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Academia (vs. Industry)

Getting To Lyrica

There’s an interesting article in Angewandte Chemie by Richard Silverman of Northwestern, on the discovery of Lyrica (pregabalin). It’s a rare example of a compound that came right out of academia to become a drug, but the rest of its story is both unusual and (in an odd way) typical.
The drug is a very close analog of the neurotransmitter GABA. Silverman’s lab made a series of compounds in the 1980s to try to inhibit the aminotransferase enzyme (GABA-AT) that breaks GABA down in the brain, as a means of increasing its levels to prevent epileptic seizures. They gradually realized, though, that their compounds were also hitting another enzyme, glutamic acid decarboxylase (GAD), which actually synthesizes GABA. Shutting down the neurotransmitter’s breakdown was a good idea, but shutting down its production at the same time clearly wasn’t going to work out.
So in 1988 a visiting Polish post-doc (Ryszard Andruszkiewicz) made a series of 3-alkyl GABA and glutamate analogs as another crack at a selective compound. None of them were particularly good inhibitors – in fact, most of them were substrates for GABA-AT, although not very good ones. But (most weirdly) they actually turned out to activate GAD, which would also work just fine to raise GABA levels. Northwestern shopped the compounds around because of this profile, and Parke-Davis took them up on it. One enantiomer of the 3-isobutyl GABA analog turned out to be a star performer in the company’s rodent assay for seizure prevention, and attempts to find an even better compound were fruitless. The next few years were spent on toxicity testing and optimizing the synthetic route.
The IND paperwork to go into humans was filed in 1995, and clinical trials continued until 2003. The FDA approved the drug in 2004, and no, that’s not an unusual timeline for drug development, especially for a CNS compound. And there you’d think the story ends – basic science from the university is translated into a big-selling drug, with the unusual feature of an actual compound from the academic labs going all the way. Since I’ve spent a good amount of time here claiming that Big Pharma doesn’t just rip off NIH-funded research, you’d think that this would be a good counterexample.
But, as Silverman makes clear, there’s a lot more to the story. As it turned out, the drug’s efficacy had nothing to do with its GABA-AT substrate behavior. But further investigation showed that it’s not even correlated with its activation of the other enzyme, GAD. None of the reasons behind the compound’s sale to Parke-Davis held up, except the biggest one: it worked well in the company’s animal models.
The biologists at P-D eventually figured out what was going on, up to a point. The compound also binds to a particular site on voltage-gated calcium channels. That turns out to block the release of glutamate, whose actions would be opposed to those of GABA. So they ended up in the same place (potentiation of GABA effects) but through a mechanism that no one suspected until after the compound had been recommended for human trials! There were more lucky surprises: Lyrica has excellent blood levels and penetration into the brain, while none of the other analogs came close. As it happened, and as the Parke-Davis folks figured out, the compound was taken up by active transport into the brain (via the System L transporter), which also helps account for its activity.
And Silverman goes on to show that while the compound was originally designed as a GABA analog, it doesn’t even perform that function. It has no binding to any GABA receptor, and doesn’t affect GABA levels in any way. As far as I can see, a really thorough, careful pharmacological analysis before going into animals would probably have killed the compound before it was even tested, which goes to show how easy it is to overthink a black-box area like CNS.
So on one level, this is indeed an academic compound that went to industry and became a drug. But looked at from another perspective, it was an extremely lucky shot indeed, for several unrelated reasons, and the underlying biology was only worked out once the compound went into industrial development. And from any angle, it’s an object lesson in how little we know, and how many surprises are waiting for us. (Silverman himself, among other things, is still in there pitching, looking for a good inhibitor of GABA aminotransferase. One such drug, a compound going back to 1977 called vigabatrin, has made it to market for epilepsy in a few countries, but has never been approved in the US because of retinal toxicity).

25 comments on “Getting To Lyrica”

  1. Nick K says:

    Thank you, Derek, for a very interesting post. This should be required reading for all Big Pharma execs, especially those tempted to kill candidates too early purely on mechanistic grounds.

  2. John Mack says:

    Nice story, but I guess Epilepsy was not a big enough medical problem to make a profit from and hence the promotion of Lyrica for the treatment of Fibromyalgia – “a real medical condition.” How does Silverman feel about that, I wonder?

  3. milkshake says:

    My grandad was fond of wild mushroom hunting but he was color-blind and his inability to tell brown from dark green made finding the mushrooms in the woods rather difficult. He kept saying that he would exchange those ones that he found for those that he missed.
    I wonder if using the thoroughly mechanism-based approach is actually an advantage over the old times when they put everything into animals and measured seizures or tail flick time.
    In old times when chemists were able to synthesize and test perhaps hundred compounds during the entire project (as opposed 3000 today) they had to be much more careful about what they put tried. Their compounds were not pre-sieved in a selection funnel that begins with a purified-fusion-protein-based highly artificial biochemical assay, then engineered cells, CYP and microsomal stability assays, then PK, in order to be allowed into animal disease model. (I am not advocating abadoning them, its just that like with personal computers these productivity tools often do not seem to make things more productive.)

  4. Jeb Bush says:

    There was an interesting article in the Chicago Tribune a week or so ago from Prof. Silverman. He talked about how his drug was wisked away behind the curtain of big pharma not to be seen or heard about for many years. Apparently when he expressed an interest in attending the launch party, he was told no. Who says big pharma doesn’t shoot themselves in the foot. Unbelievable…

  5. sroy says:

    Serendipity + discovery by animal model activity + acting through unknown or surprising mechanisms are hallmarks of anti-epileptic drugs.
    A few examples
    -phenytoin
    -carbamazepine
    -valproic acid
    -lamotrigine
    -felbamate
    -topiramate
    -levetiracetam
    Coming to think of it, only barbiturates, benzodiazepines and some older gaba analogs could have been developed by not using animal models of epilepsy in the earliest stages of drug development.

  6. sroy says:

    To Jeb Bush,
    Is this the article?
    “Drug find worth $700 million but chemist finds it a tough sell to turn over project
    http://www.chicagotribune.com/business/chi-mon_lyricamar10,0,3946048.story
    By Jon Van | TRIBUNE REPORTER
    March 10, 2008
    In a chemist’s version of a winning PowerBall ticket, Richard Silverman’s discovery eventually became a blockbuster drug that showered him and Northwestern University with more than $700 million in royalties.
    Still, there was disappointment along the way. Once Pfizer Inc., the giant pharmaceutical concern, took control of the drug’s development, Silverman was pushed aside.
    “I was an outsider,” said Silverman, 61. “There was no talk with their scientists. No comments. They had a launch party for the drug, and I asked to come. Nope. No party for me. They take your stuff and tell you to go away.”
    This hurt, Silverman said, because “scientists aren’t in this for the money. We do it for the excitement of the research. You want to know what’s happening. To take that away is a shame.”

  7. Kay says:

    I enjoyed the post until it became clear that you were not going to mention that it’s a line extension, its predecessor is essentially identical, and the sponsor is predisposed to marketing rather than science.

  8. NJBiologist says:

    I’d heard a rumor that MRL-San Diego had a gabapentin congener under development for pain, but didn’t move on it because they couldn’t pin down a mechanism. Can anyone point me to something more than a rumor to confirm or disconfirm this?

  9. Gaudisso says:

    Another “false friend of GABA” is gabapentin (Neurontin) which also has a mechanism of action independent of binding to GABA receptors. Of further interest is the potential antagonism of AMPA and NMDA receptors by gabapentin and pregabalin. Impacting these receptors seems to be the final common pathway for many disparate drugs used for similar CNS disease states.
    As a semi-rhetorical question how is it that memantine (Namenda), a NMDAR antagonist currently used in the U.S. for Alzheimer’s dementia, also has shown benefit in some children with autism?

  10. sroy says:

    Hi NJBiologist,
    Do not disturb their maunfactured reality. You might disconnect them from the matrix (and that cannot be good).
    Remember therapeutic activity is not that important. Better a useless drug with a defined therapeutic target than a useful one with a unkown mechanism of action.
    And ignore the fact that the golden age of drug discovery occured when we were willing to take risks and had a rather poor understanding of the drug targets.

  11. processchemist says:

    John Mack,
    Topamax (topiramate) was well placed in the 50 top selling drugs, so epilepsy is not an unprofitable therapeutic area

  12. CJ Croy says:

    I’m going to guess Topamax’s profitability has a lot to do with its off-label use as a general “Something’s wrong with your brain” drug. Bipolar disorder, alcoholism, you name it, someone’s tried it and probably gotten results doing it.

  13. Nick K says:

    I wonder if the mechanism is the same as that of Keppra(levetiracetam)? An extremely simple but highly effective anti-epileptic drug, discovered like this one almost by accident at UCB. As far as I know, the mechanism of action is unknown.

  14. Gaudisso says:

    Topiramate is currently being used for such “off label” conditions as migraine headaches and weight loss by a large number of primary care physicians. More interestingly, but not relevant from a profitability point of view, it’s also used to prevent cerebral ischemia in preterm neonates due to its ability to block AMPA receptors. The problem is that topiramate can only be administered orally in this subset of patients who may not have functional GI tracts. Finding an AMPAR antagonist that could be delivered intraveneously would be of great benefit for these helpless patients.

  15. epi says:

    A few corrections / expansions to some of the comments:
    – topiramate has an indication for migraine prophylaxis but not weight loss. The majority of sales is for the migraine indication. It is used as are most anticonvulsants for many other CNS conditions.
    – Keppra binds to the synaptic vesicular protein SV2A. This is thought to be related to its mechanism in epilepsy but not yet known how
    – the best discovery story in epilepsy is for valproic acid. In the 60s scientists at the Pharmacy school in Grenoble used valproic acid as a solvent. Amazingly everything they put into this solvent was anticonvulsant in animal models. Eventually the penny dropped & valproic acid was unmasked as the real anticonvulsant. Still sells $1 billion plus for Abbott in epilepsy, migraine and bipolar.
    – vigabatrin has just been filed with the FDA.

  16. retread says:

    You might all have a look at Proc. Natl. Acad. Sci. vol. 105 pp. 3628 – 3633 ’08 which reviews the various hypotheses about the mechanism of gabapentin (Neurontin) activity– e.g. acute inhibition of calcium currents in the presynaptic terminal, decreased synaptic transmission, decreased neurotransmitter release, finds the evidence for this equivocal or at least noreplicable, and comes up with a new mechanism — binding to the alpha2-delta subunit of the voltage gated calcium channel (VGCC) resulting in decreased levels of VGCC at the presynaptic terminal. Thus gabapentin has effects chronically (as the effect takes time to become manifest) but not acutely.
    As you note, no one could have predicted the effects of gabapentin (which are still under investigation). It’s also very good that you included the valproic acid story, which shows just how little we know (and still don’t know) about the way the brain works. Another example is Cade’s discovery of Lithium’s effects.

  17. retread says:

    You might all have a look at Proc. Natl. Acad. Sci. vol. 105 pp. 3628 – 3633 ’08 which reviews the various hypotheses about the mechanism of gabapentin (Neurontin) activity– e.g. acute inhibition of calcium currents in the presynaptic terminal, decreased synaptic transmission, decreased neurotransmitter release, finds the evidence for this equivocal or at least noreplicable, and comes up with a new mechanism — binding to the alpha2-delta subunit of the voltage gated calcium channel (VGCC) resulting in decreased levels of VGCC at the presynaptic terminal. Thus gabapentin has effects chronically (as the effect takes time to become manifest) but not acutely.
    As you note, no one could have predicted the effects of gabapentin (which are still under investigation). It’s also very good that you included the valproic acid story, which shows just how little we know (and still don’t know) about the way the brain works. Another example is Cade’s discovery of Lithium’s effects.

  18. Julianna says:

    Perhaps some of the researchers and drug companies inventing Lyrica should begin listening to people who are actually using this wonder drug.
    I have been taking Lyrica since the end of December, so a little over 3 months. I have only been able to work up to 150 mg at night, and 75 mg in the morning. My doctor tells me I have to work up to at least 300 mg for it to have any “medicinal benefit.” I have lost 16 pounds and have not changed anything in my life. My diet is the same and I can not exercise due to pain.
    I have severe fibromyalgia, which I developed after botched dental work and the discovery that I am highly allergic to titanium. The allergy diagnosis only took me a year and a half to discover after countless hours of research, and $25,000 in medical bills (out-of-pocket after insurance). I didn’t get the answers in the US, but had to send my blood to Belgium to be tested. I couldn’t make this up.
    I still am in a lot of pain, and still have to take 1 to 3 Vicodin a day. Lyrica hasn’t made me feel great yet. My husband thinks the weight loss means the medicine is doing some damage to my body. I told him I’d wait to stop taking it until I lost 10 more pounds, as that would be my dream weight.
    But to be honest, if I lose more than those 10 pounds I would be skin & bones. I came across this blog while searching for “Lyrica” and “weight loss.” Before this blog I stumbled across another website that had hundreds, if not thousands, of posts from men & women who had crazy weight gains. Some were gaining a pound a day, 20 pounds in a month, etc.
    How often after the trials do the drug companies pay attention to the patients? Is it only when something bad enough happens to warrant a lawsuit?
    Interested in your thoughts.

  19. RTW says:

    Well – Its nice to see an article for once recognizing the good science that Parke-Davis in Ann Arbor use to do before completly obliterated from the planet by Pfizer. I had many friends that worked on the pregabalin project. I think Dr Silverman should take issue with Pfizer for his treatment at launch, but on the other hand PD the Pfizer put a great deal of money and effort into its development. BTW those of us that worked in the trenches of R&D inside the companies rarely if ever got to go to launch parties either. People responsible for the development of some of Pfizers best drugs all where eventually forced out of the company by virtue of their later treatment, two of which had won the chairmans award (under WL).

  20. Bethany says:

    Here’s another real life scenario. I was diagnosed with ideopathic peripheral neuropathy six years ago, do not have diabetes, have both sensory and motor involvment, and was prescribed Neurontin, needing slowly increasing doses. Winter brings on pain increase and then summer brings a bit of relief. For a year and a half, I’ve been on Lyrica, which works with 1/6 the milligrams of neurontin. Being a chemist, I know that weight of a drug does not mean the same equivalents as the same weight of another drug. (In biology there is probablly a better term than equivalents.)
    My motor loss is increasing, as well as the pain reaction to cold. There may now be autonomic involvement. Can you biologists or biochemists suggest any mechanisms to keep nerves from dying?
    Keep up the scientific work in the trenches. I’m grateful for both Neurontin and Lyrica and maybe one of you will come up with something that can prevent the early death of nerves, even if it is for the next generation.

  21. Timray says:

    Bethany, I hear your pain. I wish I had Summer’s off and my wishes are you find relief….at 60 I too am losing motor loss but I have diabetes and the heart breaker is I am in excellent control. That was a very kind thought for the next generation….you are no doubt a wonderful person. I am on pain relievers that work for a while and I have learned to make the most of those moments.

  22. Dad says:

    I read this article, understood much of it, was lost on some. I read it as the father of a 16 year old girl who takes Lyrica to suppress seizures. Her side effect of weight gain is concerning. Of course we are talking with her doctor about the weight issue, but a shot in the dark here for educated opinions is why I am typing. Anyone with clinical knowledge of Lyrica and the weight gain side effect, please feel free to chime in. I feel like my own knowledge of this topic is a father’s responsibility.

  23. karen says:

    I am concerned @ the weight gain since I have put on 60+ lbs. being on Lyrica. I want to try the Neurontin, but ran across Topamax and wondered if it would help me with the nerve pain and do the same as Lyrica as to block the transmitter part of the pain. I just don’t want to feel the nerve pain and the Lyrica does that for me, but I have got to get this weight or is it fluid off of me. I would love a response so I’d know what to do. I am going to doc in the morning to ask @ switching to the Topamax. I will do further research on it and if I find anything that is conclusive to how that the similarity is close and @ the same then I will try it.

  24. milkshake says:

    Topiramate (Topamax) is an unusual anti-epilepsy med that has quite a broad spectrum of effects but a low dose should be a relatively safe thing to try. Ask your doc. It may work, Topiramate has been now FDA-approved as a component of a new weight loss combination pill. (By the way we will have Bruce Maryanoff – the guy who discovered Topiramate – giving a lecture here at the institute in few weeks and I am gonna chat over lunch with him 🙂

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