Magazine
Let's Take A Meeting
By Derek B. Lowe
"I'd like to start out this project update by going over the action items from our last meeting. . ."
But not all the actions, by any means. And I hope that you won't pick up on that fact, and odds are you won't. These presentations go on to a server somewhere – doesn't everything go on a server somewhere? -- but the only reason I've ever gone to it is to borrow slides for the next presentation after deleting my own by mistake. I can't imagine that anyone else accesses the thing at all. The folks in IS must really laugh at some of the activity logs for these things.
"As you can see, we had achieved our potency goals. . ."
Which were set before the program began, for a target no one's ever worked on before, and are therefore worth about as much as a coupon for a free order of fries. Who knows what the goals should be? But hey, we did meet them! The same goes, with chocolate sauce on it, for the selectivity data. Since most of the other enzymes in this class are even more of a black box than this one, who knows how much we need to avoid them?
". . .but we were faced with some PK difficulties that needed to be overcome."
Boy, ain't that the truth! Those blood levels were nasty, even after dosing in one of those vehicles that'll strip paint and soften a polypropylene syringe. But the fact that I'm mentioning the PK at all should be enough to tip some of you off that we've made progress on it; otherwise we'd be getting to that on about slide 27. Basically, we kept wheedling as many animal slots as we could, and dosing as many compounds as we had, until one of them worked. Which, as far as I can tell, is how a lot of PK problems get solved. Rational drug design at its finest.
"Here's the profile of our current lead compound."
Whose structure is rather similar to that of the compound we started off the project with, come to think of it! That's probably a good sign for the hit-to-lead team, if they think to take credit for it, but I have to make sure that it doesn't make us on the main project look silly. What can I say? We tried all kinds of other stuff, as you'd remember if you were awake for the previous six monthly meetings, and none of it really made things better. It's understandable, though, if that's not so obvious, since we've been telling you the whole time that things were actually improving.
"Solubility is good, as you can see."
And it has nothing to do with our PK. I mean, I know that the formulations people will like having a compound that dissolves, especially after all the powdered quartz we've been sending them so far this year. The real reason we make such a big deal about solubility here, though, is because we all think it'll give us better oral absorption. But have you ever seen most projects plot their solubility versus their blood levels? It's a hoot. You'd get a better correlation coefficient plotting the AUCs against our stock price.
"And the cellular activity is now down in the target range."
That's another correlation plot that most people around here avoid: primary assay versus cell assay. There are always those outliers, in both directions, and like as not your clinical candidate is one of them. Do I know why? Of course not. If I could predict which compounds would work in the cells, I'd be relaxing on my yacht right now and using that guy from Toxicology as a sea anchor.
"Microsomal stability is acceptable, and we show no sign of CYP inhibition."
All true, and I'm glad to say it. But if you plot those microsomal stabilities versus any of the PK parameters, you don't get a very good-looking chart, either. I mean, you'd have to think that it would be a bad idea to take a compound forward that gets chain-sawed in the microsome assay. Maybe it would give that plot a better correlation, come to think of it. And while we don't inhibit CYP, I'd just as soon that no one ask me if we induce, because I have no idea. The assay's running right now, and that's what blew up under my last project, thanks.
"No activity in the hERG assay."
And man, is THAT a relief! Everybody knows that hERG is bad news, but nobody completely trusts or believes the assay, and definitely nobody knows how to fix your compound's structure if you hit. You want to scale up and do a complete cardiovascular workup in the dog? Right: me neither, especially when that still won't let everyone relax even if it's clean. Makes you want to find the people who discovered this stuff and do some telemetry on them while you chase them down the hall.
"Here's a slide on the synthetic route."
And I'm really sorry, guys, that your last few months of work get summarized on one slide that makes it look as if everything worked. Look at how late it is in the presentation, too; by this point in the project, the chemistry is almost an afterthought. If we had one of those dramatic difficulties-overcome sections, I'd make a bigger deal out of it, but it was mostly the usual good work. Reaction went fine on one analog, didn't work on the next, worked a little on the third, and so on. Just enough to slow things down. Projects can succeed or fail on this kind of thing, but not everyone has to patience to hear about it.
"Here's our projected timeline."
And yes, fear not, it still ends with us delivering by the end of the year. Thanks to that compound that came up aces in the last rat dosing, we can indeed deliver by the December meeting, if nothing else bizarre happens before then. And of course, delivering in the second week of December is ever so much nicer than delivering in the first week of January, not that anyone's ever delivered a January clinical candidate in the history of the company. The ancient Mayans didn't worship their calendar as much as we worship ours. Let's not dwell on how they ended up.
"Which puts our projected resourcing at. . ."
OK, I should be fine here. No one yanks resource from a program that's about to deliver. Well, other than pulling off chemistry FTEs, that is, the rationale being that we've pretty much found our compound by now. Of course, we're supposed to have a backup series or two, and those are pretty spotty. We're also supposed to exemplify as many different patent areas as we can, but people never take that as a good enough reason to hold on to project chemists. Probably why we spend so much time in this industry sneaking onto each other's patents.
And there we have it, another monthly project review survived. At this rate, I'll switch to having meetings with the GLP process and clinical development teams pretty soon, which will make a nice change. But pretty soon another project will come down the log flume, and it's back to the sawmill. . .
