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The Palbociclib Saga: Or Why We Need a Lot of Drug Companies

Science has an article by journalist Ken Garber on palbociclib, the Pfizer CDK4 compound that came up here the other day when we were discussing their oncology portfolio. You can read up on the details of how the compound was put in the fridge for several years, only to finally emerge as one of the company’s better prospects. The roots of the project go back to about 1995 at Parke-Davis:

Because the many CDK family members are almost identical, “creating a truly selective CDK4 inhibitor was very difficult,” says former Parke-Davis biochemist Dave Fry, who co-chaired the project with chemist Peter Toogood. “A lot of pharmaceutical companies failed at it, and just accepted broad-spectrum CDK inhibitors as their lead compounds.” But after 6 years of work, the pair finally succeeded with the help of some clever screens that could quickly weed out nonspecific “dirty” compounds.
Their synthesis in 2001 of palbociclib, known internally as PD-0332991, was timely. By then, many dirty CDK inhibitors from other companies were already in clinical trials, but they worked poorly, if at all. Because they hit multiple CDK targets, these compounds caused too much collateral damage to normal cells. . .Eventually, most efforts to fight cancer by targeting the cell cycle ground to a halt. “Everything sort of got hung up, and I think people lost enthusiasm,” Slamon says.
PD-0332991 fell off the radar screen. Pfizer, which had acquired Warner-Lambert/Parke-Davis in 2000 mainly for the cholesterol drug Lipitor, did not consider the compound especially promising, Fry says, and moved it forward haltingly at best. “We had one of the most novel compounds ever produced,” Fry says, with a mixture of pride and frustration. “The only compound in its class.”
A major merger helped bury the PD-0332991 program. In 2003, Pfizer acquired Swedish-American drug giant Pharmacia, which flooded Pfizer’s pipeline with multiple cancer drugs, all competing for limited clinical development resources. Organizational disarray followed, says cancer biologist Dick Leopold, who led cancer drug discovery at the Ann Arbor labs from 1989 to 2003. “Certainly there were some politics going on,” he says. “Also just some logistics with new management and reprioritization again and again.” In 2003, Pfizer shut down cancer research in Ann Arbor, which left PD-0332991 without scientists and managers who could demand it be given a chance, Toogood says. “All compounds in this business need an advocate.”

So there’s no doubt that all the mergers and re-orgs at Pfizer slowed this compound down, and no doubt a long list of others, too. The problems didn’t end there. The story goes on to show how the compound went into Phase I in 2004, but only got into Phase II in 2009. The problem is, well before that time it was clear that there were tumor types that should be more sensitive to CDK4 inhibition. See this paper from 2006, for example (and there were some before this as well).
It appears that Pfizer wasn’t going to develop the compound at all (thus that long delay after Phase I). They made it available as a research tool to Selina Chen-Kiang at Weill Cornell, who saw promising results with mantle cell lymphoma, then Dennis Slamon and RIchard Finn at UCLA profiled the compound in breast cancer lines and took it into a small trial there, with even more impressive results. And at this point, Pfizer woke up.
Before indulging in a round of Pfizer-bashing, though, It’s worth remembering that stories broadly similar to this are all too common. If you think that the course of true love never did run smooth, you should see the course of drug development. Warner-Lambert (for example) famously tried to kill Lipitor more than once during its path to the market, and it’s a rare blockbuster indeed that hasn’t passed through at least one near-death-experience along the way. It stands to reason: since the great majority of all drug projects die, the few that make it through are the ones that nearly died.
There are also uncounted stories of drugs that nearly lived. Everyone who’s been around the industry for a while has, or has heard, tales of Project X for Target Y, which was going along fine and looked like a winner until Company Z dropped for Stupid Reason. . .uh, Aleph. (Ran out of letters there). And if only they’d realized this, that, and the other thing, that compound would have made it to market, but no, they didn’t know what they had and walked away from it, etc. Some of these stories are probably correct: you know that there have to have been good projects dropped for the wrong reasons and never picked up again. But they can’t all be right. Given the usual developmental success rates, most of these things would have eventually wiped out for some reason. There’s an old saying among writers that the definition of a novel is a substantial length of narrative fiction that has something wrong with it. In the same way, every drug that’s on the market has something wrong with it (usually several things), and all it takes is a bit more going wrong to keep it from succeeding at all.
So where I fault Pfizer in all this is in the way that this compound got lost in all the re-org shuffle. If it had developed more normally, its activity would have been discovered years earlier. Now, it’s not like there are dozens of drugs that haven’t made it to market because Pfizer dropped the ball on them – but given the statistics, I’ll bet that there are several (two or three? five?) that could have made it through by now, if everyone hadn’t been so preoccupied with merging, buying, moving, rearranging, and figuring out if they were getting laid off or not.
The good thing is that other companies stepped into the field on the basis of those earlier publications, and found CDK4/6 inhibitors of their own (notably Novartis and Lilly). This is why I think that huge mergers hurt the intellectual health of the drug industry. Take it to the reducio ad not all that absurdum of One Big Drug Company. If we had that, and only that, then whole projects and areas of research would inevitably get shelved, and there would be no one left to pick them up at all. (I’ll also note, in passing, that should all of the CDK inhibitors make it to market, that there will be yahoos who decry the whole thing as nothing but a bunch of fast-follower me-too drugs, waste of time and money, profits before people, and so on. Watch for it.)

13 comments on “The Palbociclib Saga: Or Why We Need a Lot of Drug Companies”

  1. Barry says:

    FreeMarket fundamentalists should be very alarmed at the diminished competition among ever fewer Drug Companies. The rest of us, too.

  2. Teddy Z says:

    Or, they can look at this as the market correcting itself, too many players in a shrinking market. Remember, the cuts/layoffs that we all bemoan are to satisfy those selfsame FreeMarket-ers: they want Mo Money and Mo Money.

  3. Steve Parent says:

    I agree completely Eric about your comment that huge mergers hurt the intellectual health of the pharma industry. All of the mergers are hurting competition and decreasing the “shots on goal” that the industry is taking when they develop drugs for targets many companies are interested in.

  4. Rubidium says:

    Probably had MBAs deciding on portfolio opportunities and not scientists

  5. Anon says:

    With how easy it is to shelve good candidates, it makes me wonder. If one was an entrepreneur, they’d poke the scientific talent (read: people who actually use a pipette on occasion) at these larger companies for candidates that are getting shelved or are likely to be shelved (working around the NDAs, of course).
    Or an employee could internally play as though a compound (or set of compounds) is mediocre, assemble a team, and try to spin it off.
    Either way, it sounds like the executive and management team at Pfizer [and others] are so aloof someone could legitimately walk off with a small to mid cap biotech.

  6. Hap says:

    In theory, though, you need both: people who understand the scientific data on a candidate and people who understand its potential markets and how much money it could make versus how much it will cost. In practice, once you get to a certain management level, the scientific data doesn’t seem to matter. While scientific merit isn’t sufficient to push something towards being a drug, it’s surely necessary (since while people can be fooled, nature can’t). In addition, market analysis seems like somewhere between voodoo, the effects of mind-altering drugs, and Dunning-Krueger effects, so there’s that.
    Perhaps the problem is that the merger effects didn’t really matter to Pfizer: they wanted the blockbusters now, and everything else be damned (which was pretty much what happened). They got what they wanted, made money in the short-term, and shrunk. It should be clear whose financial incentives run the show in pharma management, and that investors interested in the long term should probably be nowhere near pharma. That pharma is inherently dependent on performance in the long term for its success seems to bode ill for its future, but since neither the investors or management who determine things will be there in the long term, who cares?

  7. …speaking of non sequiturs… says:

    Yesterday FiercePharma had an article on possible takeover targets for Pfizer if they can’t get AZ. Among others:
    “Analysts and media reports have trotted out a variety of other potential Pfizer targets–even GlaxoSmithKline. There’s also Valeant, Bloomberg points out, but the Canadian drugmaker is embroiled in a hostile move to buy Allergan.”
    Not a big fan in general of mergers & acquisitions, but it would be fun to see Pfizer swallow Valeant- live by the sword, die by the sword.

  8. Hap says:

    But they don’t have any R+D to cut – where are the “synergies” going to come from in that merger?
    I’d like to see it, if only because their merger might create a behemoth with such hunger that the merged company would turn itself inside out like a Klein bottle and disappear. That would be a win-win acquisition!

  9. patentgeek says:

    @8 Hap: “the merged company would turn itself inside out like a Klein bottle and disappear”
    Or create a portal for Cthulhu’s entry to finally clean house. Either way, thanks Hap for the imagery!

  10. Anonymous says:

    FYI I am an academic working with this compound (no stock, no monetary interest) and it is an amazing drug and very specific (for better or worse). The Novartis and Lilly compounds aren’t nearly as good/specific/potent, because one good thing Pfizer (or Onyx) did do was lock up all the patent space for anything 3D similar to this compound. Speficity for cdk4/6 is very very tough to establish since they are so similar to many other kinases. This drug has that specificity. It will be an amazing drug in the clinic once its many many possible clinical uses are tested and established.

  11. Thats quite a long journey for a Compound almost two decades

  12. some idiot says:

    @8 Hap: “the merged company would turn itself inside out like a Klein bottle and disappear”
    Thanks for that one! That mental image made my day!

  13. sp3 says:

    One thing we forget is that there are more than 300 publicly-traded biopharma companies in the US with market caps >$100 million. Most of the new drugs are being discovered at these companies and licensed or companies acquired big pharma once they have clinical proof of concept. Let’s quit bemoaning the loss of science at big pharma and rejoice in the high quality science at start ups. They have real deadlines – the cash burn and it results in laser-sharp focus.
    In addition, big pharma is more interested in out-licensing drugs instead of putting them on the shelf. PARP inhibitors are good examples. When the Sanofi PARP inhibitor failed in the clinic, Pfizer outlicensed their compound to Clovis and Merck to Tesaro. Turns out the Sanofi compound was not a PARP inhibitor after all so both these compounds will likely make it to the market.

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