(Don’t) Blame the Chemists

Couple of days ago, I was talking to a medicinal chemist about why drug development productivity might have decreased.

Now, mind you, this guy was an “excellent chemist.” He’s been at this for over 30 years. He’s run big discovery groups for major pharmas. More recently, he’s been at small biotechs, and he’s been very productive. With 50 chemists or so, he’s managed to pop out 3 candidates in the last several years, all of which have been partnered with big pharma and are in the clinic.

He started off agreeing that there is a problem in drug development. But he thinks that the problem is not in discovery. He thinks discovery is doing great. He thinks high throughput screening is a godsend. He pins the blame squarely on downstream folks.

Say what? Now, I may be a tad defensive when people point at clinical development as being the culprit in the drug development train-wreck-in-slow-motion-over-the-last-two-decades, mostly because it’s partly true.

I pushed him to explain and here is what he said.

1) good chemists can get you good compounds against any target
2) but if the target is wrong, if there is a poor understanding of the biology, it will fail
3) we (the chemists) are doing a GREAT job because we’re getting all these great molecules that bind great and have all these other TPP qualities
4) we (the chemists) are not to blame if these molecules fail. We’re doing our part, and we’re really great at it.

Well. Talk about misaligned incentives (not that chemists are the ones setting up these incentives). Discovery groups are pumping out candidates that have lower and lower chance of helping patients and they believe they’re getting better and better at what they do. Well, you can’t really blame them, since they’re charged with producing molecules that look and act a certain way, and they’re doing exactly that. It’s hard to blame them for delivering what they’re asked to deliver.

But is that the way it should be? Is it beyond the remit of discovery groups to put out candidates that will work? Are they doing their job if they put out compounds that bind to the target like price tag adhesive on your new car window but have lower and lower probability of making it to approval?

I guess it is not their remit as things now stand. And it’s the nature of our business that it is hard to hold early stage scientists accountable for what happens 10 years later.  But boy, in what other industry could research claim success when their products don’t meet business needs (wait, don’t answer that).

The fact is that the way that discovery groups are pursuing leads now, with HTS, combichem, etc. and most importantly by targeting isolated proteins, is just not cutting it. The fact is that we have little reason to believe that selecting molecules that bind to a single protein is superior to whole animal phenotypic assays that used to be done way back when. There are folks who have told me they think whole animal assays with 100 well-selected compounds is much better than in vitro assays on a million compounds.

Sure, it’s much sexier to do “rational drug design” and to target “3D crystal structures.” But to borrow from “White Men Can’t Jump” – would you rather look good or win the game?

P.S. – definition of an “excellent chemist”: knows exactly what criteria big pharma chemists look for when they inlicense a candidate – may or may not correlate to actual chance of reaching patients as a drug