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).