There’s an interesting experiment underway at Vanderbilt, where a team from the university is taking a possible Alzheimer’s candidate into clinical trials on their own. Now, you could come up with several headlines for this, along the lines of “Academic researchers in way over their heads”, or “Plucky professors make end run around drug industry”, but neither of those are true.
That’s partly because many of the professors involved (such as Jeff Conn, ex-Merck neuroscience) have drug industry experience themselves, and they know exactly what they’re getting into. This is Vanderbilt’s Center for Neuroscience Drug Discovery, and they previously were working with AstraZeneca on M4 muscarinic compounds. That effort got derailed, though, as AZ got out of the neuroscience field entirely, and another collaboration between Vandy and Bristol-Myers Squibb ran into similar troubles. So this time, they’re going on by themselves for as long as possible.
But the other reason that this has a chance of working out is that they realize that “as long as possible” means “all the way through Phase I, we hope”. As the head of medicinal chemistry at the center put it to Endpoints, “Doing an IND on your own is quite an undertaking, including tasks largely unknown in academic circles“. That’s for sure – there’s a lot of toxicology, formulations, and manufacturing work that has to go into an IND filing, and hardly any academic discovery effort is equipped to get through them. (My bet is that a fair amount of this was contracted out by the Vanderbilt center, just as it is by smaller companies in the industry. Keeping a bunch of GLP/GMP facilities going to where they can withstand FDA scrutiny is not a cheap undertaking).
This may well be the first time an academic center has gone into Phase I like this completely without drug industry collaboration (C&E News thinks so). Does anyone else have any other examples? It’s rare enough even for the clinical compound itself to come from academia. (For those interesting in trying, I recommend this book). Even so, Vanderbilt has no intention of going all the way through the clinic. This is Alzheimer’s, after all, and the later clinical trials would take far more money than any university would (or in many cases, even could) commit. Just to get this compound into Phase I took financing from several foundations. So no, you’re not going to see Vandy-branded drugs down at the pharmacy.
The idea here, just as with a small company, is to take the drug candidate into humans and “de-risk” it to the point that a larger outfit might want to step in and do a deal. The compound itself is a selective allosteric modulator of the M1 muscarinic receptor, and that certainly takes me back. During my first years in the industry in the early 1990s, I spent a lot of time on muscarinic approaches to Alzheimer’s, and the Vanderbilt team will be the first to tell you that it’s not a new field. Previous attempts to target M1 for the disease have run into tox problems – a full agonist at the receptor is probably not the answer, and semi-selective agonists such as xanomeline have had trouble as well (although that approach is still alive). The hope is that the allosteric mechanism will give a cleaner response, but as I recall, even that has been tried before (although this does seem to be a better compound, pharmacologically, than previous attempts).
What could a drug like this do for Alzheimer’s? That’s a good question. All the muscarinic approaches are a rear-guard action, from what I know. You would not expect the underlying deterioration of Alzheimer’s to be affected, but you could improve the function of the cholinergic neurons that remain, buy some time, and improve symptoms and behavior. If I’ve mischaracterized these mechanisms, I’m sure that someone will let me know, but that’s how I’ve always seen them. So this is not any kind of Alzheimer’s cure, but if it works, it could be useful.
First, though, the compound has to get through Phase I. That stage of clinical trials is mainly to check blood levels and pharmacokinetics, to make sure that the appropriate doses have been working out for the actual disease patients in Phase II, but it’s also there to give you a read on gross toxicity. And for an M1-targeted compound, that’s the key. The sorts of side effects (gastrointestinal, cardiovascular, et al) that have derailed previous muscarinic efforts can be monitored, and the Vanderbilt team should know if they really have made a cleaner compound. At that point, they can make a case for an actual drug company to step in. Will anyone? That’s a good question, too, because it takes a lot of money and a lot of nerve to get into this field. Many of the big players in it have been going all the way to what they’re hoping will be disease-modifying therapies, rather than treating symptoms – after all, it’s going to be a long, expensive trial no matter what, and the chances of getting the symptoms right aren’t much better than the chances of hitting the underlying disease mechanism – whatever that is. So it’s no sure thing that even a successful Phase I trial would lead to a deal, although it certainly still could.
I wish the team good luck, of course. It’s a real accomplishment to get this far, and doing it from academia is harder still. I look forward to seeing how the Phase I data shake out, and how the program fares from there.