Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
A query from a reader prompts me to ask this question, in preparation for a rather long post in the new future. What do you think is the most worthwhile new pharmaceutical brought to market since 1990? That's an arbitrary cutoff, but twenty years is a reasonable sample size. And I'll let everyone define "worthwhile" as they see fit - improvement over existing drugs, opening new therapeutic areas, cost-effectiveness, what have you. Just be sure to make your case, briefly, when you nominate a candidate. Let's see, first off, if it's a topic that can be agreed on at all.
Past results, they tell you, are no guarantee of future performance. Sanofi-Aventis is ready to tell you all about that after the results of a Phase III trial of their recently acquired oncology drug, iniparib (BSI-201). This had shown very strong results in Phase II against "triple-negative" breast cancer, but it appears to have missed two survival endpoints in a larger trial. Sanofi bought BiPar, the company that had been developing the drug, a little less than two years ago.
Iniparib's a small molecule indeed - small enough that its systematic name can be immediately parsed by any sophomore chemistry student. It's 4-iodo-3-nitrobenzamide; it's the sort of thing you can order out of a catalog. But it's also an inhibitor of poly-(ADP-ribose) polymerase I (PARP1), and it's the first compound of that class to get this far in the clinic. PARP1 is part of a DNA repair pathway, although it's not on the front line. That would be homologous recombination, which is the pathway that needs the well-known BRCA to function. The idea has been that since so many aggressive breast cancers are deficient in BRCA, that they'd be especially sensitive to something that targeted PARP as well - they should accumulate so many DNA breaks that they'd be unable to replicate.
That's a perfectly reasonable theory. But it doesn't seem to have yielded perfectly reasonable results in this case. Problem is, PARP1 has a lot of functions in the cell, and inhibiting the lot of them all at once may not be such a good idea. One possibility is that effects on the Akt pathway might boomerang and reduce the effectiveness of therapy.
More broadly, this is yet another illustration of the perils of Phase II data. And it does make a person think about the idea of tightening up the endpoints of such trials even more. Problem is, you often don't get good survival numbers until Phase III, anyway, by which time you've spent the money. Like Sanofi-Aventis is spending it now. Let's hope that one of the other indications for the drug works out better.
Update: here's a rundown on competition in this field. The next round of clinical data will be quite interesting. . .
One of the authors (Mostafa Fekry) of the paper mentioned in my last post is at Cairo University. Which means that things must be rather uncertain for him right now, as it is for everyone in Egypt.
Readers will recall the mentions here of the 2009 unrest in Iran (behind-the-scenes note: my wife is Iranian), and this seems to have moved rapidly to an even more extreme stage. I have to say, I don't mind seeing autocrats and dictators (and their security forces) chased through the streets. I do wonder, though, what might replace them (which speculation seems to be helping tank the stock market today). Let's hope for the best.
I advised readers during the most recent Iran unrest (there will be more, I'm sure) to pitch in by helping to run Tor relays. This time, though, since the Egyptian government seems to have pulled the internet plug completely out of the wall, in what must (economically and socially) be a shower of plaster fragments, that may not do as much good. But events are young.
Here's the first response in the chemical literature to the arsenic-in-DNA controversy, from three authors in ACS Chemical Biology. They detail the argument, familiar to readers of the comment section here, that arsenate esters just would not be expected to have the hydrolytic stability needed for arseno-DNA to function usefully.
How far off is it? By, well, about 13 (make that 17) orders of magnitude, which is much worse than I'd thought. As the authors put it, "Overcoming such dramatic kinetic instability in its genetic material would present serious challenges to Halomonadacea GFAJ-1." Indeed it would.
A reader sent this along to me, and I figured that many folks who are in (or have been through) academia can relate. This is the Hui Zheng lab at Baylor, with their Gaga-esque production of. . .Bad Project:
Congratulations to them. It's a good thing that there was no YouTube back when I was in that position, or I might have gotten myself in a lot of trouble. . .
I wish that more journals did this! Environmental Microbiology, which I have never looked at before, has published its favorite reviewer comments from the year just passed. They're not tied to the papers that generated them, naturally, but then, many of these manuscripts didn't quite make the cut:
"The biggest problem with this manuscript, which has nearly sucked the will to live out of me, is its terrible writing style."
"I usually try to be nice, but this paper has got to be one of the worst I have read in a long time."
"I suppose that I should be happy that I don't have to spend a lot of time reviewing this dreadful paper, however, I am depressed that people are performing such bad science."
"It is sad to see so much enthusiasm and effort go into analyzing a dataset that is just not big enough."
There are plenty more, including many from people who are actually happy about what they had to read (and yes, there are some). Check 'em out!
Well, the snow is now well up over my knees here at headquarters, which accounts for the lack of posting today. There's only so much the snowplow guy can do out there; it's hard to fine places to shove the stuff to. I've been out moving piles of it around, off the driveway and off the roof, which leaves little time for Science. More tomorrow!
Um, I mean more science. Not more snow. At least, I sure hope not.
Abbott is announcing 1,900 layoffs, about 2% of the company's work force. That's on top of the 3,000 that had been announced last fall, and this is not getting 2011 off to a very good start, is it? I'm told by primary sources that there have been cuts in research as a part of this latest round, but I don't have any firm numbers yet. . .
So, me-too drugs, knock-offs, copycats: what say you? If you're a critic of the industry, you generally say quite a bit, and it's about lack of innovation, seeking easy profits and playing it safe, putting marketing over science, and so on. But what if that's not true?
We've talked about this here before, but now we can put some numbers on the topic, thanks to this article in Nature Reviews Drug Discovery. The authors have covered a lot of ground, looking at first-in-class drugs approved from the early 1960s up to 2003, with later entrants in the same areas accepted up to 2007. There are 94 of those different therapeutic classes over that period, with a total of 287 follow-on drugs coming after the pioneer compounds in each. So there you have it - case closed, eh?
Not so fast. Look at the timing. For one thing, over that nearly 50-year period, the time it takes for a second entry into a therapeutic area has declined steeply. Back in the 1970s, it took over nine years (on average) for another drug to come in and compete, but that's gone down to 1.7 years. (The same sort of speed-up has taken place for third and later entries as well). Here's what that implies:
Implicit in some of the criticism of the development of me-too drugs has been the assumption that their development occurs following the demonstration of clinical and commercial success by the first-in-class drug. However, given assessments of the length of time that is typically required for drug development — estimated at between 10 to 15 years — the data on the timing of entry of follow-on drugs in a particular class, in this study and in our previous study, suggest that much of the development of what turn out to be follow-on drugs must occur before the approval of the breakthrough drug.
That it does, and the overlap has been increasing. I've been in the drug industry since 1989, and for every drug class that's been introduced during my career, at least one of the eventual follow-on drugs has already been synthesized before the first one's been approved by the FDA. In fact, since the early 1990s, it's been the case 90% of the time that a second drug has already filed to go into clinical trials before the first one has been approved, and 64% of the time another compound has, in fact, already started Phase III testing. Patent filings tell the story even more graphically, as is often the case in this industry. For new drug classes approved since the 1970s, 90% have had at least one of the eventual follow-on drugs showing its first worldwide patent filing before the first-in-class compound was approved.
So the mental picture you'd get from some quarters, of drug companies sitting around and thinking "Hmmm. . .that's a big seller. Let's hang a methyl off it now that those guys have done the work and rake in the cash" is. . .inaccurate. As this paper shows (and as has been the case in my own experience), what happens is that a new therapeutic idea becomes possible or plausible, and everyone takes off at roughly the same time. At most, the later entrants jump in when they've heard that Company X is working in the same area, but that's a long time before Company X's drug (or anyone's) has shown that it's going to really work.
If you wait that long, you'd be better off waiting even longer to see what shortcomings the first drug has out in the real marketplace, and seeing if you can overcome them. Otherwise, you're too late to go in blind (like the first wave does). And blind it is - I can't count the number of times I've been working on a project where we know that some other company is in the same area, and wondering just how good their compound is versus ours. If you know what the structure is (and you don't always), then you'll make it yourself and check your lead structure out head-to-head in all the preclinical models you care about. But when it comes to the clinical trials, well, you just have to hold your breath and cross your fingers.
I'll let the authors sum things up:
Overall, these results indicate that new drug development is better characterized as a race to market among drugs in a new therapeutic class, rather than a lower risk imitation of a proven breakthrough. . .a race in which several firms pursue investigational drugs with similar chemical structures or with the same mechanism of action before any drug in the class obtains regulatory marketing approval. So, the distinctions that are often drawn between the relative innovative value of the development of the first-in-class and the me-too drugs in the same class may be misguided. . .
Several people have asked me about this recent press conference, where two Italian researchers (Andrea Rossi and Sergio Focardi) say that they have demonstrated anomalous nuclear reactions with nickel and copper, on a scale sufficient to produce electrical power. (To be technical, it's probably not fusion per se, but is it anything, and if so, what)?
I hope that they're right, naturally. But there are a lot of things to wonder about. They chose to announce this at a press conference, and to "publish" in a journal that actually doesn't exist. Rossi himself seems to have had some criminal problems with the Italian authorities in the past. All this does not inspire confidence (says the blogger in a scrupulously neutral tone of voice). And this whole area is absolutely saturated with cranks, sharp operators, self-deceivers, paranoids, and loose cannons of every description. I continue to think that these phenomena (if there are phenomena there at all) are worthy of study, but man, the signal-to-noise ratio in this field just could not be worse. The legitimate scientists working in it (and there are some) have my sympathy.
For what it's worth, this latest work seems to follow up on some earlier reports from another Italian physicist, Francesco Piantelli. That link, a blog written by a sceptical enthusiast, will probably tell you more than you want to know about the story, and a look through its other posts will tell you plenty about the state of the whole field. I'm going to take the same course of action that I have with all purported new energy breakthroughs in the last twenty years: wish the participants good luck, hope that they've actually found something worthwhile, and sit back to watch. If anyone does make a breakthrough, it's going to be abundantly clear. If, on the other hand, the people involved are still flopping around and issuing press releases year after year, then they're probably still having to pay their own electric bills.
Well, no sooner do I speculate about whether Luc Montagnier has lost it then he makes headlines with a "water memory" story about teleporting DNA. There are, of course, umpteen reasons for this not to be a real result. We'll start with contamination of vials, which in a system like PCR can be disastrous, and work from there. The other major problem I have with this is one of the major problems I have with homeopathy: if incredibly small dilutions of things have such an effect, then why aren't we seeing it happen all the time? There are tiny amounts of DNA everywhere: how come all our experiments aren't turning into fuzzy blurs of results from all the small but oh-so-powerful fragments and traces in every sample?
Well, Montagnier himself says that he thinks that this experiment will be replicated by others, so I'll hold my fire until that's tried out. Until then, I note that this experiment has apparently made Deepak Chopra's day. It's hard for me to imagine that anything that has inspired such a fuzzy-brained column from such a fuzzy-brained man could lead to any good. But perhaps we'll all be surprised.
Here's a topic that's come up here before: for a new cancer drug, how much benefit is worthwhile? As it stands, we approve things when they show a statistically meaningful difference versus standard of care (with consideration of toxicology and side effects). But should our standards be higher?
That's what this paper in the Journal of the National Cancer Institute is proposing. The authors look at a number of recent Phase III trials for metastatic solid tumors. It's a tricky business:
When designing a randomized phase III clinical trial, the investigators must specify in the protocol the difference (δ) in the primary endpoint between experimental and control groups that they aim to detect or exclude (24). The number of patients to be recruited and the duration of the study will depend on the value of δ; increasing the sample size will allow the detection or exclusion of smaller values of δ. Ideally, trials should be designed such that δ represents the minimum clinically important difference, taking into account the tolerability and toxicity of the new treatment, that would persuade oncologists to adopt the new treatment in place of the standard treatment. Of course, the opinions of oncologists as to what constitutes a minimal important value of δ will vary, but a reasonable consensus can be reached by seeking the opinions of oncologists who manage a given type of cancer. For example, an increase in median survival by less than 1 month for patients with advanced-stage cancer would not be regarded by most as clinically important, unless the new agent had less toxicity than standard treatment, whereas an improvement of median survival by greater than 3 months for a drug that was reasonably well tolerated would usually be accepted as clinically important.
And the problem is, given the costs of some of these drugs versus their benefits, you run the risk of, finally, paying too much for too little. I know that people say that you can't put a cost on a human life, but that's probably not true, when you're talking about an entire economy. As the article points out, the rough estimate is that the developed world can support expenditures of up to roughly US $100,000 per year of life gained, but past that, we're into arguable territory. (If someone wants to spend more out of their own pocket, that's another matter, naturally, but at these levels, we're usually talking public and private insurance).
The benefits can indeed be marginal, and you have to look at the statistics carefully so as not to be misled:
. . .several trials showed a statistically significant difference in a major outcome measure between the experimental and control groups, but the difference in outcome was of lower magnitude (eg, hazard ratio was closer to one) than that specified in the protocol. For example, the clinical trial that led to approval of erlotinib for treatment of pancreatic cancer was designed to detect a relative risk reduction of 25% (HR ≤ 0.75), but the best estimate of hazard ratio from the trial showed a relative risk reduction of 18% (HR = 0.82, 95% confidence interval = 0.69 to 0.99). The difference was statistically significant (P = .038), but the median survival differed by only 10 days.
What happens is that the trials are (understandably enough) designed to detect the minimum difference that regulatory authorities are likely to find convincing enough for approval of the drug. And the FDA has generally set the bar at "anything that's statistically significant for overall survival". These authors (and others) would like to see that raised. They're calling for trials not to go for a statistically significant P value, so much as to show some sort of meaningful clinical benefit - because it's become clear that you can have the first without really achieving the second.
I think that might be a good idea, whether or not you buy into that cost-per-year-of-life figure or not. At this point, I think it's fair to say that we can come up with drugs that provide some statistical measure of efficacy, given enough effort in the clinic, for many kinds of cancer (although certainly not all of them). But how many add-a-month-maybe therapies do we need? Not everyone's convinced, though:
Wyndham Wilson, a lymphoma researcher at the National Cancer Institute in Bethesda, Maryland, argues that the proposed clinical endpoints are somewhat arbitrary. “What constitutes a clinically meaningful difference? Six months is obvious, but where do you cut the line?” What's more, he adds, simply focusing on median responses often ignores important outlier effects that could merit approval for an experimental drug. “The difference in overall survival may not be great, but it may be driven by a great benefit to a small group,” he says.
Problem is, it's often quite difficult to figure out who that small group might be, and just treat them, instead of treating everyone and hoping for the best. And there's always the argument that these therapies are stepping stones to more significant improvements, but I wonder about that. My impression of oncology research has always been more like "OK, this looks reasonable. Lots of these tumors have UVW upregulated; let's make an UVW inhibitor. (Years later): Hmm, that's disappointing. Our UVW inhibitor doesn't seem to do as much as you'd think it should. But now it's been found that XYZ looks like it's necessary for tumor growth; let's see if we can inhibit it. (Years later): Hmm, that's not as big an effect as you would have thought, either, is it? Seems to help a few people, but it's hard to say who they'll be up front. How's the JKL antagonist coming along? No one's tried that yet; looks like a good cell-division target. . ."
It's just sort of one thing after another - that one didn't work so well, neither did that one, this other one and these three together seem to be a bit better, but not always, and so on. Would we learn as much, or nearly so, just from the earlier clinical work on such compounds as opposed to taking them to market? And although you can't deny that there's been incremental progress, I'm not sure what form it's taking. It's very likely that the answer isn't to keep turning over mechanistic ideas until we find The One That Really Truly Works - cancer is a tough enough (and varied enough) disease that there probably isn't going to be one of those.
My guess is that meaningful cancer success will come from combinations of therapies that we mostly don't even have yet. I think that we'll need to hit several different mechanisms at the same time, but that some of what we'll need to hit hasn't even been discovered. And on top of that, each patient presents a slightly different problem, and ideally would receive a more customized blend of therapies (not that we know how to do that, either, in most cases).
What I'm saying is that we'll probably need combinations of things that already work better than most of what we have already, and that these will stand out enough in clinical trials that we'll know that they're worth developing. As it stands, though, companies see hints here and there in the clinic, enough to run a Phase III trial, and if it's large enough and tightly controlled enough, they see enough efficacy to get things through the FDA and onto the market. Would we be better off to not proceed with the marginal stuff, and put the significant amounts of money into things that stand out more? Or would that choke off the market too much, since we mostly end up making marginal things anyway (damn it all), leaving no one able to keep going long enough to find the good stuff? It's a hard business.
Well, this is a question that (I must admit) had not crossed my mind. Courtesy of Slate, though, we can now ask how we can make pharmaceuticals more environmentally friendly. No, not the manufacturing processes: this article's worried about the drugs that are excreted into the water supply.
It's worth keeping an eye on this issue, but I haven't been able, so far, to get very worked up about it. It's true that there have been many studies that show detectable amounts of prescription drugs in the waste water stream. The possible environmental effects mentioned in the article, though, are seen at much higher concentrations. I think that much of the attention given to this issue comes from the power of modern analytical techniques -if you look for things at parts-per-billion level (or below), you'll find them. Of course, you'll also find a huge number of naturally occurring substances that are also physiologically active: can the synthetic estrogen ligands out there really compete against the huge number of phytoestrogens? I have to wonder. To me, the sanest paragraph of the article is this one:
Developing "benign-by-design" drugs poses a series of vexing challenges. In general, the qualities that make drugs effective and stable—bioactivity and resistance to degradation—are the same ones that cause them to persist disturbingly after they've done their job. And presumably even hard-core eco-martyrs (the ones who keep the thermostat at 60 all winter and renounce air travel) would hesitate to sacrifice medical efficacy for the sake of aquatic wildlife. What's more, the molecular structures of pharmaceuticals are, in the words of Carnegie Mellon chemist Terry Collins, "exquisitely specific." Typically, you can't just tack on a feature like greenness to a drug without affecting its entire design, including important medical properties.
And even that one has its problems. That "persist disturbingly" phrase makes it sound like pharmaceuticals are like little polyethylene bags fluttering around the landscape and never wearing down. But it's worth remembering that most drugs taken by humans are metabolized on their way out of the body, and most of these metabolites don't maintain the activity of the parent compound. Other organisms have similar metabolic powers - as living creatures, we've evolved a pretty robust ability to deal with constant low levels of unknown chemicals. (Here's a good chance to point out this article by Bruce Ames and Lois Swirsky Gold on that topic as it relates to cancer; many of the same points apply here).
No one can guarantee, though, that pharmaceutical residue will always be benign. As I say, it's worth keeping an eye on the possibility. But it will indeed be hard to do something about it, for just the reasons quoted above. As it is, getting a drug molecule that hits its target, does something useful when that happens, doesn't hit a lot of other things, works in enough patients to be marketable, has blood levels sufficient for a convenient dose, doesn't cause toxic effects on the side, and can be manufactured reproducibly in bulk and formulated into a stable pill. . .well, that's enough of a challenge right there. We don't actually seem to be able to do that well enough as it stands. Making the molecules completely eco-friendly at the same time. . .
A discussion with a colleague the other day brought up a point about drug patents. When you're thinking about the chemical matter you have for your project, one of the things you have to worry about is the patent situation. Are your molecules patentable? For that to be the case, you need novelty and utility. Utility is pretty much a given in this business - you wouldn't be interested in the compounds if they didn't do something - so novelty (prior art) is what we spend time wondering about.
There's usually a way through on that, though. I mean, sure, there are all these generic claims out there in other patent applications that take everything out to the asteroid belt, but you should only get worried about the stuff that the claims are teaching toward and the compounds that have been enabled (that is, actually made). Prior art is crucial, but it's also crucial to only pay attention to what deserves attention. (We last talked about this problem here).
Then there's "freedom to operate". In that case, you're asking not "can I get a patent on this", but "can I do anything with it without infringing someone else's patents". For FTO considerations, you have to look at what IP rights other people have (or are likely to have by the time you'll be ready to go). That can get rather involved, since patents are limited in several dimensions: time (they expire eventually), space (coverage varies country by country), and in "IP space" (what territory the claims stake out). Depending on what comes up, you might decide that you're in the clear. Or you might try to invent yourself out of a tight spot, if you can do that. Or you could pay someone for rights to their IP, or trade them some of yours, if you have something to trade.
But here's where we got to talking: in the drug business, where we're patenting particular chemical matter (and the use of it for particular medical needs), it seems like freedom to operate isn't as big a deal as it is in some other areas. That's partly because it's hard to get sweeping medical claims issued, and it's hard to make them stand up if they do. There have been attempts to stake out whole modes of action ("We claim the method of treating a patient in need of lowering their XYZ levels with any inhibitor of XYZase"), but fortunately, that hasn't taken hold.
So when you're talking chemical matter, does anyone know of drugs (or programs) that have been derailed in development just because of freedom-to-operate concerns? Drug patents get challenged all the time, often by generic companies, but those are patentability issues, trying to overturn the whole filing. But what about FTO? Any examples?
So, as had been suspected, the reason that Merck's thrombin antagonist vorapaxar ran into clinical trouble was excessive bleeding. This is always the first thing to suspect when an anticoagulant has difficulty in human trials.
It's really a delicate balance, the human clotting cascade, and it's all too easy to end up on the wrong side of it. When you think about it, the whole pathway has to be under very tight regulation - I mean, here's the fluid that transports oxygen and nutrients and removes waste. Absolutely crucial to the life of every cell in the body. And here's an option to have that fluid thicken up and turn to jelly, very quickly, and once it happens it can't be reversed. No, you're going to want a lot of safeguards around that switch. But if you lean over too far the other way, well. . .there's a lot of vascular plumbing in the body, and it gets a lot of stress. Leaks and rips are inevitable. You have to have a method for patching holes, and it has to be ready to go everywhere, at all times. Dial it down just a bit too much, and hemorrhages are inevitable. Thus all the different clotting mechanism steps, and the different drugs targeting them.
As Matthew Herper explains at that link above, the prospect for this drug are completely dependent on which side of the line it ends up on. In this patient population, it's already stepped over - another result like this one, and vorapaxar could be completely sunk.
Here's a problem that I've seen at every company I've worked at, and there are good reasons to believe that it afflicts every company out there. That's because I think it's grounded in human nature: dog-and-pony-itis.
That's the phrase I use for what happens to meetings over time. Many readers will be familiar with the process: a company gradually accumulates regular meetings on its internal calendar - project team meetings, individual chemistry and biology meetings inside that, overall review meetings, resourcing, planning, interdisciplinary meetings. . .everyone who's anyone, in some companies, has to be calling a meeting of their very own.
Eventually, someone says "Enough!" and purges the schedule, replacing the tangle of overlapping meetings with A Brand New Meeting or two. These will actually discuss issues, for once, and people are encouraged to actually say what's really going on with their projects. For once. And who knows, maybe that's the case (for once) - but it doesn't last.
Because every time, in my experience, the Brand New Meeting itself starts to collect barnacles. Over time, it becomes less useful, and more of a show. The music starts up, the Pomeranian dogs start hopping around and barking, and the trained horses make their entrance from the wings. It becomes more expedient to just get up and tell people the broad strokes of a project, especially the broad strokes that are actually working, and leave the messy details out. And gradually, other meetings spring up to try to take up the slack, since nothing ever seems to get done at the Brand New. . .
The thing is, I don't know how to stop this from happening. It comes on like rust. I've lost count of the we've-got-to-get-rid-of-this-stupid-meeting initiatives I've seen over the years, and every time the cycles eventually repeats. So here's a question: has anyone broken out? And if you have, how? Suggestions welcomed in the comments. . .
He highlights the experience of the blog Retraction Watch (which I hadn't heard of until now), when they tried to find out why a paper had been pulled from the Annals of Thoracic Surgery. The journal's editor responded to their query by informing them that "it's none of your damn business".
Gotta disagree there, chief. I think that this is actually important information, and that it should be disclosed as much as possible. There are all sorts of reasons for papers to be retracted, ranging from benign to evil, and it's in the interest of readers to know what category things have fallen into. I understand that in some cases papers are the subject of ongoing investigations, so these details aren't always available, but in that case, why not say something like: "The data in Table II have not been reliably reproduced by other workers. While some of the co-authors of the original work have stated that they stand b