drafting the leader through the whole race then sprinting the last hundred meters to win springs irresistibly to mind.

  4. Saamaanyan says:

    Overall, the Forbes piece is balanced. There are several people key to Keytruda success that were left out in that article. Some of the remaining Organon leaders who fought it hard during the double merger for program prioritization don’t get credit in this piece. Steve Farrand (currently at Jounce), for example, was instrumental in scaling up and timely delivery of the drug supply from a CMC perspective. There were several clinical /preclinical leaders who oversaw the plan and execution of the early studies that get no mention. The MK-3475 team was phenomenal in its planning and execution.

  5. Nowhere Man says:

    Regarding the bit about “being out the door” if the decision did not pan out – how does one rebuild after something like that? I haven’t seen it up close and personal (yet!) and it’s something I’m curious about as to how someone bounces back from that…

  6. Imaging guy says:

    I don’t get that blog post. How could he write about PD1 without ever mentioning the Japanese scientist Tasuku Honjo (1)? The patent landscape of checkpoint inhibitors is well covered in this article written by a patent lawyer (2).
    1) PD-1 and PD-1 ligands: from discovery to clinical application (2007) PMID: 17606980
    2) Intellectual property issues of immune checkpoint inhibitors (2016) PMID: 26466763

  7. cytirps says:

    It’s so sad that Organon was destroyed by some greedy CEO.

  8. ORCUSAcolleague says:

    Michel Streuli is another name the story left out. He was the champion after Merck had closed the Cambridge MA site where pembro was first discovered and moved to Pali Alto to lead the program there. Without him and likely many more this couldn’t have happened.

  9. John Adams says:

    As someone unceremoniously ripped from Mother Merck’s teat after a long career with eyes wide open, I strongly believe Roger’s push on this target was as much, or more, about his ego / desire to be known as the “man who (immuno-)cured cancer” as anything else. I further suspect he “hoppered” the program initially because it had Peter Kim’s name all over it (to wit, his push to destroy ALL that remains of the Merck Research Labs in New Jersey because the sites reached their peak under Vagelos and Scolnick) and not for any other reason. Why no discussion of what the pipeline looks like beyond Pembro?? P.S. – It might entertain those of you who don’t know that in his earlier incarnation at Merck, Roger DIDN’T support the DPP4 program…

  10. Anonymous says:

    Trastuzumab (Herceptin) was discovered and developed at UCLA. I don’t remember the entire history, but I think there was some early interest from Big Pharma but they stopped funding early on. R&D had continued starts and stops and the project nearly died several times. Dennis Slamon had to run around raising money from Hollywood celebrity donors who kept the research going. Eventually, Big Pharma was back in and got it thru the FDA. It is now a billion dollar molecule for Genentech.

    According to some personal accounts, SKF tried to kill cimetidine (Tagamet) several times during the course of its R&D. The small group working on it kept it going on the back burner. When several “approved” projects didn’t pan out, cimetidine rescued SKF from a period of drought and became a blockbuster (and Nobel Prize for James Black). Graham Durant, the chemist on the team, eventually became Pres (or VP?) of Cambridge Neuroscience (in Cambridge, MA) (CEO = Elkan Gamzu). CNS is now defunct. One of the most heavily endowed biotechs, I don’t think that they ever made a drug.

  11. Derek Sheader says:

    An interesting story and one I like telling people every time we pretend we can predict the future!

    Keytruda means a lot to the charity I work for – LifeArc (previously MRC Technology). We were responsible for humanising the antibody on behalf of Organon at our Mill Hill labs. It’s the income from Keyturda that will hopefully allow us to do many more good things in the future.

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