In the Pipeline

Worst And/Or Craziest Misconceptions

Fri, 25 May 2012 07:35:40 -0500

You run into a lot of scientific and medical misconceptions (particularly when you have a blog with a working e-mail address plastered on the front page of it!) There are plenty of harmless ones that are easy to correct, and at the other end of the scale there are major weltanschauung problems (like the "drug companies don't want to find a cure for cancer because it would put them out of business" line). Those involve what Kingsley Amis called "permanent tendencies of the heart and mind", and I'm not sure if they can be fixed at all.

I got to thinking about this subject again after seeing this item, which is pointing out to physicians that a meaningful number of their patients may well opt out of surgery for cancer because they believe that cancer spreads when exposed to air. This turns out to be a common enough belief that it's addressed on many medical sites. It's not one that I'd heard before, and I thought I'd heard quite a few of these.

So, in the spirit of discussions like this one, I'll toss out these questions: what's the farthest-from-reality misconception about medical/pharma topics you've encountered? And what widespread one do you think does the most harm? (Warning about that link: it goes to a hugely long thread, which will soak up your time as you continue running into yet-more-ridiculous beliefs that people have expressed).

My own candidates: the weirdest one I've encountered might be the person who still believed in spontaneous generation (that old bread just sort of "turned into" living mold, etc.). And the most harmful one, from a drug research perspective, might well be the constellation of "the government does all drug research" beliefs, or the one mentioned above, the "drug companies don't want to cure X" one, which shades into the "drug companies have a cure for X but they don't want to release it" belief.

An Oral Insulin Pill?

Thu, 24 May 2012 07:11:00 -0500

Bloomberg has an article on Novo Nordisk and their huge ongoing effort to come up with an orally available form of insulin. That's been a dream for a long time now, but it's always been thought to be very close to impossible. The reasons for this are well known: your gut will treat a big protein like insulin pretty much like it treats a hamburger. It'll get digested, chopped into its constituent amino acids, and absorbed as non-medicinally-active bits which are used as raw material once inside the body. That's what digestion is. The gut wall specifically guards against letting large biomolecules through intact.

So you're up against a lot of defenses when you try to make something like oral insulin. Modifying the protein itself to make it more permeable and stable will be a big part of it, and formulating the pill to escape the worst of the gut environments will be another. Even then, you have to wonder about patient-to-patient variability in digestion, intestinal flora, and so on. The dosing is probably going to have to be pretty strict with respect to meals (and the content of those meals).

But insulin dosing is always going to be strict, because there's a narrow window to work in. That's one of the factors that's helped to sink so many other alternative-dosing schemes for it, most famously Pfizer's Exubera. The body's response to insulin in brittle in the extreme. If you take twice as much antihistamine as you should, you may feel funny. If you take twice as much insulin as you should, you're going to be on the floor, and you may stay there.

So I salute Novo Nordisk for trying this. The rewards will be huge if they get it to work, but it's a long way from working just yet.

Publishing Without Consent

Thu, 24 May 2012 06:15:16 -0500

Here's a note on an ugly situation: when a post-doc publishes a paper without the permission of the principal investigator. Now, this is a fairly rare situation, but still not as rare as you might imagine - the article itself has several citations, and it quotes a journal editor who's seen it happen a number of times.

In most of these cases, there seems to be a more fundamental confusion about ownership of data, with publishing as the sequel. People leave a research group with their piles of results, and decide that since it's theirs, that it's time to get it out into the literature with their name on it. But as the article points out, if work is done under NIH funding, then the results belong to the institution, and the grantee/PI is the person who decides when and where things are published. You may, as a grad student or post-doc, feel that the data you worked so hard to generate are rightfully yours, but most of the time that's just not the case.

In industry we have our own disputes, but this isn't one of them. There's rarely any argument about ownership of data: that's all company property, and you sign documents when you're hired that explicitly spell that out. And publication is rarely as bitter a business as it is in academia (where it's the coin of the realm). We argue about whether a particular project is advanced enough (or dead enough, more likely) to be written up for a journal, but these are secondary questions.

Who gets on the patent is a slightly bigger question, but it's not like you get a cut of the profits based on whether your name is on the list. That's as opposed to Germany, where that's exactly what happens, and I've often wondered if we should try that here. That system leads to some elbow-throwing when it comes to inventorship on a hot project, but it also leads to everyone having a clear idea of the legal requirements to be an inventor. Ownership is, naturally, not in dispute at all. Every invention realized at the company is company property, too (those same documents take care of that back when you're hired on).

So while rogue academic publishing is a known phenomenon, rogue industrial patenting isn't. Well, as far as I know it isn't - anyone have an example of someone who tried to get away with it?

How Come?

Wed, 23 May 2012 11:16:56 -0500

I'm baffled by this abstract. Why would you go to the trouble of putting an unusual group (a ferrocene) on a molecule, and then show that putting it on seems to do little or nothing to the properties and activity of the parent compound? "We put a ferrocene on and it didn't kill the molecule" doesn't seem to be enough grounds for a full J. Med. Chem. paper. Does it?

Drug Discovery on Radio 4

Wed, 23 May 2012 06:34:09 -0500

Several readers sent along a link to this Radio 4 program ("The End of Drug Disocvery") from the BBC on drug discovery. From what I've heard, it's a very good overview of the current state of the field for people outside it, and gets across just how difficult it's been to find good drug candidates.

Another Vote Against Rhodanines

Wed, 23 May 2012 06:17:02 -0500

For those of you who'd had to explain to colleagues (in biology or chemistry) why you're not enthusiastic about the rhodanine compounds that came out of your high-throughput screening effort, there's now another paper to point them to.

The biological activity of compounds possessing a rhodanine moiety should be considered very critically despite the convincing data obtained in biological assays. In addition to the lack of selectivity, unusual structure–activity relationship profiles and safety and specificity problems mean that rhodanines are generally not optimizable.

That's well put, I think, although this has been a subject of debate. I would apply the same language to the other "PAINS" mentioned in the Baell and Holloway paper, which brought together a number of motifs that have set off alarm bells over the years. These structures are guilty until proven innocent. If you have a high-value target and feel that it's worth the time and trouble to prove them so, that may well be the right decision. But if you have something else to advance, you're better off doing so. As I've said here before, ars longa, pecunia brevis.

The NIH's Drug Repurposing Initiative: Will It Be a Waste?

Tue, 22 May 2012 11:12:46 -0500

The NIH's attempt to repurpose shelved development compounds and other older drugs is underway:

The National Institutes of Health (NIH) today announced a new plan for boosting drug development: It has reached a deal with three major pharmaceutical companies to share abandoned experimental drugs with academic researchers so they can look for new uses. NIH is putting up $20 million for grants to study the drugs.

"The goal is simple: to see whether we can teach old drugs new tricks," said Health and Human Services Secretary Kathleen Sebelius at a press conference today that included officials from Pfizer, AstraZeneca, and Eli Lilly. These companies will give researchers access to two dozen compounds that passed through safety studies but didn't make it beyond mid-stage clinical trials. They shelved the drugs either because they didn't work well enough on the disease for which they were developed or because a business decision sidelined them.

There are plenty more where those came from, and I certainly wish people luck finding uses for them. But I've no idea what the chances for success might be. On the one hand, having a compound that's passed all the preclinical stages of development and has then been into humans is no small thing. On that ever-present other hand, though, randomly throwing these compounds against unrelated diseases is unlikely to give you anything (there aren't enough of them to do that). My best guess is that they have a shot in closely related disease fields - but then again, testing widely might show us that there are diseases that we didn't realized were related to each other.

John LaMattina is skeptical:

Well, the NIH has recently expanded the remit of NCATS. NCATS will now be testing drugs that have been shelved by the pharmaceutical industry for other potential uses. The motivation for this is simple. They believe that these once promising but failed compounds could have other uses that the inventor companies haven’t yet identified. I’d like to reiterate the view of Dr. Vagelos – it’s fairy time again.

My views on this sort of initiative, which goes by a variety of names – “drug repurposing,” “drug repositioning,” “reusable drugs” – have been previously discussed in my blog. I do hope that people can have success in this type of work. But I believe successes are going to be rare.

The big question is, rare enough to count the money and time as wasted, or not? I guess we'll find out. Overall, I'd rather start with a compound that I know does what I want it to do, and then try to turn it into a drug (phenotypic screening). Starting with a compound that you know is a drug, but doesn't necessarily do what you want it to, is going to be tricky.

The Counting of Beans

Tue, 22 May 2012 07:52:34 -0500

This article from the Telegraph has nothing to say at all about the drug industry. But you might find it strangely familiar and appropriate, starting with the headline: Bloodless Bean Counters Rule Over Us:

You find this hollowing-out everywhere. In schools, the head who does not teach is now a familiar, indeed dominant figure. University vice-chancellors, instead of being dons who move from their subject into administration for a period of their lives, are now virtually lifelong managers, with hugely increased salaries to match. It is even commonplace for charities to be run by people with no commitment to the charity’s specific purpose, but proud possession of what they call the necessary “skill-sets”, such as corporate governance. . .

. . .These habits are now pervasive across industry and the public services. “Diversity” is always “celebrated”, but it never means diversity of thought. The people who tell you they are “passionate about” X or Y are usually the most bloodless ones in the outfit.

In such cultures, just as the experts, the professionals and the technicians bitterly resent the managerialists for neither understanding nor caring, so the managerialists secretly detest the professionals who, they believe, get in the way of their rationalisations. They are desperate to “let go” of such people. Very unhappy organisations result.

Or then again, perhaps you haven't encountered anything like this after a few years in the industry. What, after all, are the odds?

A New Way to Kill Amoebas, From An Old Drug

Mon, 21 May 2012 12:14:00 -0500

Here's a good example of phenotypic screening coming through with something interesting and worthwhile: they screened against Entamoeba histolytica, the protozooan that causes amoebic dysentery and kills tens of thousands of people every year. (Press coverage here).

It wasn't easy. The organism is an anaerobe, which is a bad fit for most robotic equipment, and engineering a decent readout for the assay wasn't straightforward, either. They did have a good positive control, though - the nitroimidazole drug metronidazole, which is the only agent approved currently against the parasite (and to which it's becoming resistant). A screen of nearly a thousand known drugs and bioactive compounds showed eleven hits, of which one (auranofin) was much more active than metronidazole itself.

Auranofin's an old arthritis drug. It's a believable result, because the compound has also been shown to have activity against trypanosomes, Leishmania parasites, and Plasmodium malaria parasites. This broad-spectrum activity makes some sense when you realize that the drug's main function is to serve as a delivery vehicle for elemental gold, whose activity in arthritis is well-documented but largely unexplained. (That activity is also the basis for persistent theories that arthritis may have an infectious-disease component).

The target in this case may well be arsenite-inducible RNA-associated protein (AIRAP), which was strongly induced by drug treatment. The paper notes that arsenite and auranofin are both known inhibitors of thioredoxin reductase, which strongly suggests that this is the mechanistic target here. The organism's anaerobic lifestyle fits in with that; this enzyme would presumably be its main (perhaps only) path for scavenging reactive oxygen species. It has a number of important cysteine residues, which are very plausible candidates for binding to a metal like gold. And sure enough, auranofin (and two analogs) are potent inhibitors of purified form of the amoeba enzyme.

The paper takes the story all the way to animal models, where auranofin completely outperforms metronidazole. The FDA has now given it orphan-drug status for amebiasis, and the way appears clear for a completely new therapeutic option in this disease. Congratulations to all involved; this is excellent work.

A Molecular Craigslist?

Mon, 21 May 2012 08:46:47 -0500

Mat Todd at the University of Sydney (whose open-source drug discovery work on schistosomiasis I wrote about here) has an interesting chemical suggestion. His lab is also involved in antimalarial work (here's an update, for those interested, and I hope to post about this effort more specifically). He's wondering about whether there's room for a "Molecular Craigslist" for efforts like these:

Imagine there is a group somewhere with expertise in making these kinds of compounds, and who might want to make some analogs as part of a student project, in return for collaboration and co-authorship? What about a Uni lab which might be interested in making these compounds as part of an undergrad lab course?

Wouldn’t it be good if we could post the structure of a molecule somewhere and have people bid on providing it? i.e. anyone can bid – commercial suppliers, donators, students?

Is there anything like this? Well, databases like Zinc and Pubchem can help in identifying commercial suppliers and papers/patents where groups have made related compounds, but there’s no tendering process where people can post molecules they want. Science Exchange has, I think, commercial suppliers, but not a facility to allow people to donate (I may be wrong), or people to volunteer to make compounds (rather than be listed as generic suppliers. Presumably the same goes for eMolecules, and Molport?

Is there a niche here for a light client that permits the process I’m talking about? Paste your Smiles, post the molecule, specifying a purpose (optional), timeframe, amount, type of analytical data needed, and let the bidding commence?

The closest thing I can think of is Innocentive, which might be pretty close to what he's talking about. It's reasonably chemistry-focused as well. Any thoughts out there?

The Genetic Diversity of Cancer Cells

Fri, 18 May 2012 08:10:23 -0500

For those of you interested in the recent work on the diversity of different cancer cell genotypes inside single tumors, there's a review out that covers the field well. The authors also go into some of the major unanswered questions: does having a tumor cell population with a lot of genetic diversity correlate with a poor prognosis for treatment? Can small populations of potentially troublesome cells be identified ahead treatments that might give them too free a field to work in? Can the huge genetic diversity be reduced to a more manageable set of practical phenotypes, to make therapeutic recommendations? This will keep everyone busy for a long time to come.

Strangely Good Results in Diabetes and Cardiovascular Disease

Fri, 18 May 2012 06:55:16 -0500

I've read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn't something you'd necessarily think would do much good - it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong:

In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.

A note to the conspiratorially minded, should any such come across this: it's worth noticing that this "maybe everyone should take statins" result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn't (and probably couldn't have, since we didn't have as much data as we do now).

Now to another (often related) disease, type II diabetes. It's been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense - obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent:

Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.

Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it's something to do with secretion of hormones from the gut itself, and you'd also have to think that nutrient sensing gets profoundly altered. It's not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you'd imagine:

Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned.

Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer's, the subject of yesterday's post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it's a death sentence. Good to know that things can work in the other way once in a while.

Is HDL Always "Good Cholesterol"?

Thu, 17 May 2012 11:00:26 -0500

The failure of Roche's dalcetrapib has a lot of people wondering just what's going on with HDL as a cardiovascular drug target. And this isn't the first time - there have been a number of puzzling findings in the lipoprotein field that point out to us that we don't know nearly as much about this area as we might think. Many promising therapeutic ideas in it have turned out disastrously.

Now there's a new paper in The Lance that underscores this, and how. The authors have done large genome-wide association studies looking for polymorphisms that affect lipoproteins, and they're following those up with clinical data on cardiovascular outcomes. Untangling the effects of HDL, LDL, triglycerides and other factors isn't easy, but they did find one mutation that appears to raise HDL alone. Looking at the people carrying that one, they find that there's no amelioration of risk in them at all. That's as opposed to the mutations that lowered LDL levels, which were consistently associated with lower risks.

This doesn't (necessarily) mean that HDL is useless as a predictor of cardiovascular risk, but it definitely means that it isn't as simple as "HDL = Good Cholesterol!". What this means for things like CETP inhibition is anyone's guess.

The Breslow Chirality Paper Mess, Resolved

Thu, 17 May 2012 08:43:27 -0500

Just a note: the Breslow origins-of-chirality paper, also known more widely (thanks to some bizarre PR work at the ACS) as the "alien dinosaur" paper, has been withdrawn, and on the correct grounds. The pun in the headline is intended.

A Preventative Trial for Alzheimer's: The Right Experiment

Thu, 17 May 2012 06:22:48 -0500

Alzheimer's disease is in the news, as the first major preventative drug trial gets underway. I salute the people who have made this happen, because we're bound to learn a lot from the attempt, even while I fear the chances for success are not that good.

A preventative trial for Alzheimer's would, under normal circumstances, be a nightmarish undertaking. The disease is quite variable and comes on slowly, and it's proven very difficult to predict who might start to show symptoms as they age. You'd be looking at dosing a very large number of people (thousands, even tens of thousands?) for a very long time (years, maybe a decade or two?) in order to have a chance at statistical significance. And you would, in the course of things, be giving a lot of drug to a lot of people who (in the end) would have turned out not to need it. No, it's no surprise that no one's gone that route.

But there's a way out of that impasse: find a population with some sort of amyloid-pathway mutation. Now you know exactly who will come down with symptoms, and (unfortunately) you also know that they're going to come down with them earlier and more quickly as well. There are several of these around the world; the "Swedish" and "Dutch" mutations are probably the most famous. There's a Colombian mutation too, with a well-defined patient population that's been studied for years, and that's where this new study will take place.

About 300 people will be given an experimental antibody therapy to amyloid protein, crenezumab. This was developed by AC Immune in Switzerland and licensed to Genentech, and is one of many amyloid-targeted antibodies that have come along over the years. (The best-known is bapineuzumab, currently in Phase III). Genentech (Roche) will be putting up the majority of the money for the trial ($65 million, with $16 million from the NIH and $15 million in private foundation money). Just in passing, weren't some people trying to convince everyone a year ago that it only costs $43 million total to develop a new drug? Har, har.

100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don't want to know their status. Everyone will go through a continuing battery of cognitive and psychological tests, as well as brain imaging and a great deal of blood work, which (if we're lucky) could furnish tips towards clinical biomarkers for future trials.

So overall, I think that this trial is an excellent idea, and I very much hope that a lot of useful information comes out of it. But I've no firm hopes that it will pan out therapeutically. This will be a direct test of the amyloid hypothesis for Alzheimer's, and although there's a tremendous amount of evidence for that line of thought, there's a lot against it as well. Anyone who really thinks they know what will happen in this situation hasn't thought hard enough about it. But that's the best kind of experiment, isn't it?