Let’s talk failure. (They tell you that you should start off with a snappy lead that makes people want to see what comes next. How can things do anything but improve after an opening like that?)
Failure is something that everyone in the drug discovery and development world knows very well — a lot more intimately than success, for sure. I run into Success every once in a while, and we’ve had some great times together. But Failure’s always the one who’s hanging around the labs. Reactions don’t work out, SAR series go nowhere, whole projects don’t make it to the clinic, or wipe out when they do. We all know the numbers, and one way or another, we’ve all come to terms with them.
That adjustment, it’s worth remembering, is not something that everyone can manage. When I started out in the industry, I had a co-worker who was, like me, fresh out of the academic labs. We both worked hard and had a lot of ideas for our respective projects, and we both submitted a lot of compounds. And, as these things go, most of those good ideas didn’t quite work out. We pushed the structures too hard in the wrong direction, or ran into PK or tox problems, and had to back up and try again.
That’s medicinal chemistry for you. And I learned that the cells in the dish (and the rats in the cages) didn’t care very much about how excited I was about my latest compounds, or how strong the flash of inspiration was that led to them. In fact, their interests didn’t seem to overlap with mine very much at all.
My co-worker had a tough time with that, and took these failures hard. How could those insights into the SAR (that’s Structure-Activity Relationship, to laymen) not lead to something? Why did the best ideas always seem to be the ones that went down in flames most spectacularly? He could never quite assign the blame to The Way Things Are, and kept more of it for his personal use, which is not a blueprint for happiness. Eventually he left the lab completely, finding the whole business too frustrating to continue.
A similar problem occurs at a macro level, when you deal with clinical trial data. Here the news can be really hard to take, since you’re not just looking at one person’s good idea, but the hard work of dozens, hundreds, or even thousands of people. (And I haven’t even mentioned the money yet!) I started thinking about this connection again after reading a recent analysis in Nature Reviews Drug Discovery that looked at Phase II failures, which are the most common type.
They should be. We’ve learned, or should have learned, enough about pharmacokinetics and basic safety pharm that Phase I failures have become increasingly rare — not that I haven’t been in on one or two, but that’s another story. No, by now, the sorts of compounds that are likely to wipe out at that stage shouldn’t even make it to that stage. Phase II is where things really get serious, so it’s fitting that most of the failures should show up there. A solid percentage of these, that analysis found, went down due to efficacy, which is just what these trials should be aiming at. There were also quite a few “strategic failures,” where a company pulled out due to competition or the like, but many of those might also be classified as efficacy failures — not quite efficacious enough, to be specific. (The remaining failures were via toxicity and side effects, as you’d figure.)
But it’s also true that Phase III failures have been on the rise, proportionally, which I put down to two factors. The first, as I mentioned in my previous column, is moral hazard: the tendency for a small company to design a Phase II trial so that it’s just good enough to attract a deal, but not quite powerful enough to reveal trouble. The second factor is working on diseases for which a big Phase III trial is the only way to see if anything’s really working at all. Alzheimer’s — and other neurodegenerative diseases — are the first to come to mind, but a lot of cardiovascular/metabolic stuff is moving into that category, too.
These are just the areas that Bernard Munos (ex-Lilly, now consulting) is telling people that they should consider avoiding completely. After all, the failure rate for these conditions is nasty, and we haven’t made any notable breakthroughs to make us more sure that we understand what’s going on. So why would you take the same beating as you would in Phase II, but move it to the expensive, time-consuming world of Phase III instead?
Just as bench scientists need to adjust their perspective at the discovery level, the industry might need to adjust its view at the clinical one. And that’s Mr. Munos’ point. Just as medicinal chemists might manage to convince themselves that their chances of success are greater because they’ve had this great idea, companies can talk themselves into some very expensive risks because they’ve got such a great potential drug. There no doubt that the first company to find an effective Alzheimer’s therapy will coin money — but how many of them will crash while trying? Would it be better to wait until we have more of a clue about what causes the disease before committing another few billion dollars?
The counterargument is that we get those clues by spending those billions, that the expensive clinical failures are the only way to learn. And while I agree that we learn from them (we’d better!), I still have to wonder if that’s the only way. The other counterargument is that “waiting until we know more” is just what companies have been doing — that everyone who’s taken an Alzheimer’s drug into the clinic has believed that Now Is the Time, that we finally have enough knowledge that things will go differently. All I can say about that is: the size of the potential market has a way of distorting ones perception of reality, and it can be a tough call to say if things have really changed, or if it’s just that you really want to believe that they’ve changed.
The problem is that discovery scientists can usefully redefine success for themselves. Sure, active compounds are great, and clinical candidates are great, but you also have to know when you’ve done a good job, whether the rats agreed with you or not. A fast, thorough job is worth being proud of no matter what. But in the clinic, well, success is hard to argue with and hard to argue away from: do your compounds work? Well enough so that people will pay money for them? If not, well . . . there really is a bottom line out there, and by the time you’re in the clinic, it’s very much in sight.
No, there’s no way to sidestep our clinical failure rates. They’re going to have to improve, and we’re going to have to find a way to spend less money, either by running them better or avoiding some of them completely. It’s not easy. If you think that fighting City Hall is hard, try fighting reality.
In the Pipeline – Process Chemistry Makes the Headlines
Not a common occurrence, that. But this Wall Street Journal article (http://on.wsj.com/jbjYy0) goes into details on some efforts to improve the synthetic route to Viread (tenofovir) (or, to be more specific, TDF, the prodrug form of it, which is how it’s dosed). This is being funded by former president Bill Clinton’s health care foundation:
The chasm between the need for the drugs and the available funding has spurred wide-ranging efforts to bring down the cost of antiretrovirals, from persuading drug makers to share patents of antiretrovirals to conducting trials using lower doses of existing drugs.
Beginning in 2005, the Clinton team saw a possible path in the laboratory to lowering the price of the drugs. Mr. Clinton’s foundation had brokered discounts on first-line AIDS drugs, many of which were older and used relatively simple chemistry. Newer drugs, with advantages such as fewer side effects, were more complex and costly to make . . . A particularly difficult step in the manufacture of the antiretroviral drug tenofovir comes near the end. The mixture at that point is “like oatmeal, making it very difficult to stir,” explained Prof. Fortunak. That slows the next reaction, a problem because the substance that will become the drug is highly unstable and decomposing, sharply lowering the yield.
Fortunak himself is a former Abbott researcher, now at Howard University. One of his students does seem to have improved that step, thinning out the reaction mixture (which was gunking up with triethylammonium salts) and improving the stability of the compound in it. (Here’s the publication on this work (http://bit.ly/johxUM), which highlights that step, formation of a phosphate ester, which is greatly enhanced with addition of tetrabutylammonium bromide). This review has more on production of TDF and other antiretrovirals: http://bit.ly/mPVhpW
This is a pure, 100% real-world process chemistry problem, as the readers here who do it for a living will confirm, and it’s very nice to see this kind of work get the publicity that it deserves. People who’ve never synthesized or (especially) manufactured a drug generally don’t realize what a tricky business it can be. The chemistry has to work on large scale — above all! — and do so reproducibly, hitting the mark every time using the least hazardous reagents possible, which have to be reliably sourced at reasonable prices. And physically, the route has to avoid extremes of temperature or pressure, with mixtures that can be stirred, pumped from reactor to reactor, filtered, and purified without recourse to the expensive techniques that those of us in the discovery labs use routinely. Oh, and the whole process has to produce the least objectionable waste stream that you can come up with, too, in case you’ve got all those other factors worked out already. Not an easy problem, in most cases, and I wish that some of those people who think that drug companies don’t do any research of their own would come down and see how it’s done.
To give you an example of these problems, the paper on this tenofovir work mentions that the phosphate alkylation seems to work best with magnesium t-butoxide, but that the yield varies from batch to batch, depending on the supplier. And in the workup to that reaction, you can lose product in the cake of magnesium salts that have to be filtered out, a problem that needs attention on scale.
According to the article, an Indian generic company is using the Howard route for tenofovir that’s being sold in South Africa. (Tenofovir is not under patent protection in India). Interestingly, two of the big generic outfits (Mylan and Cipla) say that they’d already made their own improvements to the process, but the question of why that didn’t bring down the price already is not explored. Did the Clinton foundation improve a published Gilead route that someone else had already fixed? Cipla apparently does the same phosphate alkylation, but the only patent filing of theirs that I can find that addresses tenofovir production is this one (http://bit.ly/iTvl4u), on its crystalline form. Trade secret?
from http://pipeline.corante.com/ on 5/13/2011
Copyright Derek Lowe, 2011
Derek B. Lowe has been employed since 1989 in pharmaceutical drug discovery in several therapeutic areas. His blog, In the Pipeline, is located at http://www.corante.com/pipeline and is an awfully good read. He can be reached at email@example.com.