About this Author
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: derekb.lowe@gmail.com
Twitter: Dereklowe
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Category Archives
October 13, 2009
Posted by Derek
Chronic fatigue syndrome has long been controversial and mysterious. Is the mystery clearing up, or getting deeper? There have been diagnoses of something like CFS for a long time, under a lot of different names. The common sign is persistent fatigue with no obvious physical cause, often accompanied by joint pain, disrupted sleep, and other symptoms. It's more common in women than in men - but then, so are a lot of autoimmune disorders, which has made some sort of immune syndrome a popular explanation. All sorts of contradictory data have been generated around that idea, but nothing convincing has emerged.
There's a preprint in Science from teams at the National Cancer Institute, the Cleveland Clinic, and Whittemore Peterson Institute that's attracting a lot of interest. It presents evidence for a viral infection which is far more common in patients diagnosed with CFS. What's even more intriguing is that the virus (XMRV, a mouse retrovirus) is already one that's suspected of involvement in some cases of prostate cancer, as shown by analysis of biopsy samples. (Commentary on that work here). About two-thirds of the CFS patients were found to be positive for the virus, as opposed to about three per cent of the control group. The WPI people are now saying that since the manuscript went in that further work has shown 98% of a 300-CFS-patient sample as positive for XMRV. More on that below.
In the case of the prostate patients, there seems to be a link with a deficiency in the RNAse L pathway, which is part of the interferon-induced antiviral response. It may be that patients with this immune system vulnerability are more susceptible to infection by XMRV, which then goes on to cause (or exacerbate) prostate cancer. There may be a link between RNAse L function and a diagnosis of CFS as well. It makes a neat story, and I hope that it's true.
But we're not quite there yet. No one's seen the data yet on that 300-patient cohort mentioned above, and it's not clear if a different diagnostic method was used on them compared to the group in the Science paper. And that paper itself doesn't have enough details on the patients to satisfy some readers - a specialist at the CDC complained about this to the New York Times, and said that his team would try to reproduce the results, but that he wasn't hopeful. (Working on chronic fatigue has not been the sort of thing that breeds a hopeful outlook, to be sure). Other researchers in the field have voiced their doubts to Science (who, to be sure, did accept the original paper).
One of the problems in this area has been defining who's a patient and who isn't. It's a bit of a catch-all diagnosis, or can be, so there's always the suspicion that even if there's a solid underlying cause that the data are hard to dig out of a heterogeneous patient sample. And there's the whole psychological-or-physical question, too, which is a sure route to raised voices and waving fists. My thinking is that there are very likely a number of people with other issues (which I will leave undefined) piled into this area, and that the necessary attempts to draw boundaries will be sure to leave someone upset.
As for this retrovirus angle, there are a number of other steps that need to be taken. Looking over historical blood and tissue samples will be very interesting - could you find that a person showed no sign of the virus when younger, then went positive before showing signs of the disease? Or does it stay latent for a longer period before finally breaking through? Are there animals that are susceptible to infection, and do they show similar symptoms to humans? Can we at least demonstrate infection of cultured cells in vitro? (Update: I see that they've shown that, which is a very good step). Do any of the existing antiretroviral drugs have any effect on either of those processes, and if so, what happens when you give them to patients with CFS? What about the 3% or so of the population that seems to be positive for XMRV but shows no sign of either prostate cancer or CFS - what's different about them, if anything? And so on.
The Whittemore Peterson Institute people are way out in front on these questions, for better or worse. You may have said, as I did, "Who they?", but it turns out that they've only been around since 2004. The institute was set up by the parents of a CFS patient to do research in the field, and they've apparently been quite busy. Their web site gives the impression that the question of CFS as a retroviral infection is basically settled, but I'm not there yet. I have a lot of sympathy for the unidentified-infectious-agent line of thinking, and I believe that there are probably several things out there that will eventually fit into this category, but it can be a hard thing to prove. Let's hope this one is solid, so we can get to work.
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+ TrackBacks (0) | Category: Infectious Diseases | The Central Nervous System
October 7, 2009
Posted by Derek
This was another Biology-for-Chemistry year for the Nobel Committee. Venkatraman Ramakrishnan (Cambridge), Thomas Steitz (Yale) and Ada Yonath (Weizmann Inst.) have won for X-ray crystallographic studies of the ribosome.
Ribosomes are indeed significant, to put it lightly. For those outside the field, these are the complex machines that ratchet along a strand of messenger RNA, reading off its three-letter codons, matching these with the appropriate transfer RNA that's bringing in an amino acid, then attaching that amino acid to the growing protein chain that emerges from the other side. This is where the cell biology rubber hits the road, where the process moves from nucleic acids (DNA going to RNA) and into the world of proteins, the fundamental working units of a day-to-day living cell.
The ribosome has a lot of work to do, and it does it spectacularly quickly and well. It's been obvious for decades that there was a lot of finely balanced stuff going on there. Some of the three-letter codons (and some of the tRNAs) look very much like some of the others, so the accuracy of the whole process is very impressive. If more proofs were needed, it turned out that several antibiotics worked by disrupting the process in bacteria, which showed that a relatively small molecule could throw a wrench into this much larger machinery.
Ribosomes are made out of smaller subunits. A huge amount of work in the earlier days of molecular biology showed that the smaller subunit (known as 30S for how it spun down in a centrifuge tube) seemed to be involved in reading the mRNA, and the larger subunit (50S) was where the protein synthesis was taking place. Most of this work was done on bacterial ribosomes, which are relatively easy to get ahold of. They work in the same fashion as those in higher organisms, but have enough key differences to make them of interest by themselves (see below).
During the 1980s and early 1990s, Yonath and her collaborators turned out the first X-ray structures of any of the ribosomal subunits. Fuzzy and primitive by today's standards, those first data sets got better year by year, thanks in part to techniques that her group worked out first. (The use of CCD detectors for X-ray crystallography, a technology that was behind part of Tuesday's Nobel in Physics, was another big help, as was the development of much brighter and more focused X-ray sources). Later in the 1990s, Steitz and Ramakrishnan both led teams that produced much higher-resolution structures of various ribosomal subunits, and solved what's known as the "phase problem" for these. That's a key to really reconstructing the structure of a complex molecule from X-ray data, and it is very much nontrivial as you start heading into territory like this. (If you want more on the phase problem, here's a thorough and comprehensive teaching site on X-ray crystallography from Cambridge itself).
By the early 2000s, all three groups were turning out ever-sharper X-ray structures of different ribosomal subunits from various organisms. The illustration above, courtesy of the Nobel folks, shows the 50S subunit at 9-angstrom (1998), 5-angstrom (1999) and 2.4-angstrom (2000) resolution, and shows you how quickly this field was advancing. Ramakrishnan's group teased out many of the fine details of codon recognition, and showed how some antibiotics known to cause the ribosome to start bungling the process were able to to work. It turned out that the opening and closing behavior of the 30S piece was a key for this whole process, with error-inducing antibiotics causing it to go out of synch. And here's a place where the differences between bacterial ribosomes and eukaryotic ones really show up. The same antibiotics can't quite bind to mammalian ribosomes, fortunately. Having the protein synthesis machinery jerkily crank out garbled products is just what you'd wish for the bacteria that are infecting you, but isn't something that you'd want happening in your own cells.
At the same time, Steitz's group was turning out better and better structures of the 50S subunit, and helping to explain how it worked. One surprise was that there was a highly ordered set of water molecules and hydrogen bonds involved - in fact, protein synthesis seems to be driven (energetically) almost entirely by changes in entropy, rather than enthalpy. Both his group and Ramakrishnan's have been actively turning out structures of the ribosome subunits in complex with various proteins that are known to be key parts of the process, and those mechanisms of action are still being unraveled as we speak.
The Nobel citation makes reference to the implications of all this for drug design. I'm of two minds on that. It's certainly true that many important antibiotics work at the ribosomal level, and understanding how they do that has been a major advance. But we're not quite to the point where we can design new drugs to slide right in there and do what we want. I personally don't think we're really at that stage with most drug targets of any type, and trying to do it against structures with a lot of nucleic acid character is particularly hard. The computational methods for those are at an earlier stage than the ones we have for proteins.
One other note: every time a Nobel is awarded, the thoughts go to the people who worked in the same area, but missed out on the citation. The three-recipients-max stipulation makes this a perpetual problem. This is outside my area of specialization, but if I had to list some people that just missed out here, I'd have to cite Harry Noller of UC-Santa Cruz and Marina Rodnina of Göttingen. Update: add Peter Moore of Yale as well. All of them work in this exact same area, and have made many real contributions to it - and I'm sure that there are others who could go on this list as well.
One last note: five Chemistry awards out of the last seven, by my count, have gone to fundamental discoveries in cell or protein biology. That's probably a reasonable reflection of the real world, but it does rather cut down on the number of chemists who can expect to have their accomplishments recognized. The arguing about this issue is not be expected to cease any time soon.
Comments (40)
+ TrackBacks (0) | Category: Analytical Chemistry | Biological News | Current Events | Infectious Diseases
June 2, 2009
Posted by Derek
Well, there's someone who certainly believes in the deuterated-drug idea! GlaxoSmithKline has announced today that they've signed a deal with Concert Pharmaceuticals to develop these. There's a $35 million payment upfront, which I'm sure will be welcome in this climate, and various milestone and royalty arrangements from there on out. I know that the press story says that it's a "potential billion dollar deal", but you have to make a useless number of assumptions to arrive at that figure. Let's just say that the amount will be somewhere between that billion-dollar figure and. . .well, the $35 million that Glaxo's just put up.
Where things will eventually land inside that rather wide range is impossible to say. No one's taken such a compound all the way through development, and every one of them is going to be different. (Deuterium might be a good idea, but it ain't magic.) It looks like the first compound up for evaluation will be an HIV protease inhibitor, CTP-518, which is a deuterated version of someone's existing compound - Concert has filed paten applications on deuterated versions of both darunavir (WO2009055006) and atazanavir (WO2008156632). The hope is that CTP-518 will have an improved enough metabolic profile to eliminate the need to add ritonavir into the drug cocktail.
The company is also providing deuterated versions of three of GSK's own pipeline compounds for evaluation, which is interesting, since that's the sort of thing that Glaxo could do itself. In fact, that's one of the key points to the whole deuterated-compound idea: the window of opportunity. Deuteration isn't difficult chemistry, and the applications for it in improving PK and tox profiles are pretty obvious (see below). It's a good bet that drug company patent applications will hencrforth include claims (and exemplified compounds) to make sure that deuterated versions of drug candidates can't be poached away by someone else. This strategy has a limited shelf life, but it's long enough to be potentially very profitable indeed.
One more note about that word "obvious". Now that people are raising all kinds of money and interest with the idea, sure, it looks obvious. And I'm sure that it's a thought that many people have had before - and then said "Nah, that's too funny-sounding. Might not work. And besides, you might not be able to patent it. And besides, if it were that good an idea, someone else would have already done it. There must be a good reason why no one's done it, you know". Getting up the nerve to try these things, that's the hard part. Roger Tung and Concert (and the other players in this field) deserve congratulations for not being afraid of the obvious.
Comments (25)
+ TrackBacks (0) | Category: Business and Markets | Drug Development | Infectious Diseases | Pharmacokinetics | Who Discovers and Why
May 8, 2009
Posted by Derek
Kary Mullis is an outlier among Nobel Prize winners. Attendees some of his invited talks in the years after his award will know what I’m talking about. These were famously random affairs, with the audience never knowing quite what to expect when the next slide came up on the screen. And his own book, Dancing Naked in the Mind Field , will give you about as much flakiness as you can stand.
But although he's been way off base about a lot of things, he may not be that way about everything. I notice (h/t Biotechniques) that he gave a lecture recently at San Jose State, and instead of hearing about the discovery of PCR, the students got an update on Mullis’s company Altermune, whose website website is intertwined with Mullis's own. The site is worth a look. Mullis has a vigorous writing style, and the rest of the front page is his pitch for his company’s approach to immunotherapy for infectious disease:
We have been slowly developing chemistry- the art of dealing, using instruments we devise, with things that are much too small for us to see. They have plus and minus charges on them that we can't feel; they have oily places on them much too tiny for us to notice oil and they have water-loving patches too small for us to see oil droplets beading up on the water. Microbes need all of these things, specific types of them, in fact, to survive, and none of them are beyond the scope of our instruments and our synthetic tools. That's our advantage. Just in this last century we have come to know these things the way we used to know javelins and swords.
How can we help our immune system? Altermune has a shot at it.
Give its antibodies - its workhorse molecules - bionic arms. That's right, little chemical extensions that allow an old antibody to do new tricks. Altermune, LLC, in collaboration with Biosearch in Novato, CA, this summer, fitted up some antibodies whose job used to be binding to something called galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, with new bionic arms, synthesized on an Applied Biosystems ABI 3900, arms that can tightly sieze an influenza virion, shake it a little bit for emphasis, and turn it over to a hungry human macrophage for further processing. The change was accomplished with a swallowed drug. No need to send the antibodies back to the factory. Viruses never saw the ABI 3900 coming.
It looks like he’s using DNA aptamers as recognition elements for specific pathogens, which are used to bring on a response from the ubiquitous antibodies that target 1,3-Gal-Gal antigens. Here's the patent on the technique. And I have to say, that’s not necessarily a crazy idea at all. That epitope has been suggested before as a way to boost immune response, and marrying that to an aptamer could work. (Other aptamer conjugates are under investigation). Of course, the problem (as with all nucleic-acid based things) is, how do you dose it (and how long does it hang around once you do?)
Mullis seems to be talking about oral delivery, which is a real challenge. But that makes me wonder about a report from a company called RXi, which claims to be having some success in delivering their RNAi therapy to macrophages through the gut. They're packaging things in beta-glucan particles and taking advantage of a transport system (and of the fact that there are macrophages in the gut wall waiting for whatever comes out of the food supply). Perhaps something like this would do the trick for a immunological approach like Altermune's?
The immune system scares me, to be honest. I think that evolutionarily we've always walked a narrow path between "strong enough to fight off threats" and "touchy enough to get you killed". Versions of the machinery that threw their hosts into anaphylactic shock too easily have been weeded out by strong selection pressure - you probably wouldn't live long enough to pass that blueprint on. But it's still a tricky thing to mess with (ask TeGenaro). Using existing antibodies might be the most sensible way to do it. . .
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+ TrackBacks (0) | Category: General Scientific News | Infectious Diseases
April 27, 2009
Posted by Derek
Swine flu: is it time to panic yet? Actually, it never is, and this is a particularly useless time to start running in circles, despite the apparent non-stop coverage on the cable news channels. I had some exposure to those during my recent vacation, which only confirmed the complete ban on the damned things in my own house.
I’m reminded of a line from Michael Lewis’s article on New Orleans in the immediate aftermath of Hurricane Katrina. He described a neighbor as suffering from a severe information handicap: his TV was on. But I can’t get all superior about the Internet, either, since Drudge and others are running piled-up red headlines in the same manner. What’s the real situation?
As far as I can make out, it’s this: over the past many weeks, about one thousand cases of influenza have been reported in Mexico, with about seventy of them fatal. Travelers returned from Mexico have shown up ill in several other locations. But none of them have died – in fact, many of them don’t seem to be all that sick, and appear to be recovering without incident. This flu seems to have spread human-to-human in Mexico, but I’m not aware of any reports of that happening in other locations yet.
And here’s what we don’t know: the number of people actually infected in Mexico is unclear and will remain so. Seventy deaths in a thousand cases of flu is a very alarming figure, and that’s what’s driving all the attention. But we don’t know if that number should really be five thousand, or even ten. And we don’t know if all of those seventy patients even had influenza (or this strain of it) at all – the great majority of them don’t appear to have been serotyped.
So no, it’s not time to sound the sirens just yet. Odds are that this will wind down, just like many other outbreaks of influenza do. But we don’t know that for sure. If I had a nonessential trip to Mexico City scheduled, I’d postpone it. (Not that I’m looking to spend a lot of time in the city in general: one factor in the apparently high fatality rate there might be the awful air quality).
One thing an outbreak like this does, though, is to remind everyone that viral epidemics are potentially a real problem. I don’t think that this one is the Pandemic We’ve Been Waiting For, but that one might well be out there, and there’s no way to know when it might appear. If and when it does, we may not have many pharmacological weapons against it, for the reasons I’ve outlined here. For now, keep an eye on whether any of the cases outside Mexico develop into anything more serious than a day or two in bed, and whether any of these transmit to people around them. And don't watch any cable news. Here's the CDC's page on the outbreak, and here's the WHO.
Comments (34)
+ TrackBacks (0) | Category: Current Events | Infectious Diseases
April 13, 2009
Posted by Derek
We get a lot of surprises in this business, most of them not so good. That's understandable, since there are lot more ways for drugs and their mechanisms to go wrong than there are for them to go right. But once in a while, you do see something that's unexpectedly good news.
That may be what's happened to a small San Diego outfit, Ardea. As Xconomy details, the company (formed out of the remnants of IntraBiotics and Valeant) was testing an HIV compound in the clinic when they noticed significant declines in blood levels of uric acid.
That rang a bell: something that decreases uric acid levels would be useful for gout, and there's only been one new gout drug approved in the last 40 years. Follow-up work showed that the effect seemed to be coming from a metabolite of the original drug, and thanks to the HIV trial data, they already had good hopes for that compound's safety. The new compound, RDEA594, has made it through Phase I and is headed for Phase II, and the trials look to be manageable affairs that the company can afford to run. The market is there: more people have gout in the US than are HIV-positive (although the two diseases clearly aren't comparable in other respects!). But the state of HIV research now means, weirdly, that the serious medical needs in that population are actually being met more completely than those in many other disease areas. (Ardea's HIV compound is progressing as well).
So good luck to them, on both fronts. It's a reminder to always look through all your data, and to be alert for whatever opportunities might be hiding in there. We don't get as many as we'd like, so we can't let any of them slip away.
Comments (8)
+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
March 25, 2009
Posted by Derek
There's an idea that shows up in the antibiotic field that seems a bit crazy by the standards of other therapeutic areas. Since bacteria develop resistance to single agents, why not take two different classes of antibiotic molecule and, y'know, string 'em together somehow? How about that, eh?
Well, it's the sort of thought that occurs either to people who don't know much about drug discovery, or to those who know an awful lot. In between, you're probably going to dismiss that one as something of an eye-roller. But while it's got some problems, it's not quite as much of a bozo move as it appears. Here's an example that just showed up in J. Med. Chem., where a group tied Cipro (ciprofloxacin) to neomycin.
The first objection is "Why don't you just give people two pills, instead of trying to make them all into one molecule?" (Here's a review that talks about both options). Well, one answer is that two different agents are going to have different absorption and PK, whereas a conjugate drug will be coming on all at the same time, which could be an advantage. But a more compelling answer is that the new conjugate is going to be a different creature at both of its drug targets, and might well be different enough at both to qualify as a new agent to the resistant strains.
The molecules described in that paper above are, depending on your point of view, fluoroquinolones with a lot of sugars hanging off of them - most unusual as far as traditional quinolone SAR - or neomycin oligosaccharides with some odd heterocycles hanging off of them in turn, which is also not the sort of thing that's usually tried on that scaffold. So if you can still hit both targets, you may well be able to hit them with something they haven't seen before (and may not yet know how to deal with). Importantly, in the case of those quinolone/neomycin thingies, some evidence is shown in the paper that bacteria have a harder time developing resistance to the new compounds. (In order to completely evade them, the bacteria will have to mutate out of both targets, too, but that advantage mostly holds with two separate pills as well).
But all this brings up the second objection: how do you think you're going to get away with hanging all that stuff off an active compound? Well, that's why this trick is usually done with known antibiotics. The SAR of these things has been well worked out by now, and that includes the parts of the molecule that don't seem to have much effect on things. Those will be the preferred positions to attach your linking groups, they're the nonessential region(s) of the molecule that can be messed with.
There's a potential show-stopper in all this, though, and it can be seen on display in the J. Med. Chem. paper. Sticking two drug molecules together, no matter how you do it, is going to make a rather large entity. Neomycin, for its part, didn't start out very small, and the linkers used in this paper aren't the tiniest things on the shelf, either (although I do like the use of the triazole click reaction, mentioned yesterday as well). It turns out that the resulting double-barreled compounds are better than plain neomycin, but worse than plain Cipro. And this happens in spite of the fact that when you assay them against the fluorquinolone target enzymes (DNA gyrase and topoisomerase IV), the new compounds are actually more potent than the original drug. So what's the problem?
Well, the problem, almost certainly, is that these things are probably just too huge. The disconnect between enzyme and bacterial potency here may well reflect trouble getting into the bacteria (although that doesn't seem to be hurting the neomycin end of the activity so much). Larger molecules are trouble when dosed orally, too, and I'd expect compounds like the ones shown to be difficult to develop as traditional pills. (That said, there's a real need for IV-based antibiotics for nasty hospital-derived infections, so something like this could still fly, as long as it showed activity against real bacteria).
So this idea is hard to realize, but it's not necessarily crazy. It keeps showing up in the antibiotic world, and here's an account of the same concept being applied to malaria therapy. Eventually someone's going to get this to work.
Comments (19)
+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
March 13, 2009
Posted by Derek
A few readers have told me that I’m being too hard on antibacterial drug discovery, at least on target-based efforts in the field. The other day I asked if anyone could name a single antibacterial drug on the market that had been developed from a target, rather than by screening or modification of existing drugs and natural products, and the consensus was that there’s nothing to point to yet.
The objections are that antibacterials are an old field, and that for many years these natural products (and variations thereof) were pretty much all that anyone needed. Even when target-based drug discovery got going in earnest (gathering momentum from the 1970s through the 1980s), the antibacterial field was in general thought to be pretty well taken care of, so correspondingly less effort was put into it. Even now, there’s still a lot of potential in modifying older compounds to evade resistance, which is not something that a lot of other drug discovery areas have the option of doing.
And I have to say, these points have something to them. It’s true that antibacterials are something of a world apart; this was the first field of modern pharmaceutical discovery, and the struggle against living, adapting organisms makes it different than most other therapeutic areas even today. The lack of target-driven successes is surely due in part to historical factors. (The relative success of the later-blooming antiviral therapeutic targets is evidence in favor of this, too).
That said, I think that it’s not generally realized how few target-based drugs there are in the field (approximately none), so I did want to highlight that. And it does seem to be the case that working up from targets in the area is a hard row to hoe. There’s a rather disturbing review from GlaxoSmithKline that makes that case:
"From the 70 HTS campaigns run between 1995–2001 (67 target based, 3 whole cell), only 5 leads were delivered, so that, on average, it took 14 HTS runs to discover one lead. Based on GSK screening metrics, the success rate from antibacterial HTS was four- to five-fold lower than for targets from other therapeutic areas at this time. To be sure, this was a disappointing and financially unsustainable outcome, especially in view of the length of time devoted to this experiment and considering that costs per HTS campaign were around US$1 million. Furthermore, multiple high-quality leads are needed given the attrition involved in the lead optimization and clinical development processes required to create a novel antibiotic.
GSK was not the only company that had difficulty finding antibacterial leads from HTS. A review of the literature between 1996 and 2004 shows that >125 antibacterial screens on 60 different antibacterial targets were run by 34 different companies25. That none of these screens resulted in credible development candidates is clear from the lack of novel mechanism molecules in the industrial antibacterial pipeline. We are only aware of two compounds targeting a novel antibacterial enzyme (PDF) that have actually progressed as far as Phase I clinical trials, and technically speaking PDF was identified as an antibacterial target well before the genome era."
So although the history is a mitigating factor, the field does seem to have its. . .special character. The GSK authors discuss some of the possible reasons for this, but those can be the topic of another post or two; they're worth it.
Comments (2)
+ TrackBacks (0) | Category: Drug Assays | Drug Industry History | Infectious Diseases
March 11, 2009
Posted by Derek
Just as an addendum to this morning's post, a quick question: can anyone name an antibiotic that was brought up through a target-driven approach? That is, not one that's a variation on an existing class, or has its origins in a hey-that-killed-bugs assay. I mean, one that started off with people saying "OK, XYZase looks to be essential in bacteria, and higher organisms don't have it. Nothing's on the market that works that way, but it looks to be a good target, so let's go after it".
Off the top of my head, I can't think of one. There may be an example somewhere, but just the fact that I'm having to rack my brain about it says something. Doesn't it?
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+ TrackBacks (0) | Category: Infectious Diseases
Posted by Derek
I’ve had the opportunity to learn more about antibacterial drug discovery in the last year or so – that was one of the few therapeutic areas I hadn’t worked in, actually. And although I already knew that it was no picnic in the park (I’d heard the complaints), doing it myself has given me a new respect for the nasty resilience of bacteria.
I’ve been used to having my compounds go into cell assays, where a good number of them fail. That’s expected – every medicinal chemist knows that some of the potent compounds in the primary assay (against the purified protein target) are going to wipe out when they go up against cells. Cells have membranes, for one thing, and they have bailing pumps built into them to spit out molecules that they don’t recognize. I’ve seen compounds, as has everyone who does drug discovery, that bounce right off the cell assay while closely related analogs work just fine. That’s why you run the assay, to weed those guys out – you may not every understand what specifically went wrong, but you at least get a chance to try to avoid it as you go on.
But bacteria are different beasts. Their independent, free-living nature makes them nastier than even tumor cell lines. Cancer cells, aggressive creatures though they are, still expect to get their food delivered (and their garbage hauled) by the bloodstream. (That’s what makes angiogenesis a drug target in oncology). But bacteria have to search out their own meals, fighting it out with every other bacterium in the area while doing so. Their membranes are like armor plate compared to a lot of higher-organism cell lines, with the gram-negative organisms taking the trophy. Or is it the mycobacteria? (They're both awful, and the proportion of compounds that fail when you move past the pure-protein stage is thus far higher). They react to threats, communicate with each other, and reproduce like crazy. It’s like dealing with a swarm of tiny, self-replicating attack submarines.
So yes, finding an effective new antibacterial drug is a real triumph, and it’s not a triumph that’s been happening very often in recent years. This gets mentioned a lot in the popular press, when they feel like running a Coming of the Superbugs piece, and one of the usual explanations is that drug companies got out of the area years ago because they thought the problem wasn’t big enough to worry about. That’s part of the explanation – or was, quite a while ago. And the finances are different in this space, true. You’re never going to have a multibillion dollar blockbuster, because a new agent is going to be reserved just for infections that are unresponsive to the older drugs. But it’ll still sell.
No, there are plenty of companies working in the area now, and many that never left. And the need for new agents is clear, and has been for quite a while now. The real reason that we don’t have lots of new antibacterial drugs is that it’s really hard to find them, for one thing, and the the bacterial are more than capable of fighting back when we try.
Update: for more on the topic, see here.
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+ TrackBacks (0) | Category: Infectious Diseases
February 13, 2009
Posted by Derek
If you want a good example of the way that the popular media handle a drug discovery story, take a look at all the headlines this morning on the news of the sequencing of the common-cold rhinoviruses.
There are a couple of "Cure For the Common Cold Unlikely" ones, but most of the others seem to regard this as a big step forward. "Cure May Be Found", "Getting Closer" , "May Lead to Cure", "Could Help to Cure" - that's the sort of thing. The problem is, how many viral diseases can we cure? I mean, really cure with drugs after a person's been infected, wipe out and make go away? Right. Do I hear a zero? Viral diseases can be very difficult to get a handle on, because there aren't many moving parts in there. If none of them are amenable to small-molecule drug approaches, people like me are pretty well out of the game.
The best chance you have with a viral infection is with a vaccine. But what this genomics work is telling us, actually, is that a vaccine is going to be rather hard to come by. This paper sequenced ninety-nine different rhinovirus strains, and if there are that many, there are surely that many more. Or there will be, after the next cold season - just wait. These things are mutating all the time - which is, of course, why we get colds year after year. The team working on this project was able to bin the viral genomes into fifteen different classes, but what are we going to do, develop fifteen different (and simultaneous) vaccines? Against a scurrying, hopping, moving target like this one?
No, this is very interesting work, and it'll tell us a lot about how viruses do their nasty viral business out in the real world. But I wouldn't start throwing around the "C" word. All that can do is disappoint people, I'm afraid.
UpdateOK, so who's giving the wrong impression here? As per the comments to this post, here's one of the article's co-authors, Dr. Steve Liggett, as quoted in the New York Times:
"We are now quite certain that we see the Achilles' heel, and that a very effective treatment for the common cold is at hand," said Dr. Stephen Liggett, an asthma expert at the University of Maryland and co-author of the finding.
Say what? That's just a bizarre thing to say. But perhaps he was misquoted, because you can also find this, which seems to be a lot more grounded in reality:
There is hope that a careful study of the viral genomes will reveal one central point of attack that could be exploited by drug makers. "What we would like is a single Achilles' heel for all the viruses that we have found so far, and we could attack in that direction," Liggett said.
But the viruses are found to have impressive powers of change. The study shows that some human rhinoviruses result from the exchange of genetic material from two separate strains infecting the same person. Such recombination had not been thought possible for rhinoviruses.
That recombination is one reason why a vaccine against the common cold appears to be impossible, said Ann C. Palmenberg, director of the Institute for Molecular Virology at the University of Wisconsin, and lead author of the sequencing effort. The viruses just keep changing too much.
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+ TrackBacks (0) | Category: Infectious Diseases
February 9, 2009
Posted by Derek
Viropharma has announced that their Phase III trial of maribavir, a compound targeting cytomegalovirus, failed big-time. Well, they didn't used the term "big-time", but they might as well have. The treatment group (patients with recent bone marrow transplants) showed no difference in CMV infection rates compared to placebo. This is especially disappointing, considering that the compound looked pretty good in Phase II. That's a useful lesson in the difference between Phase II and the real world.
The company has been through this before. Back in the late 1990s, they were working on another antiviral, Pleconaril, that in those heady days caused their stock to shoot up well over $50/share. Some people had gotten it into their heads that the stuff was going to cure the common cold and who knows what else besides. In the spring of 2000, the bad news came in that the drug would do nothing of the kind. I was short the stock at that point, and I've long wished that I had a videotape of me trying to call my broker after I saw the stock quote that morning. I kept missing the buttons on the phone; it was pretty entertaining.
Maribavir isn't one of VPHM's own creations, actually - they licensed it from GSK, and it's a good ol' nucleoside analog in the tradition of many antivirals. But that's a tough area to work in, and today's bad news is just more proof.
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
April 16, 2008
Posted by Derek
A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go.
For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing.
Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge.
Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use.
There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible.
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
April 4, 2008
Posted by Derek
This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.
Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.
Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.
The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.
The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.
There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.
The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.
They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases
April 3, 2008
Posted by Derek
I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:
Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.
Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.
CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.
Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.
Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.
Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.
Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.
OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.
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+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
March 5, 2008
Posted by Derek
There’s an interesting article coming out in J. Med. Chem. on antibiotic compounds, which highlights something that’s pretty clear if you spend some time looking at the drugs in that area. We make a big deal (or have made one over the last ten years) about drug-like properties – all that Rule-of-Five stuff and its progeny. Well, take a look at the historically best-selling antibiotic drugs: you’ve never seen such a collection of Rule of Five violators in your life.
That’s partly because a lot of structures in that area have come from natural products, but hey, natural products are drugs, too. Erythromycin, the aminoglycosides, azithromycin, tetracycline: what a crew! But they’ve helped an untold number of people over the years. It’s true that the fluoroquinolones are much more normal-looking, but those are balanced out by weirdo one-shots like fosfomycin. I mean, look at that thing – would you ever believe that that’s a marketed drug? (And with decent bioavailability, too?)
No, you have to be broad-minded if you’re going to beat up on bacteria, and I think some broad-mindedness would do us all good in other therapeutic areas, too. I don’t mean we should ignore what we’ve learned about drug-like properties: our problem is that we tend to make allowances and exceptions on the greasy high-molecular weight end of the scale, since that’s where too many of our compounds end up. It wouldn’t hurt to push things on the other end, because I think that you have a better chance of getting away with too much polarity than you have of getting away with too little.
One reason for that might be that there are a lot of transporter proteins in vivo that are used to dealing with such groups. It’s easy to forget, but a great number of proteins are decorated with carbohydrate residues, and they’re on there for a lot of reasons. And a lot of extremely important small molecules in biochemistry are polar as well – right off the top of my head, I don’t know what the logD or polar surface area of things like ATP or NAD are, but I’ll bet that they’re far off the usual run of drugs. Admittedly, those aren’t going to reach good blood levels if you dose them orally; we’re trying to do something that’s rather unnatural as far as the body’s concerned. But we could still usefully take advantage of some of the transport and handling systems for such molecules.
But that’s not always easy to do. We all talk about making our compounds more polar and more soluble, but we balk at some of the things that will do that for us. Sure, you can slap a couple of methoxyethoxys on your ugly flat molecule, or hang a morpholine off the end of a chain to drag things into the water layer. But slap five or six hydroxyls on your molecule, and you’ll be lucky not to have the security guards show up at your desk.
There are, to be sure, some good reasons why they might. Hydroxyls and such tend to introduce chiral centers, which can make your synthesis difficult and dramatically increase the amount of work needed to fill out the structural possibilities of your lead series. That’s why these things tend to be (or derive from) natural products. Some bacterium or fungus has done most of the heavy lifting already, both in terms of working out the most active isomers and in synthesizing them for you. Erythromycin’s a fine starting material when you can get it by fermentation, but no one would ever, ever consider it if it had to be made by pure total synthesis.
There’s another consideration, which gets you right at the bench level. For an organic chemist, working with charged, water-soluble compounds is no fun. A lot of our lab infrastructure is built for things that would rather dissolve in ethyl acetate than water. A constant run of things with low logD values would mean that we’d all have to learn some new skills (and that we’d all probably have to spend a lot of time on the lyophilizer). Ion-exchange resins, gel chromatography, desalting columns – you might as well be a biochemist if you’re going to work with that stuff. But in the end, perhaps we might be better off, at least part of the time, if we were.
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+ TrackBacks (0) | Category: Drug Industry History | In Silico | Infectious Diseases
October 31, 2007
Posted by Derek
The post here the other day on resistant bacterial infections prompted some readers to wonder why the drug industry isn’t doing more to come up with compounds in this field. It’s not like there’s no money to be made, and it’s not like there’s no history of antibiotic research, after all. But since my industry doesn’t have a history of knowingly leaving money on the table (what industry does?), you’d figure that there’s more to the story.
Money aside, there’s a real problem with finding good targets. For as long as I can remember in the industry, the infectious disease field has suffered from a relatively small target landscape. Almost all the known drugs in the area work through just a handful of basic mechanisms, and adding new ones to the list has been very difficult for at least the last twenty or thirty years.
That was supposed to change, in theory, starting about ten years ago. I interviewed around then at a company that was working in the field, and everyone was quite excited about the bacterial genome sequences that were starting to appear. Surely this would open the sluice gates and let that long-delayed swell of new targets come washing down the flumes. Hasn’t happened. Not yet, anyway.
I have the impression that the same problems that have affected the translation of human genomic data to new drugs have been the problem here as well. In some cases, not as many genes came out as some people were hoping for. And of these, the function of many of them was (to put it mildly) obscure. Of the ones whose use was at least partially known, many of them have proved not to be useful targets for killing the bacteria or limiting their growth. And of the ones that made that cut – and we’re down to an all-too-manageable set by now – screening hasn’t turned up much chemical matter for people like me to work on.
In fact, there’s a persistent feeling among many people in the field that bacterial and fungal proteins have a lower hit rate than you’d assume they would. Even enzymes that are fairly homologous to those in higher organisms, so the story goes, don’t turn up as many hits in the screens as expected. I’m not sure if this is true or not, but as folklore it’s pretty well known. The combination of all these factors with the perceived lack of opportunities for profits (even if you do find something) has made for slow going.
In recent years it’s become clear that the medical need has grown to the point that antibiotic research can indeed be financially worthwhile – but there are any number of financially worthwhile drug outcomes that we haven’t been able to realize. (See obesity, Alzheimer’s, and many other therapeutic areas for examples of multibillion-dollar opportunities waiting for a good idea to come along. Resistant bacteria have their name on one more sword stuck in yet another stone.
Update: there's clearly another reason why developing good antibacterials is hard, and it's the same reason we need more of them. Bacteria are well-stocked with efflux pumps to get rid of molecules they don't like (and with other weapons as well), and they evolve so fast that you can watch them do it. I wrote about efflux on the site a while back - another post is well worth doing soon.
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+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
October 29, 2007
Posted by Derek
There’s been a steady stream of reports in the news about methacillin-resistant Staph. aureus. It’s not a new problem, but (like other nasty infections) it does get a lot of press when the media start paying attention. Works in reverse, too – on the viral front, have you noticed the much reduced number of bird-flu-will-kill-us-all stories this year as we head toward winter? This despite the likelihood of bird flu killing us all being as high (or low) as ever, as far as I can tell.
But the resistant bacteria problem is certainly no joke, and there doesn’t seem to be any reason why it won’t gradually get worse over time. It struck me the other day that antiinfectives, as a drug research field, might be moving toward a similar spot to oncology. In both cases, you have a problem with rapidly multiplying cells, giving you a serious medical outcome - often in cancer, and increasingly with infections. The average tumor is a lot more worrisome than the average infection, of course, but that’s something we can only say with confidence in the industrialized world, and we've only been able to say it for the last sixty or seventy years. As cancer gradually becomes more manageable and infections gradually become less so, the two might eventually meet – or even switch places, which would be bad news indeed. (In some genetically bottlenecked species, in fact, the two problems can overlap, which is fortunately extremely unlikely in humans).
There are, of course, a lot of differences between the two fields, not least of which is that you’re fighting human cells in one case and prokaryotes (or worse, viruses) in the other. But many of those differences actually come out making infectious diseases look worse. The transmissibility of bacteria and viruses make them serious contenders for causing havoc, as they have innumerable times in human history, and they can grow more quickly in vivo than any cancer. It’s only the fact that public health measures allow then to be contained, and the fact that we’ve had useful therapies for many of them, that makes people downrate the infectious agents. If either (or both) of those change, we’re going to be rethinking our priorities pretty quickly.
What this means for drug development is that some researchers will have to rethink their attitudes towards antiinfective drugs. For serious infections, we're going to have to think about these projects the way we've traditionally thought of oncology agents - last-ditch therapies for deadly conditions. Anticancer therapies have long had more latitude in their side effects, therapeutic ratios, and dosing regimes, and antibiotics for resistant infections are in the same position. For some years now, there's been a problem that new drugs in this field would perforce have small markets, since they'd be used only when existing agents fail. That market may not be as small as it used to be. . .
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+ TrackBacks (0) | Category: Cancer | Drug Development | Infectious Diseases
July 9, 2007
Posted by Derek
One of the stories I missed while on hiatus has been Roche's recall of antiretroviral Viracept (nelfinavir) tablets. As readers may know, a problem with many batches of the drug became known in June. It's a mesylate (aka methanesulfonate) salt, but some of the tablets turned out to have ethyl mesylate in them as well, which is definitely sonething I'd go out of my way to avoid ingesting. A worldwide recall (except for North America, which is on a different supply chain) has been the result.
Methanesulfonate is a very happy anion, which is one of the reasons why methanesulfonic acid is used to make salts of basic drugs. The ions of these formulations tend to not be too tightly bound or paired, making the salt forms generally easier to dissolve. (The stronger the interactions between the ions, the harder it is for water to break up the party and dissolve them). But the contentedness of the sulfonate anion makes it a good leaving group when it's part of a covalent molecule. It would rather be off floating around with a negative charge on it again than be tied up in a regular bond, so sulfonate esters and the like tend to be pretty reactive.
Alkyl mesylate esters, then, are also pretty toxic. Just how toxic is the question, though. The stuff will react with nucleophiles wherever it finds them, and if that's some protein on the surface of a soon-to-be-shed epithelial cell, then no harm done. But there are many other situations that won't work out so well, going all the way up to DNA damage.
So how did this nasty stuff get in there in the first place? When I heard about the contaminant, my first thought was that someone had been washing out the reactors where the salt was formed with ethanol, and that appears to be exactly the case. Alcohol plus free acid under strong acid catalysis will give you ester, in what's literally one of the oldest reactions in the book. Roche appears to have been able to keep the contaminant down below regulatory levels normally, but someone's mind has been wandering over in Switzerland. In consequence, the fearsome Swiss reputation for purity and consistency takes a torpedo below the water line.
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+ TrackBacks (0) | Category: Infectious Diseases | Why Everyone Loves Us
May 22, 2007
Posted by Derek
As the cost of sequencing goes down, a lot of once-crazy experiments become feasible. There's a good case in point this week in the preprint section of PNAS. A team of researchers looked at a single patient undergoing treatment with vancomycin for a serious infection. (Just saying "vancomycin" makes the "serious infection" part redundant, since it's often the last resort). They periodically isolated Staphylococcus aureus bacteria from the patient's blood during the course of the treatment to look at how resistance to the antibiotic developed.
Fine, fine - except the way they watched the process was to sequence the whole genome of each bacterial isolate. What they found were a total of 35 mutations, which developed sequentially as the treatment continued (and the levels of resistance rose). Here's natural selection, operating in real time, under the strongest magnifying glass available. And it's in the service of a potentially serious problem, since resistant bacteria are no joke. (Reading between the lines of the PNAS abstract, for example, it appears that the patient involved in this study may well not have survived).
The technology involved here is worth thinking about. Even now, this was a rather costly experiment as these things go, and it's worth a paper in a good journal. But a few years ago, needless to say, it would have been a borderline-insane idea, and a few years before that it would have been flatly impossible. A few years from now it'll be routine, and a few years after that it probably won't be done at all, having been superseded by something more elegant that no one's come up with yet. But for now, we're entering the age where wildly sequence-intensive experiments, many of which no one even bothered to think about before, will start to run.
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+ TrackBacks (0) | Category: Infectious Diseases
May 7, 2007
Posted by Derek
Back in 2005, the government of Brazil threatened to break the patent on Abbott's HIV medication Kaletra if the price didn't come down (see here and here). But after a lot of arm-wrestling, a deal was reached. Now it's Merck's turn, with their efavirenz, and this time things went all the way: on Friday, Brazil's president issued a compulsory license to produce the drug outside Merck's patent.
My problem with this, other than the obvious problem I have with expropriation of someone else's property, is that Brazil is trying to have things both ways. The government spends much of its time talking about how the country is an emerging power, with the 12th-largest economy in the world, huge natural resources, its own successful aircraft industry and space program, and so on. But when it comes time to pay for HIV medications, which are important both medically and politically, suddenly they're a poor third-world country being exploited by the evil multinational drugmakers. A look back at the second blog link above, with its quotes from Brazil's Minister of Health on how nationalizing drug patents would help the country's industry, shows that this issue probably has more to do with the first worldview than the second one.
During the Kaletra dispute, I asked a question:
I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?
And now Merck is basically asking Brazil the same thing:
"Research and development-based pharmaceutical companies like Merck simply cannot sustain a situation in which the developed countries alone are expected to bear the cost for essential drugs in both least-developed countries and emerging markets. As such, we believe it is essential to price our medicines according to a country's level of development and HIV burden, thereby ensuring equitable access as well as our ability to invest in future innovative medicines. As the world's 12th largest economy, Brazil has a greater capacity to pay for HIV medicines than countries that are poorer or harder hit by the disease.
This decision by the Government of Brazil will have a negative impact on Brazil's reputation as an industrialized country seeking to attract inward investment, and thus its ability to build world-class research and development."
It should have, anyway. Look, intellectual property law is not pretty, and doesn't give anyone a warm feeling. It's not meant to. But the alternative Jolly-Roger world is even worse, and anything that takes us toward that is a bad move.
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+ TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP
April 25, 2007
Posted by Derek
Pfizer got a tiny bit of good news yesterday when an FDA panel recommended their new HIV drug, Maraviroc, for approval. There are several stories that can be told about this news, so let's try a few: The business story is that this is not going to make a lot of difference for the company, because the drug isn't going to be a first-line therapy. They have to hope that it performs well and can expand its use, because a $25 to $50 million/year drug is a roundoff error on the scale of Pfizer's financial concerns. So much for the money.
The drug development story is that this will be the first CCR5 inhibitor to reach the market. That's a useful benchmark by the standards of this blog, because back in 2002, in my second month of blogging, I wrote about this class of drugs. The first CCR5 inhibitors had already made it into human patients by that time, and here we are, five years later, and one of them is just about to make it to market. Patience is supposed to be a virtue, but in the drug business, it's a case of making that virtue out of necessity.
And the big philosophical story is how the world has changed in the last twenty years. Here's a new HIV medication, one with a new mechanism, and it makes the second business page of the paper if it makes it at all. A completely new drug for a dreaded disease is coming, and no one thinks it'll do all that well, because of all the competition, y'know. It'll be given to people who've failed courses of treatment with all the other HIV drugs out there, and unless you're paying attention it's hard to keep up with all of them.
For people who remember the 1980s, all this still feels strange - imagine a message from the future popping up in 1985, saying: "In twenty years, the viral disease with by far the most crowded market, the largest number of possible therapeutic options and the widest variety of drug mechanisms will be. . .HIV". Actually, that would have scared everyone even more than they already were, because it would sounded like the worst predictions from that era had come true. In reality, HIV isn't even in the top 15 causes of death in the US, with the most recent figures I can find putting its contribution to the death rate a bit below that of aortic aneurysm. (Some other parts of the world are a different story, of course, although the 1980s predictions for them were even more apocalyptic.) But all in all, I'm fine with living in a world where new drugs against deadly diseases aren't necessarily front-page news. . .
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+ TrackBacks (0) | Category: Infectious Diseases
April 13, 2007
Posted by Derek
I've been out of the research labs for over two months now, and you know what I miss the most? No, not the safety meetings (hah!) or the smell of the solvents - what I miss is getting fresh data on experiments. Waiting for results on something crucial is hard to take, but it's also exciting, and there's nothing I've found outside of science that compares.
I've sat at my desk holding a warm printout from an LC/MS, or with a newly arrived e-mail from the biologists, and I swear, I've closed my eyes for a moment before I've looked at them. That's the last moment of not knowing; after that you're living in the new world that the experiment made. I don't know what I'd do with a job that didn't have that feeling in it, and honestly, that's one reason I'm still looking.
It occurs at all sorts of levels - checking the NMR to see if your reaction worked or not, waiting for the PK results to see if your idea raised the blood levels, holding your breath when the compound goes into two-week tox testing. And beyond that things get really terrifying, when human data start coming in from the clinic.
Ask Vertex. I wrote here about their antiviral compound (telaprevir, VX-950) for hepatitis. It's a huge market that really needs a better drug, and a lot of people have taken swings at it. Well, on Saturday night in Barcelona, the company is presenting their latest clinical data, and investors are checking their heart rates. The drug's success would be the biggest event in the history of the company (and a huge advance in hepatitis therapy), and failure (the antiviral norm, unfortunately) would be very, very hard to take.
The company's top clinicians already know the answer, of course, because a person's got to have time to make slides. They've had the experience I was talking about, on a scale that few people have ever felt. You click a button, turn a page, and the future writes itself out there in front of you. . .
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Who Discovers and Why
February 7, 2007
Posted by Derek
Antiviral drugs are one of those big unmet medical needs that we talk about in the drug industry. The reason we talk about them is, of course, that from a business standpoint - and this is a business, for sure - "unmet need" is equivalent to "unmade profit".
The problem is, the reason that some of these big opportunities are unclaimed is that they're not easy to address. As I've said here before, one big problem with antivirals is that there are a very limited number of good targets for drugs. After all, viruses are pretty stripped-down to start with: they do a limited number of things, but they do them very well indeed. Compared to a relatively target-rich therapeutic area like cancer, infectious disease is a desert.
One well-known oasis, though, contains the viral proteases. Many viruses carry these as a key part of their machinery, to help "unpack" necessary proteins from larger precursors. Famously, that's how many of the anti-HIV drugs work, and the same general strategy should be applicable to several other viral types.
Hepatitis C has been one of the big targets for many years now. Various development programs have come and gone, but no one has been able to really nail this one. Vertex is now in the middle of trying to, and as Adam Feuerstein points out, they're really betting a large part of the company on the attempt. Over the next few months, results should start coming out for their PROVE trials of telaprevir (VX-950), and for Vertex's sake, the drug had better work. A herd of competitors, probably led by Schering-Plough, is ready to take over should anything slip.
"Work" is defined as "work well enough so that people don't have to take injections of interferon". That'll depend, as always, on the balance of efficacy and toxicity, and it's the side effect profile that everyone will be watching, since it's widely assumed that the drug will in fact do some good against the disease. The nerve-wracking thing about working for a small-to-medium sized company has always been that your future ends up depending on single events like this, and I wish everyone at Vertex good luck. (Of course, as people at Pfizer will tell you, your future even at a gigantic company can end up depending on the results of one clinical trial - this industry is getting altogether too exciting for a lot of people to take).
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
October 18, 2006
Posted by Derek
There's a curious paper (subscriber-only link) in the latest Nature that's getting some attention, titled "A linguistic model for the rational design of antimicrobial peptides". For non-subscribers, here's a synopsis of the work from the magazine's news site.
A group at MIT headed by Gregory Stephanopolous has been studying various antimicrobial peptides, which are secreted by all kinds of organisms as antibiotics. Taking the amino acid sequences of several hundred of these and feeding them into a linguistic pattern-analysing program suggested some common features, which they then used to synthesize 42 new unnatural candidates. The hit rate for these was about 50%, which is far, far more than you'd expect if you weren't tuning in to some sort of useful rules.
It's the concept of "peptide grammar" that seems to be the news hook here. But I'm quite puzzled by all the fuss, because looking for homology among protein sequences is one of the basic bioinformatics tools. I have to wonder what the MIT group found with their linguistics program that they wouldn't have found with biology software. What they're doing is good old structure-activity relationship work, the lifeblood of every medicinal chemist. Well, it's perhaps better described as sequence-activity relationships, but sequence is just a code for structure. There's nothing here that any drug company's bioinformatics people wouldn't be able to do for you, as far as I can see.
So why haven't they? Well, despite the article's mention of a potential 50,000 further peptides of this type, the reason is probably because not many people care. After all, we're talking about small peptides here, of the sort that are typically just awful candidates for real-world drugs. And I'm not just babbling theory here - many people have actually tried for many years now to commercialize various antimicrobial peptides and landed flat on their faces.
You won't see a mention of that history in the Nature news story, unfortunately. They do, to their credit, mention (albeit in the fourth paragraph from the end) that peptides are troublesome development candidates. That's where it also says that there are reports that bacteria can become resistant even to these proteins, which prompts me to remind everyone that bacteria can become resistant to everything short of freshly extruded magma. It's in the very last paragraph of the story, though, that Robert Hancock of UBC in Vancouver says just what I was thinking when I started reading:
(Hancock) questions how different the linguistics technique is from other computational methods used to find similarities between protein sequences. "What's new is the catchy title," he says.
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+ TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases
September 11, 2006
Posted by Derek
It's been a while since I wrote about the neuraminidase inhibitors (Tamiflu and Relenza, oseltamavir and zanamivir). As we start to head into fall, though, I'm sure that avian flu will invade the headlines again, if nothing else (and I hope it's nothing else).
There's an interesting report in Nature (subscriber link) on how these drugs work. Bird flu is a Type A influenza, but there are two broad groups inside that class, which are defined by what variety of neuraminidase enzyme they express. (There are actually nine enzyme variants known, but four of them fall into one group and five into the other).
The drugs were developed against group-2 enzymes, but they're also effective against group-1 influenzas. Since the X-ray crystal structures showed the the drugs bound in the same way to all the group-2 neuraminidases, and since the active sites of all the subtypes across the two groups are extremely similar, no one ever thought that their binding modes would be different. Well, until last month, anyway, when the X-ray crystallographic data came in.
And what it showed was that the active sites of the group-1 enzymes, sequence homology be damned, have a much different structure than the group-2s. As it turns out, though, they can adopt a similar shape when an inhibitor binds to them, which is why the marketed inhibitors still work on them, but they're fundamentally quite different.
I can't resist the urge to use this example to illustrate some of the real problems in our current state of the art for computation and modeling. The differences between these two enzymes are due to their different amino acid residues far away from the active site, which makes modeling them much, much more difficult (and makes the error bars much, much wider when you do). That's why no one realized how far off the group-1 and group-2 neuraminidases were until the X-ray structure was available: modeling couldn't tell you. Any modeling efforts that tried would probably have decided, incorrectly, that the two groups were nearly identical. Why shouldn't they be?
But if we'd had that X-ray data from the start, modeling would very likely have told you, incorrectly, that there was little chance that either Relenza or Tamiflu would work on the group-1 enzyme variants. Why should they? The "induced fit" binding modes, where the enzyme changes shape significantly as the ligand binds, are understandably very difficult to model. There are just too many possibilities, too many of which are within each other's computational error bars.
Now, it's true that this latest work isn't based on molecular modeling at all. (You have to wonder how close these guys got, though). But plenty of projects that are using it are just as much in the dark as a neuraminidase team would have been, and they may not even realize it. Most molecular modelers are well aware of these limitations, but not all of them - or all of the managers over them - are willing to accept them. And when you get out to investors or the general public, it's all too easy for modelers or managers to act as if things are perfectly under control, when in reality they're lurching around in the dark. Like the rest of us. . .
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+ TrackBacks (0) | Category: In Silico | Infectious Diseases
July 19, 2006
Posted by Derek
I wrote some time ago (Ay! Four years ago - have I been doing this for that long?) about the Roche/Trimeris HIV drug Fuzeon (T-20, enfuvirtide), and its costly manufacturing process. Roche built a factory in Colorado just to make the drug, which is a 26-amino acid peptide. And instead of doing it recombinantly, they're producing it the good old chemical way, by peptide coupling. (Here's a not incredibly competent collection of whiz-bang photos of the place, which at least have no purple spotlights in them)
Back in 2002, I had some thought that Roche had perhaps lost its corporate mind. But as this article from Chemical and Engineering News points out (subscriber-only, I think), they've actually done everyone a favor, whether by losing their minds or not. Their decision to go fully synthetic, and the massive investment that followed, has lowered the cost of all sorts of peptide synthesis reagents, starting materials, and equipment, to the point that it's now become enough of an industry to attract a lot more production interest. (And one of the big players in the contract business is. . .Roche's Colorado facility!)
As the article points out, recombinant technology (producing the peptide in engineered cells) is a wonderful thing, but only when it's working perfectly. And getting it to that point can be a long, expensive task. There are a lot of potential cell lines to choose from, each with its own advantages and disadvantages, and uncountable ways to engineer them and culture them. Even then, the purification of the target protein can be a whole new nightmare - as one chemist interviewed by C&EN says, at least synthesis doesn't give you back ten times as many different things as you put into it.
Peptides still aren't anyone's first choice for development when there's a small-molecule alternative. But for the targets that no small molecule is going to hit, they're worth looking at. Recent years have seen improvements in metabolic stability and duration of action, as people come up with all sorts of nifty delivery systems and conjugate polymers. You could do a lot worse.
But perhaps Roche could have done better. There were all sorts of glowing forecasts about Fuzeon when it was first approved, and all sorts of grumbling from people who took the optimistic numbers and calculated that Roche would be making its money back in two or three years at the prices they'd set. Well, that hasn't happened yet, since the drug isn't selling nearly as well as had been hoped.
Another two or three years should do it, if nothing better comes along to cut into Fuzeon sales. And stipulating that (which is no sure bet) Roche might be selling it for a long time to come, since the barrier to generic manufacture is going to be rather high. So, even after that wild factory in Colorado, they're still probably going to go into the black on Fuzeon, but it does make you wonder how the return compares to some of the other drugs in Roche's portfolio.
But that's their problem. In the meantime, it looks like they've helped everyone else in the business by making industrial peptide synthesis more affordable. Adam Smith's invisible hand strikes again. . .
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May 10, 2006
Posted by Derek
There's been a lot of press coverage the last week or so about two new routes to Tamiflu (oseltamavir). Roche famously starts from shikimic acid, most of which they get from Chinese star anise, and the new syntheses are attempts to get around that bottleneck.
E. J. Corey's getting more attention than Masakatsu Shibasaki, partly because he's a Nobel winner and partly because he's made a point of placing his synthesis in the public domain. (Shibasaki's applied for a patent). It's nice to see organic synthesis make the headlines, but unfortunately, a lot of the coverage has been of the "Nobel Prize Winner Solves Tamiflu Problem" sort. I've also seen several stories that suggest that Corey's route opens the door (at last, right?) to mass production.
Not so fast. Roche has already been producing rather large amounts of oseltamavir, although they'd be glad to find a better route. And it's not like they haven't been trying themselves, as this PDF will make clear. And it's far from clear that Corey's route will be of commercial value, even though his overall yield, as given, is about 27%, which news articles are saying is roughly twice the yield from shikimic acid. (Note, though, that that Roche PDF claims a higher yield than Corey's - I'm not sure who's right).
Let's get technical and take a look at the chemistry. First off, the repeated claim that Corey's route starts from two of the cheapest feedstocks available - butadiene and acrylic acid - is only partly true. The key Diels-Alder reaction actually uses trifluoroethyl acrylate, which is substantially more expensive than acrylic acid, although admittedly ten times cheaper than the same amount of shikimic acid from the same source. Moving on, there are eleven steps, and according to the supplementary material for the paper (where the full experimentals are), steps 1, 3, 4, 5, 6, and 8 have chromatography in their workup. The others are run through a plug of silica or are taken on crude, which tells me that Corey's students probably tried to do the same with the remaining steps but took a hit on the yields. Every chromatographic purification adds a great deal to the cost of a process route, needless to say.
There are other wrinkles. Steps 1 and 2 start at -78 degrees before coming up to more process-friendly temperatures. Step 8 is a slow addition at -40, and step 9 is an inverse addition at -20. Low-temperature reactions are certainly doable on scale, but again, they'll add to the cost and complexity. Those last two steps involve an acylaziridine intermediate, whose thermal stability would need to be checked out, and could partially negate the advantage of not using azide in the route.
The scale of the reactions in this paper is in the ten-gram range, which is fine, until you get to steps 8 and 9. Those low-temperature reactions are shown on 300 and 160 milligrams, respectively. That tenfold drop in scale indicates another area that would need to be checked out; there can be a huge difference between something that works on a couple of hundred mgs and a useful process, especially in the cold.
All this isn't to say that Corey's route doesn't work, or that it can't work on scale. But it's important to keep in mind that the kind of chemistry done in his lab is about as far from industrial scale as you can get. It may be that the more interesting features of his route (the catalyzed Diels-Alder, for example) could be combined with some of Roche's own process ideas and turned into something feasible. But for now, this is an interesting route that's a long way from solving anyone's Tamiflu shortage.
To be fair, Corey himself isn't responsible for some of the hype, except I wish he wouldn't let himself be quoted as saying that the thinks that the Tamiflu production problems are "solved". Headline writers know nothing about organic chemistry or drug development, and they run with what's in the press releases. Of course, there's the larger question hanging over all of this: will Tamiflu even do anyone any good if there is a human outbreak of avian flu? And that, nobody knows.
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+ TrackBacks (1) | Category: Chemical News | Infectious Diseases
January 19, 2006
Posted by Derek
So, are the neuraminidase inhibitors (Tamiflu and Relenza, oseltamivir and zanamivir) going to be of any use against bird flu? The press coverage is a mass of confusion. Headlines range from stuff like "Newer Flu Drugs Work Better" to "Don't Use Older Flu Drugs, Experts Warn" to "Tamiflu Not Effective Against Bird Flu". The problem is, we're looking at two different classes of drugs, and two different sorts of flu.
A few days ago the CDC issued a warning that the prevalent H3N2 flu strains this year have mutations that make the older class of flu antivirals (the aminoadamantanes) ineffective. But I'm not sure how many people even get these any more, since they were never very impressive to start with. I don't think anyone has seriously proposed them as a defense against H5N1 avian influenza, should that ever take off.
But Tamiflu and Relenza are a different story; a blizzard of hype has surrounded their possible use. Lost in the bird-flu noise is their use against "regular" influenza, a market where they've never performed up to expectations - no doubt they're selling rather better so far this season - and the CDC recommended their use for this purpose.
Comes now a report in The Lancet from a group in Rome (available to subscribers here), looking over all the published studies on the various drugs. They also recommend that that adamantanes be retired, and they aren't very positive on the use of the NA inhibitors against the standard forms of flu, which I'd say is in line with the clinical experience. And they found no evidence that either Tamiflu or Relenza is effective against bird flu, which leads to all the jumpy headlines.
But this isn't really a surprising finding, since there hasn't been (to my knowledge) any published study on the use of the drugs against avian influenza in humans. (Cell culture, yes, but that's a long way from the real world). There hasn't been enough time (and there haven't been enough patients, fortunately). A better headline would have been "Tamiflu's Effectiveness Against Bird Flu Unknown", but we already knew that. Didn't we?.
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+ TrackBacks (0) | Category: Infectious Diseases
November 14, 2005
Posted by Derek
Andrew Stimpson isn't a scientist. If he were, he might have heard the line about extraordinary claims requiring extraordinary evidence. And his claim is indeed extraordinary - he says that he has managed to clear HIV from his system without therapy. Well, other than vitamins, don't you know - and if he says that he got them from Matthias Rath, I'm going to have to go lie down for a while.
This story has generated all sorts of irresponsibly breathless headlines, but when you read the stories underneath them you find that there's not much behind it. Stimpson received a positive HIV diagnosis on the basis of two antibody tests in 2002. Near the end of 2003, he was found to be negative, and was asked to repeat the test to confirm it. He refused, and sued the British health trust that did the testing.
Update: Press reports disagree about this. Some have the story as above, and others say that Stimpson tested negative on several occasions during 2002 and 2003. His initial postive tests showed what is being described as "an extremely low viral load."
Here's where things get messy. Stimpson appears to have sued because he felt that the original tests were in error. (The agency naturally stood by both its positive results). When no money was forthcoming, he then seems to have gone to a couple of the British tabloids with his miracle recovery story: ". . .I am just one person who managed to control (HIV), to survive from it and to get rid of it from my body", he's quoted as saying, which is an interesting statement from someone who was previously claiming not to be infected at all. Update: Stimpson eventually received a letter from the National Health Service calling his HIV-negative status "exceptional and medically remarkable", so he at least didn't come by his miracle-recovery story alone.
Stimpson hasn't been tested again, and doesn't seem to be available at the moment. I am not inclined to believe any claim such as his, to put it mildly, until he's been poked and prodded from every angle - to put it mildly. You would think that he might wish to help other HIV sufferers if he really has reversed the disease, wouldn't you? The article link above quotes the head of a charity in England as saying "The answer may turn out to be very complex. We must not jump to conclusions." Actually, I'm close to jumping to the conclusion that the answer might be rather simple.
Update: Press reports also disagree - markedly - about Stimpson's willingness to undergo further tests. My final sentence isn't meant to suggest some complex biochemical rationale. I'm thinking that the chances are best that the first positive results were in error - after all, their false-positive rate is surely much higher than the spontaneous-clearance-of-HIV rate. The health agency that tested him, though, might well prefer to treat this as an amazing medical anomaly rather than as a botched test. And given that he wasn't able to collect damages, it became in Andrew Stimpson's financial interest to go with that explanation as well, selling his story to the British tabloids for an undisclosed amount.
In the end, I agree with this quote, from the Nature.com news item on this story: ""If it is real, it's very interesting," says Jonathan Weber, an expert on infectious diseases at Imperial College London. But he cautions that the most likely scenario based on the current evidence is "either a false positive [in 2002], or he's still infected".
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+ TrackBacks (2) | Category: Infectious Diseases
November 9, 2005
Posted by Derek
While the Wall Street Journal is opening its site for free this week, may I recommend this excellent article on the vaccine and antibiotic markets? It's a clear-eyed look at why drug companies haven't put more time and money into these areas over the years. The headline makes it sound as if it's going to be a pharma-bashing-festival, but the authors (Scott Hensley and Bernard Wysocki) lay out the facts, which are just as I understand them from my vantage point, too.
The second article in the series is also up here. It's an equally good overview of the possible incentives that are being discussed to encourage work in vaccines and anti-infectives. I'm glad to see the idea of incentives being discussed, because as it stands, the market isn't necessarily going to give us what we need in the time we need it. New antibiotics are generally reserved for use in resistant cases only, so you can't make your money back there. And new vaccines can end up costing too much in liability suits (many - most - of which aren't particularly well justified). But put some incentives in there, and perhaps the numbers can work out. The article goes into detail on some of the proposals - straight cash, guaranteed purchases, extra product exclusivity, and so on.
I know that some people will hear these ideas and wonder why the government doesn't just do the research itself, rather than cough up money to the drug companies. The biggest reason is that the drug companies are better at it, and faster as well. We stay on our toes competing against each other. The biggest pitfall in these incentive plans, as far as I'm concerned, is that it might end up with companies that have no one breathing down their neck. Better to have two or three organizations racing each other and throwing elbows to grab the prize, than to have someone ambling over to pick it up.
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+ TrackBacks (0) | Category: Infectious Diseases
November 2, 2005
Posted by Derek
In the first post below, I said that we would be in big trouble if we had to rely on a vaccine for all of our protection against a flu pandemic. The problem is, if we're relying on antiviral drugs, we're in even worse shape. (See my post on this from last March.)
Right now, the only drugs likely to do much of anything against an influenza pandemic are the neuraminidase inhibitors like Tamiflu and Relenza. But the problem is, these drugs really have to be taken early in the course of the infection to be most effective. By the time many people realize that they have the flu, it may be too late to do much about it.
One way to get around that problem would be to take the drugs prophylactically, but that has two serious disadvantages. For one thing, this route might well lead to a quicker development of resistant viral strains, which is something that we already know can happen. And for another, it would burn through huge amounts of drug, and we don't happen to have huge amounts of either one.
Why is that? Well, for one thing, neither compound was selling very well until recently. The companies involved have never had to ramp up production to the levels that people are talking about now. It's doable, but it won't be fun. The ten-step Roche synthetic route to Tamiflu uses some azide chemistry, which is potentially toxic and explosive, but it's nothing that a good bunch of industrial chemists can't handle. (It helps, for example, that India's Cipla already has experience making AZT, because that relies on similar chemistry). But any ten-step route is not going to be trivial to implement if you've never done it before, azide or no azide.
A bigger problem is that these drugs have syntheses from a starting material called shikimic acid. That's a component of an important metabolic pathway in plants. (It's important enough that the well-known herbicide Roundup works by shutting it down). Shikimic acid is found in small quantities in a lot of plant species, but star anise, a spice used in Chinese cooking, has a lot of it. (If you'd like to extract some from any star anise you have in your kitchen, here's how). Roche already has a network of suppliers in China, and the generic companies who plan to produce the drug are having a hard time sourcing the shikimate. It can also be produced by fermentation, which Roche uses for some of its supply, but that's an even more specialized process.
All in all, I think it's prudent to stockpile these drugs, although I'm not sure, for the reasons given above, where the US government is going to find the quantities it's looking for. But even if we can pile the stuff up to the rafters, we have to be ready for the possibility that these drugs may or may not do us much good. I see that I've ended both of these posts on the same note. . .
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+ TrackBacks (1) | Category: Infectious Diseases
Posted by Derek
The government's proposed plan for dealing with a flu pandemic is worth some comment, although it's going to undergo mutations just as surely as the viruses do. It's hard to argue with the overall approach, but there are some details that need explaining.
For example, there's a proposed boost for research into vaccine production through cell culture techniques (as opposed to the famous chicken-egg methods), and I think that this is a fine idea. Unfortunately, it was just as fine an idea two or three years ago, and we'd probably be in better shape now if this idea had been pushed back then. Money doesn't convert to time quite as easily in basic research as it does in some other areas (although it doesn't hurt, true). Some of the companies that do work in this area are pointing this out today, in rather testy tones of voice:
. . .so far the government has not backed development of three cell-based vaccines that have received or are close to receiving regulatory approval in the United States and Europe - including one developed by a Meriden (CT) biotechnology company. Instead, the Department of Health and Human Services last April funded only one cell-based flu vaccine - $97 million for a vaccine that has not yet been tested in animals or humans.
"I don't know what the hell they are thinking about," said Dan Adams, president and chief executive officer of Protein Sciences. . ."
This is the voice of a man whose company missed out on a $97 million dollar contract, so that has to be taken into account. But it does appear that HHS and the FDA have been overly cautious about moving to cell-culture based vaccines.
But "caution" is a popular word in the vaccine field, in the financial, medical, and legal senses. and that brings up another provision in the President's proposal that I haven't seen anyone else comment on yet: liability protection for vaccine producers. As you might figure, I think that this is on principle a good idea, but the trial lawyers (and some others) will think differently. This will be an interesting fight, but it might take place largely out of sight. "Fight for your right to sue the people who are trying to protect you from bird flu" isn't a very catchy slogan.
My last comment on vaccines in this context is to point out that - cell culture or no cell culture - if we get to the point that we're relying on a vaccine to save people from a pandemic, then we could be in big trouble. There's an inevitable delay in vaccine development and production - months and months and months of delay, and that's when things are really zipping along. Viruses can mutate in the time it takes to fight their previous versions. If we're lucky, the vaccines that are being developed now will have enough protective effect against whatever flu strain might cause a pandemic. But they might well not, and we need to realize that.
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+ TrackBacks (1) | Category: Infectious Diseases
October 13, 2005
Posted by Derek
Note: This post has a follow-up with Jim Cramer's reaction to it here.
The small-pharma flavor of the month seems to be Biocryst Pharmaceuticals, but it's not one of their current development projects that has everyone jumping up and down. It's a drug that failed its Phase III trials two years ago. Despite the best efforts of various stock newsletters and of multimedia stock tout Jim Cramer, though, I'm managing to resist the company's stock.
The words "avian influenza" are the missing piece to this puzzle. The drug, peramivir, is a neuraminidase inhibitor developed as a flu treatment, which is the same mechanism as the marketed drugs Relenza and Tamiflu. With the current worries about a possible pandemic, antivirals of all sorts are getting a second look.
In this case, you have to go back a few years for the first look. Peramivir was in Phase II trials during the late 1990s, and in 1999 the results were announced: not too bad. Their endpoint was reduction of viral titer, the blood marker of flu virus infection, and they hit it. On to Phase III, then, to see if that effect was worth anything in the real world.
There were some rough patches. Biocryst's development partner, Johnson & Johnson, pulled out of the deal before the Phase III trials got properly off the ground. (So much for the Valentine-card sentiment about them being the "ideal partner" at the end of that 1999 press release). J&J seems to have taken a look at the market performance of the other neuraminidase inhibitors and concluded that they had better places to put their money.
They were probably right about that. Tamiflu and Relenza were supposed to be much more successful than they've turned out to be. I wrote about this a couple of weeks ago in the context of a Canadian effort to develop new antivirals. The Canadians make an appearance in at least one article on Biocryst, from the New York Times, which also talks about the unhappiness of the smaller companies (Gilead, Biota) that first discovered Tamiflu and Relenza:
Tamiflu's inventor, Gilead Sciences, a California biotechnology company, told Roche in June that it wanted to take back the rights to the drug, accusing Roche of a "consistent record of inactivity and neglect" since the medicine was approved by the F.D.A. in 1999.
A Roche spokesman, Terence J. Hurley, said the company had fulfilled all its obligations to Gilead to promote and manufacture the drug and the dispute was in arbitration. . .
Biota, which is based in Australia, filed a lawsuit there against Glaxo last year, saying it did not adequately try to market Relenza. After the drug's first year on sale, "essentially all promotion was stopped," Mr. Molloy said.
Biota is seeking about $300 million in royalties it says it would have earned if Glaxo had done an adequate job. (Biota has now teamed up with Sankyo to move Sankyo's version of Relenza forward under a $5.6 million grant from the National Institutes of Health in the United States.) Glaxo denies Biota's accusations in the case, which is headed toward arbitration later this year.
"We lost a lot of money, quite frankly, promoting it, and the demand wasn't there," said David Stout, Glaxo's president for pharmaceutical operations.
I especially like that last quote, since I thought that the drug industry was always supposed to be stampeding people into buying stuff that they didn't need. Maybe Glaxo could hire Marcia Angell as a consultant to show them how it's done. Just thinking out loud here. . .ah, what a match it would be. . .
OK, where were we? Ah, back in early 2000, as Biocryst was preparing to go it alone in their Phase III effort. They did manage to get things off the ground, but the results were very disappointing. The endpoint this time wasn't just reducing viral load, but reducing flu symptoms. And the drug managed to decrease the time to improvement of symptoms by. . .about half a day, with no statistical significance, and this at doses up to 800 mg/day. They dropped the compound immediately, and rightly so.
Although that press release doesn't go into the details, Biocryst has told the press that one reason that peramivir might have failed was poor blood levels after oral dosing. I'm going to reserve judgment on that explanation, because the blood levels were certainly high enough to go through Phase II and Phase III trials – blaming them now sounds a bit ex post facto. Injected versions of the drug seem to perform well in rodent models of avian flu infection, and they're looking to get a human trial going via the same route. (This was an option before, too, of course, but the drug had no commercial chance as an injectable versus two non-injectable compounds as competition). And in all the noise about injectable peramivir, I haven't heard anyone say how it performs versus injections of Tamiflu or Relenza, either. Surely they can be formulated for it.
The prospect of a flu pandemic has changed things, but the problem is, it's too soon to say if people are now being more realistic or just more hysterical. In the last few weeks, though, I think things have tipped toward the latter. Avian flu, if it crossed over into some highly infectious human form, could be very bad news. But we're not seeing that happen (yet) with the current bird flu. It's worth remembering that flu viruses of this type have already crossed over into humans in recent years without taking off around the world. That doesn't mean that it can't happen, but it does mean that it's not inevitable.
So, no one knows how likely a pandemic is, when it might occur, and how it might behave. It's prudent to take a look at marginal compounds like peramivir, whose possible use against avian flu was being spoken about years ago. But it's not prudent to buy, or urge others to buy Biocryst's stock after it's already tripled in price. Looking at that price and the implied value of peramivir, The Biotech Stock Blog says:
"An NPV of $350 million, for example, implies $900 million of sales next year at a 50% gross profit and discounting back 15%. If you assume there is risk associated with the company realizing future cash flow from peramivir, then the implied future cash flow is considerably larger. For example, handicapping the likelihood of BioCryst winning a government contract and selling product next year at 50%, implies BioCryst sells $1.8 billion worth of peramivir next year!
Any way you slice it, the expectations for BioCryst are wildly optimistic based on the current stock price. This is not to say that peramivir does not ultimately become a successful drug or that there isn't money to be made on BioCryst. Ultimately, however, reality will come back to the stock and the fast money will go elsewhere. When the music stops, you don't want to be the one without a chair."
(Link via The Stalwart). I agree with this analysis completely. Would Jim Cramer, in between shouting into the microphone and waving his arms, care to comment on these numbers? Or are we going to have a historial re-enactment of 1999, with Biocryst playing the part of Viropharma and Cramer taking on the role of Tokyo Joe? Since his analysis of BCRX so far includes the phrase "Trading is all about the buzz", that's just what we might be in for.
I made a lot of money shorting VPHM back then, and (although I haven't yet) I'm tempted to go short BCRX now. I wonder if there are any shares left to borrow?
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+ TrackBacks (1) | Category: Infectious Diseases
October 3, 2005
Posted by Derek
The Medicine/Physiology Nobel for Barry Marshall and Robin Warren is a fine thing. It's important to realize just how odd it seemed that ulcers could be caused by bacterial infection, when Everyone Knew that they were due to excess stomach acid, no doubt caused by stress and such things. (Check out the retrospectively insane passage from 1967 cited here in an excellent review of the H. pylori discovery. It's a respectable review article with authoritative research showing that over-dominant mothers were responsible for most ulcers. Sigmund Freud has a hell of a lot to answer for.)
H. pylori is the source of almost all ulcers, and is involved in many stomach cancers as well. Infectious agents are now suspected to play a role in many other chronic conditions. The germ theory of disease has become more important than ever in the last twenty years, and these are two of the scientists most responsible.
Marshall and Warren pursued their line of research despite raised eyebrows and dismissive head-shaking, even to the point of ingesting a culture of bacteria to show that it could infect the stomach lining. And they were absolutely correct, as the scientific world came to realize. An important (and encouraging) part of the story is how they were able to prove their case and completely change medical opinion within just a few years. It's good to think about that when people start going on about Dogmatic Intolerant Scientists and Science As A New Religion and so on.
Crazy ideas won't necessarily get you tossed out of the club. Crazy ideas with nothing to back them up will. But just come back with the evidence, and they won't be crazy any more. Show me the religion that takes its heretics and makes them bishops, won't you?
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+ TrackBacks (1) | Category: Infectious Diseases
September 26, 2005
Posted by Derek
The CBC has an article claiming that:
"Formulas for new, inexpensive influenza drugs that could expand the world's tiny arsenal of weapons against pandemic flu are gathering dust because the pharmaceutical industry isn't interested in developing them, scientists say.
They believe governments should fund the testing and development of the drugs, side-stepping big pharma and bringing them to market as cheap generic medications.
And they point to the story of Relenza - one of only four flu drugs currently sold - as evidence public-sector involvement will be needed if crucial new flu drugs are ever going to hit pharmacy shelves. . ."
Which scientists say these things? Well, one of them is Mark von Itzstein, of Griffith University in Australia, who is quoted as saying that he has "three compounds that are ready to be tested in animals and could be available on a commercial basis in three to five years for about $10 a treatment course". You have to get to the end of the article to get to some of the problems with that statement, and some of them never make it to the surface at all.
For one thing, having three compounds that are ready to be tested in animals is not as big a number as it might sound. I've been on projects where many more compounds than that - about ten times more, in some cases - went into animal testing, and nothing still came out the other end. It's good to have compounds that you believe in, but Prof. von Itzstein (who helped discover the drug now sold as Relenza) surely knows, you usually need a lot more shots on goal than that.
Another little detail is that going from this unspecified "animal testing" (efficacy model? two-week toxicity?) to "available on a commercial basis" in under five years is rather unlikely. That's a very, very short time for drug development, and I don't see how all the regulatory requirements could be met so quickly. And having a cost estimate in hand makes it seem as if there's already a bulk synthesis of the compounds, but why would you do that before you've even come close to going into animals?
This all has to do with a Worthwhile Candian Initiative called ICAV, which aims to get more antiviral drugs on the market. I certainly can support that idea, but I think that the people involved will soon find out one reason why there aren't more of them already: antiviral drug development is very hard. There are a lot of disparaging references in that CBC article about the profit-driven drug companies ignoring all these worthy drugs, but then there's this:
"ICAV is trying to get buy-in from governments around the world, starting with Canada. It has asked the federal government for $70 million over seven years to promote development of antiviral drugs for a number of diseases, including influenza, HIV and hepatitis C."
You know, I could have sworn that those indications could all support profitable drugs - if of course, they, like, work and everything. One of the problems with neuraminidase inhibitors like Relenza is that they have to be administered rather soon in the disease's progression, or they're basically useless. That's one reason that they haven't caught on, together with their often less-than-compelling efficacy. But getting antivirals with compelling efficacy is, as mentioned, hard. Those of us over in the profit-driven drug industry can only agree with Prof. von Itzstein wholeheartedly when he's quoted as saying "We need new antivirals." The only thing I would add is just a "good" in the middle of that sentence.
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+ TrackBacks (1) | Category: Infectious Diseases
July 25, 2005
Posted by Derek
In the drug industry, we tend to look down a bit at academia's attempts at pharmaceutical research. We don't go out of our way to hire people with university degrees in medicinal chemistry, for example, which you'd think would be a perfect fit. (Here's why.) And we're always insinuating that the professoriat just doesn't understand what it takes to develop a drug, and what kind of timelines have to be met. I've made a number of comments like that here, and I'll surely make some more.
But I have to admit that it's not always true. There are a few drugs that have come out of academic research, although in all the cases I'm aware of, much of the expensive heavy lifting was done after signing a deal with a pharma or biotech company. (Scroll down to the September 2004 posts herefor more ranting than you may need on the "all drugs come from academic research anyway, right?" position.)
One notable success story has been the antiretroviral Emtriva (emtricitabine), a nucleoside mimic that acts as a reverse transcriptase inhibitor. It was discovered in a longstanding program to find new antiviral agents at Emory, with the chemistry coming from Prof. Dennis Liotta and his group. (Personal disclosure: I nearly went to Emory for grad school to work in Liotta's group, and was strongly considering doing a post-doc with him afterwards. And I've attended his Gulf Coast Chemistry Conference a couple of times as well.)
I mention all these connections, I guess, because word comes now that Emory has cut a deal cashing in all future royalties for a record-setting $525 million dollars. They're selling 65% of the royalty stream to Gilead, the company that markets Emtriva (the orginal deal was done with Triangle Pharmaceutical, a firm of Burroughs Wellcome refugees later bought by Gilead), and 35% to VC firm Royalty Pharma. And the deal provides that the University itself gets 60% of that, with the rest to be split between Liotta, Raymond Shinazi (on the medical side), and former Emory researcher Woo-Baeg-Choi.
That is 210 million dollars to be split between the three of them. My heartiest congratulations, from down here on the floor where I'm fanning myself. I can tell you that if I come up with a winning drug here in industry, I'll likely get promoted, and may well even see a bonus. But I will most definitely not see any seventy million dollars. Maybe this academic model for drug discovery has something to it after all. . .
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+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases
July 17, 2005
Posted by Derek
It's no wonder that there's still so much argument over autism and vaccines. Paranoia is an endlessly renewable resource - big glowing hunks of it are always being dug out of the ground and put to use. For an unfortunately typical example, take a look at this piece from the New York Times. Some fifteen years ago, studies were carried out in New York to determine the safety and efficacy of pediatric doses of the existing HIV medications:
The controversy extends back to a bleak period in New York City history when well over a hundred children a year were dying of AIDS, most under the age of 5. As many as one in every five children infected with H.I.V. were dead by 2, doctors now say; up to 50 percent were dead by 4.
There were no AIDS drugs approved for children in those years. The first AIDS drug, AZT, was approved for adults in 1987. Babies were being abandoned in hospitals, their mothers unable to care for them and with no foster homes available. About 40 percent of the children with H.I.V. were in foster care.
As a result, pediatricians began pressing pharmaceutical companies to let them try drugs shown to work in adults. . .
. . .One center that took part in the trials was a small boarding home for H.I.V.-infected foster children called Incarnation Children's Center, the brainchild of Dr. Stephen W. Nicholas, now director of pediatrics at Harlem Hospital Center. With as many as 24 infected children abandoned in the hospital in 1988, the idea of finding them a home outside the hospital came to him after a young patient greeted him with, "Hi, Daddy."
Working with Columbia University and the Catholic Archdiocese of New York, Dr. Nicholas became the medical director of Incarnation, on Audubon Avenue in Washington Heights, which opened in 1989 and added an outpatient clinic in 1992. Foster children there and elsewhere were enrolled in trials - at first, trials of single drugs like AZT, and later, of multiple-drug cocktails and protease inhibitors, which by 1996 were helping turn AIDS into a manageable, if still chronic, disease.
For his trouble, Dr. Nicholas became the focus of attention from one Liam Scheff, who published a screed 18 months ago on Indymedia (and didn't I groan when I saw that phrase in the article) accusing the Incarnacion facility of forcing poisonous drugs down the throats of innocent children, killing who knows how many in the process, et cetera, et cetera. I should mention that Scheff doesn't think that HIV is likely to be the cause of AIDS, doesn't think that the drugs against it necessarily have done any good, and so on - just so you all know where he's coming from.
Witness now how avalanches start: That Indymedia piece set off a group called the Alliance for Human Research Protection, whose publicity got the New York Post going, which led to a BBC-financed film ("The New York Experiment - Guinea Pig Kids"), which ignited the activists at a Brooklyn-based group that seeks reparations for slavery and whose leader claims (with no apparent evidence) that many of the children didn't even have HIV:
What we know already," he said, "is that 98 percent of the children experimented on were black and Latino and that the fundamental basis of why they chose those kids was racism. They have the arrogance to say it was for their own good, but we know it was racism."
That brought a couple of city councilmen into camera range, and things have continued to deteriorate. At this point, what really happened in the late 1980s doesn't seem to matter much, but for the record:
"Pediatricians involved in the trials say they are mystified by the onslaught. While powerful drugs do have side effects, many said, they remembered no fatal reactions. At Incarnation, Dr. Nicholas said, no child had died of a reaction and "no child ever had an unexpected side effect."
He said that, with one exception, no children had been included in the trials without "absolute proof" by advanced testing methods that they were infected and not simply carrying their mother's antibodies. He said the exception was a trial that proved that by giving AZT to pregnant, infected women and then to their newborns in the first six weeks of life it was possible to sharply reduce the rate of H.I.V. transmission from mother to child. He called that study "the most important clinical trial in the history of AIDS."
Well, yeah, fine - but what about the secret experiments? Evil corporations and secretive government agencies? Racist plots and toxic drugs administered by sinister doctors? What about the good stuff? Hasn't Dr. Nicholas watched any TV, seen any hit movies? Doesn't he know how this country really works?
My heart goes out to him, actually. From all I can tell, he has done the world a real service, and saved more children than could we can count from awful, lingering deaths. For this, he and his co-workers get the Mengele/Tuskegee treatment from publicity hounds and people who've rotted their brains reading Indymedia. What a reward.
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+ TrackBacks (0) | Category: Infectious Diseases | Press Coverage
July 7, 2005
Posted by Derek
I didn't plan on becoming the defender of Abbott's pricing decisions, particularly after that Norvir business in 2004, which I though reflected poorly on them. But these are special circumstances. Since we're on the subject of Brazil and its compulsory licensing threat, I thought it would be worth going to the source. Here, then, is the statement of Brazil's Minister of Health on the matter, dated June 27th. There are some interesting features in it that I'd like to highlight (emphasis added):
"This stage may come to represent the first step for introducing a new phase in our local ARV production. An additional target is to support our national manufacturing industry in this respect, as we are totally committed in maintaining high quality in the medicines available in the public health services.
The Brazilian law allows compulsory licensing in cases of public interest or emergency situations. These are related to issues that involve health, nutrition, protecting the environment, and the technological or sociological development of the country."
Now, much of the rest of Dr. Humberto Costa's statement emphasizes pricing. But I find the industrial-policy aspects rather troubling. How much of this decision is predicated on economic nationalism? We can argue about to what extent Abbott should forgo Kaletra profits in order to help poor Brazilians who are infected with HIV. But should they forgo profits in order to develop the Brazilian generics industry? Here's some more from Dr. Costa:
"In spite of being successful in reducing prices over the period, Brazil still pays exorbitant and unacceptable prices even from the point of view of the full application of capitalist principles."
Wow, even from the point of view of capitalism and everything. . .we've gone about as far as we can go, I guess. How annoying that the antiretroviral drugs have pretty much all come from people who hoped to earn back the immense cost of their development. All I can say to Dr. Costa is: if you think the prices you're paying are unacceptable, you should see what other people have to pay to make up for yours.
And here comes some more capitalism, so get braced: if you go ahead and confiscate someone else's intellectual property, companies will have to factor the chance of that happening again into their future development costs and pricing decisions. And no, in case you're wondering, that will not make prices go down, and it will not make people eager to do more business in Brazil. Not to worry, though: if countries around the world follow your example and seize whatever drugs suit them, eventually there won't be many drugs to seize.
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+ TrackBacks (0) | Category: Infectious Diseases
July 6, 2005
Posted by Derek
Just how much should an anti-HIV drug cost? What if you're selling it in a place where most of the patients can't afford it? These questions have been fought out in Africa and other parts of the developing world over the last few years (and the stagnating world, too, unfortunately.) Now Brazil may be making good on a threat of outright patent confiscation.
The Brazilian government is unhappy with the price of Abbott's combination therapy, Kaletra (PDF), which they already pay just over $100 million per year for. Mind you, that's the lowest price in the world outside Africa. Online pharmacies claim that the average US retail for Kaletra tablets is about $4.06 each, and they offer it at about $3.60. Brazil's paying $1.17, and they're saying that they'll issue a compulsory license if the price doesn't come down to 68 cents.
They've threatened to do this before, but have never come this close to following through. The worry for Abbott is that once the Brazilian generic companies start making the stuff, it'll end up all over the rest of the world at a base of $0.68/tablet. And where do you think demand for it will be strongest? In the countries where it's already the most expensive, which Abbott is counting on for their profits.
Opinions vary a bit, as you'd figure. You can find no shortage of activists cheering the Brazilians on. To wit, from the AP article linked above:
"We are the hostages of these companies, and compulsory licensing is a defense against the abuse of monopolies," said Jorge Beloqui, the leader of a Sao Paulo-based AIDS support group.
Beloqui, a university math professor, has taken 30,000 anti-AIDS pills provided free by the government since 1991. If Brazil breaks the patent, he says, activists will pressure Brazilian politicians to go a step further and let its generic drug makers produce much more of Abbott's drug so it can be shipped around the world to needy patients.
"These medicines are essential to the world, and I think Brazil should sell them," he said.
Actually, Prof. Beloqui is the hostage of a retrovirus, but his comments seem pretty representative of the "stick it to The Man!" point of view. Well, speaking for The Man (to crib a line from Tom Wolfe), I have to say that Brazil seems to be playing to the galleries here. There are accusations that the country is spending less on anti-HIV medications than it did five years ago, and they turned down $40 million in US money not so long ago. There's another problem, too. Brazil is acting according to WTO language about breaking patents in case of a public health crisis. But you have to wonder
Allowing Brazil to use the "public health crisis" justification creates a dangerous and perverse incentive for governments of the developing world: if you as a government are responsible and work hard to uphold a fiscally manageable public health program, then you will be punished by having to pay for expensive drugs, but if you fail or simply ignore the problem and cry "crisis," then you will be rewarded with permission to trample on intellectual property rights.
I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?
Comments (43)
+ TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP
June 30, 2005
Posted by Derek
Gruntdoc wonders about why a particular combination therapy isn't available yet. Skin infections with methacillin-resistant staphylococcus aureus (MRSA), which I hope I never come any closer to experiencing, are treated with one of several antibiotic combinations, but they're all administered as separate drugs.
The answer is what you might suspect: the FDA would want clinical trials of the single-dose combination, just to make sure that things work the way that they're supposed to. Any company developing the combo would have to recoup those costs, not to mention the costs of then beating the drum for the idea that the new combination is a better idea. But the antibiotics in question are generics, which means that there could be some real cost-containment issues over the use of a more expensive combination.
But we have a rather close example at hand: the recently approve BiDil. (Here's the package insert, in PDF format.) That's a combination of two generics, too, which (famously) shows far better effects in the black population than it did in general clinical trials. Nitromed, the developer of the therapy, had to run some pretty reasonable-sized ones, and they spent a lot of money in the process.
They started by establishing that the blood levels of the two drugs were reasonable when given in combination, and went on to a group of 186 male patients. That trial (with 273 in the placebo group) didn't show a benefit, but hinted at one in the black subjects. The company also ran an 804-patient trial against enalapril, and saw the same trend, which led to the definitive 18-month trial in 518 black patients (with a roughly equal number in the placebo arm.) Keep in mind, this is all for two drugs whose individual efficacy was well-studied.
Note added after original post: Nitromed was after something more than the individual efficacy of each drug. Their hypothesis was that the combination would make the blood-pressure-lowering effect much more pronounced, and that this would translate into clinical benefit as seen in eventual mortality. Why this only seems to be the case in the black population is a head-scratcher. The situation for combination antibiotics would be simpler. So. . .
A combination antibiotic trial wouldn't be as long, or as expensive. But it wouldn't be negligible, either, and it's likely that some companies have run the numbers and decided that the investment would be unlikely to pay off.
Comments (3)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Infectious Diseases
June 22, 2005
Posted by Derek
This is the first one of these I've had since I started blogging. It's in response to this recent post, and I thought I'd celebrate by sharing it with everyone:
"You are a shameful individual Mr. Lowe - to make a living in the pharmaceutical industry, whether past or present and then turn around and cast Dr. Rath, who presented clear evidence that his formulations work not only with AIDS but also cancer, as some greedy vitamin pusher when contrasted with the pharmaceutical industry which makes profits over and above 20,000 times the cost of drugs is beyond absurd - it is a baseless slander scheme. You guys may believe you can hide the truth from people, and maybe you might, God will have done what God sees fit to allow, but the day will come when you and your cohorts will have to answer for your lies, deceptions and greed-driven undermining of the health and welfare of many nations - on that Day justice will be served."
Dr. Rath's clinical trials were conducted where, exactly? By whom? With what sorts of controls and in what patient population? And reached what sort of statistical significance against which endpoints? The governments of Switzerland, England, and South Africa disagree with him for what reasons?
Your figure of "20,000 times the cost of drugs" comes from where? Arrived at by what measure? If a drug makes ten billion dollars of profit over its patented lifespan (a mighty fine number, one that most never reach), does that mean, if we divide it out, that the "cost" of that drug was. . .$500,000? On whose planet?
And Dr. Rath's profit margins are. . .what, exactly? The money for his international operation and his high-profile advertisements comes from. . .where?
I'll take my chances with God if and when the time comes, as will Matthias Rath. At least I won't have to explain why I urged thousands of people to forsake the medications that could keep them alive. I can, if I choose to, show my face in South Africa without fear of arrest. Can Dr. Rath?
Comments (38)
+ TrackBacks (0) | Category: Infectious Diseases
June 16, 2005
Posted by Derek
Well, as a comment to Tuesday's post mentioned, no sooner do I talk about the antifungal market than Pfizer turns around and buys a company with a promising antifungal drug. Vicuron has concentrated on antiinfectives in general, which has been a rough place to be over the last ten years or so. Good ideas are hard to find, and if you come up with an amazing new antibiotic, you can expect to see its use restricted as much as possible. And rightly so, in hopes of delaying the onset of resistance. That's good medical practice, but it does tend to put a kink in the sales figures.
Pfizer's deal makes a lot of sense. Their last big new antibiotic ran into trouble a few years ago over side effects: Trovan (alatrofloxacin), another fluoroquinolone. They acquired Zyvox (linezolid), the first oxazolidinone antibiotic, when they purchased Pharmacia/Upjohn, and they still sell an awful lot of Zithromax (azithromycin). But I don't believe that there was much coming along in their antiinfectives portfolio, and they have immediate problems to be fixed. Last summer, Pfizer lost patent protection for Diflucan (fluconazole, which I mentioned the other day), and the patent for azithromycin expires later this year.
The Pfizer deal-makers have been on hiatus recently, but they'll probably keep busy for a while now, because the company is facing even more patent expirations over the next few years. As the clock keeps ticking, Pfizer will probably be forced to go out and buy things before their mighty marketing machine starts sucking air. They're already talking about cutting costs and head count, and I've heard from inside the company that some people there are uneasy about the future. And perhaps they should be - no one's ever tried to have a drug company as big as Pfizer before, and it's not for sure that it's such a great idea. Not everything scales up. Research productivity, for example, may actually have a negative correlation with size.
I've wondered, loudly, for years how they're going to manage. Nothing's made me change my mind. An antibiotic and an antifungal will help, but Pfizer's going to need a lot, lot more.
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+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases
June 14, 2005
Posted by Derek
You want a tough therapeutic area to work in? Try antifungals. There are plenty of problems that conspire to make it a real headache.
For one, fungal infections have a way of binning themselves into two categories, marked "pretty trivial" and "pretty life-threatening." Athlete's foot is a good example of the first one, and coccidioidomycosis is a good example of the second. Actually, that disease shows another form of the trivial/deadly dichotomy. Many people with coccidioidomycosis never realize that they had it, or that they had anything at all. It shows up as a mild cough or cold, and then disappears. But in some people, most especially HIV sufferers or other immune-comprimised patients, it's extremely bad news indeed.
So there are large markets where people aren't willing to pay much to be treated, and a number of much smaller, very desperate markets scattered all over the place. That's a tough situation, and the best thing would be to find a real blunderbuss antifungal that would pitch in for all of them.
And there actually is one, but it's a pretty nasty drug. For the worst systemic fungal infections, though, amphotericin B is basically all there is. It's given intravenously, and you have to keep a close watch on the side effects, which run to things like high fever, vomiting, and kidney damage. A less vicious, orally available drug that works as effectively would be a real advance.
It's not like people haven't tried. Fluconazole and Itraconazole are worthy attempts, but they suffer from their own side effect problems. Check out the general information here, and note, for example, the number of drug interactions. The "conazoles" are notorious for interacting with some key drug-metabolizing enzymes, particularly CYP 3A4, and thus sending the blood levels of other medicines all over the place.
And to top it all off, there aren't that many good drug targets in this area, or at least, not any more. There are companies that have bailed out of the whole field for lack of anything reasonable to do. There's some hope that the sequencing of fungal genomes might lead to some new targets, but that hasn't worked out too well with other organisms, and I include humans in that list. We can always hope.
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+ TrackBacks (0) | Category: Infectious Diseases
June 9, 2005
Posted by Derek
There's a doctor named Matthias Rath who for some years has been taking out big ads in the New York Times and the International Herald Tribune. Rath is a big proponent of megavitamin therapy for just about everything, and by some cosmic coincidence he also has a line of vitamins for sale. No doubt he has a web site and a half, but damned if I'll link to it.
His ads are thunderous, paranoid denunciations of the pharmaceutical industry, the likes of which I haven't seen since the Church of Scientology took off after Eli Lilly and Prozac in the early 1990s. If you want some Instant Rath, take those and add some Lyndon Larouche-level conspiracy theories (for a while there, Rath was all but blaming drug companies for 9/11), and mix well. Season to taste, but if you've really got a taste for this stuff stuff, there's no hope for you.
His latest manifestos have been targeted to South Africa, and they're just what that country doesn't need. Rath rants about antiretroviral drugs being sinister poisons, while apparently everyone could be cured of HIV if they'd just guzzle his multivitamins without pause. The South African activist groups demanding free retroviral drugs are, according to him, tools of the "international drug cartel" that exists in the fevered reaches of his head.
It's hard to know how to answer such otherworldly accusations. Try, for example, the idea of drug companies funding groups who are screaming for their patents to be abrogated and their profits confiscated. I'm having a hard time making the connection. All in all, I'd rather be stuck in an elevator for three days with a dozen Intelligent Design advocates than spend five minutes with Matthias Rath.
South Africa's attitudes and policies toward HIV are enough of a mess already, as those who remember former president Mbeki's handling of the epidemic know. According to an article in Nature Medicine, the South African Traditional Healer's Association has sided with Rath, and a recent press conference from health minister Manto Tshabalala-Msimang featured one of her many endorsements of garlic, lemon peel, and beets instead of antiretrovirals. Meanwhile Rath is lobbying South Africa's parliament directly, amid accusations that he's planning to set up a factory to sell his own vitamin pills.
And meanwhile, at least 20% of South Africa's adult population is infected with HIV. What could be a great nation is threatened with an ugly slide back into the third world, while wastes of good carbon like Matthias Rath spend their time fighting the only known treatments. It makes you wish you could just avert your eyes.
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+ TrackBacks (0) | Category: Infectious Diseases | Snake Oil
May 18, 2005
Posted by Derek
Vertex announced some impressive clinical data against hepatitis C the other day, which has been a fine thing for their stock price. It looks to be a fine thing for people infected with hepatitis as well, with better results than the current interferon therapy in a much shorter time.
I'd have to guess that the side effects are lower, too, interferons being rather powerful things. Schering-Plough and Roche have been beating each other silly in that market for years now - these results point to a future where they might each end up with a much lower market share. (If Vertex's drug works even better in combination with them, though, everyone might still do just fine.)
Other things being equal, or even in the neighborhood of equal, a small organic molecule is going to beat a biotech protein every time. They're easier and cheaper to make, and easier to store and dispense. And as for dosing, well, you can get orally active small molecules (like Vertex's) - try getting an orally active protein, and get back to me when you do. Mind you, it looks like Vertex's compound really has to be taken in mighty quantities (750 mg t.i.d., that is, three times a day), but anti-infectives often have to be hammered in like this. It's still surely going to be cheaper than interferon therapy.
Vertex being Vertex, I'm sure that there's a nice presentation about all the contributions that molecular modeling made to this compound's development. But I've no doubt that their large bunch of capable medicinal chemists made their mark on it, too. Congratulations to the lot of them!
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+ TrackBacks (0) | Category: Infectious Diseases
April 13, 2005
Posted by Derek
This is the 50th anniversary year of the announcement of Jonas Salk's polio vaccine, as you've probably been noticing. There a new book out on the discovery, and plenty of newspaper and magazine articles.
I'll save comment on the vaccine (and Salk himself) for another time. What got me thinking was an incident during the late phases of of the research (which was recounted in a recent article in Smithsonian magazine, taken from the book mentioned above.)
Salk and his team were injecting patients who had already had polio with their vaccine candidates, hoping to show a fresh antibody response. Blood samples were taken after a few days, and the corresponding blood serum was added to a cell culture along with fresh virus and a dye, Phenol Red. If the cells lived - that is, if there were enough antibodies in the serum to inactivate the virus - they would clear the dye color to yellow as the medium became more acidic. If they died, the red color would remain. (This was an assay developed by Julius Youngner. You can see the two colors of Phenol Red here.)
On the morning that the test results were ready for their most promising vaccine candidate, the rack of cell culture tubes showed up completely yellow. There was much celebrating, but Salk finally turned to everyone and said "OK, now let's make sure that we can do it again."
Good for him, I thought when I read that. My fellow researchers will recognize Salk's comment as that of someone who knew his way around a lab. Some of the best scientific advice that you can get is don't trust anything until you've done it at least twice. All kinds of ridiculous stuff happens sporadically, and you'll go crazy if you react to all of it. I've been kicked around like a soccer ball by "N of one" data too many times myself. Nope, don't break out the party hats until the second experiment works, and don't despair until the second one fails.
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+ TrackBacks (0) | Category: Infectious Diseases
February 22, 2005
Posted by Derek
I mentioned yesterday that sometimes you can find an antiviral target that doesn't depend on what the virus itself has to offer. As fate would have it, there are a few drugs coming along that use just such a mechanism against HIV.
They're based on their affinity toward a protein called CCR5, which sits straddling the outer membrane of some types of cells. It's one type of receptor protein, whose lot in life is to latch onto specific other molecules if and when they come by. Our lot in life in the drug industry is to make small molecules that bind to them - the various kinds of receptors are hugely important drug targets. (For those outside the field, briefly, part of a receptor stays on the outside of the cell membrane, and part of it loops to the inside. When a molecule binds to the outside loops, that binding event changes the shape of the whole protein and sets off a signaling cascade in the cell, which signals can be tied into just about every cell process you can think of.)
In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.
This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. But "quick" is a relative term in the drug development world. I think that the relevant chemical series were found to bind to CCR5 somewhere around 1996 or 1997. The projects at the different companies took off from there - and here it is 2005, and we're starting to begin to talk about something getting close to being submitted for the FDA's consideration. The thing is, that's not a slow calendar at all. It's normal to fast, unfortunately for all of us.
Schering-Plough (whose preclinical research team included several former colleagues of mine), GSK, and Pfizer are in the lead in this area, with several other companies also taking a crack at it. Early clinical results were promising, and we should be hearing more soon. Here's hoping that they all work.
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+ TrackBacks (0) | Category: Infectious Diseases
February 21, 2005
Posted by Derek
If avian flu does gain a foothold in humans, what can drug companies do about it? (This should give you the latest headlines on the disease.) It's definitely something to worry about. There hasn't been a real rampager of a flu epidemic in a long time, and a pessimist would say that we're overdue.
The answer to my question is "Work on a vaccine!" Because if you rephrase it and ask "What can people like this Derek Lowe guy and his hotshot medicinal chemistry buddies do?", the answer is "Not much." It's not a widely appreciated fact among the public, but we have hardly any drugs that affect viral diseases. The disease with by far the largest number of therapeutic options is HIV infection, and if you find that an unnerving thought, you should.
The problem, as I've mentioned before, is that viruses don't give you much to work with. They have very small genomes, and thus code for a bare-bones set of proteins. Since those are generally what we'd attack, we're often at a loss to find a good drug target. Sometimes you can find a target in the human cells that the virus attacks, but that takes a lot of basic research into the infection process.
And even if we find a target, we're years away from a drug. Getting a chemical lead structure, optimizing it, making sure that it actually does some good (and doesn't do a corresponding amount of harm!) - it's a terribly slow process. And it's remained that way despite hundreds of millions of dollars waiting to be picked up off the ground by the first company that can shorten it. The incentives are there; the technology isn't.
That time scale probably won't be much use if we get into an epidemic one of these years. The virus will outrun us. The best thing we can be doing now is learning everything we can about the whole class of H5N1 influenza viruses and how to make broadly active vaccines against them and their combinations with human agents. Prevention, monitoring, and immunology are going to have to save us if we get into trouble. Because though it pains me to say it, people like me aren't going to be able to help.
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+ TrackBacks (0) | Category: Infectious Diseases
August 19, 2004
Posted by Derek
Yesterday I was writing about a proposal to encourage new antibiotics, partly by not putting so much effort into discouraging the use of the current ones. The economist who's advocating this, Paul Rubin, also would like for the FDA to consider accelerating the approval process (and at the very least, not making it even harder than for other classes of drugs.)
I like the sound of that part, as you'd guess, though always with a nervous look up in the sky for the circling silhouettes of the product-liability attorneys, whose razory talons were the subject of yesterday's post. But there's another problem with just stepping out of the way of the new antibiotics: there aren't very many coming through.
Many companies have been scaling back their anti-infectives research over the last few years, and I don't think that the regulatory environment is the main reason. The whole therapeutic area is rather target-poor. We've exploited the obvious vulnerabilities of bacteria, thus the -cillins and -sporins, the fluoroquinolones and the erythromycins. Extended searching hasn't turned up many more modes of attack, at least not of that quality. The most recent new class of antibiotics that I can think of are the oxazolidinones, but resistance to the first one is already showing up.
Here's a rundown of newer antibiotics (the situation hasn't changed much since this appeared.) Note that most of the things on this list have been known for a long time and are being re-examined, or are improved versions of things we already have.
I know where Rubin is coming from - drug resistance wouldn't be as much of a problem if we had a steadier stream of new antibiotics with new mechanisms of action. But I don't know if we can hold up our end. Providing incentives by loosening regulatory requirements could persuade some companies to get into the hunt (or stay in it), but the hunt itself is the real limiting factor. It's not a good situation, and I think that we in the industry are kind of at a loss as to what to do about it. . .
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+ TrackBacks (0) | Category: Infectious Diseases
August 18, 2004
Posted by Derek
Forbes has an article on some recent work of Paul Rubin, an economist at Emory. He's looking at the situation in approvals of new antibiotic drugs, which isn't an encouraging sight.
He's of the opinion that too much government effort has gone into cutting overuse of the existing drugs (to try to slow down the development of resistant bacteria) and not enough has been done to make new drugs easier to bring to market. The use of antibiotics in general is being discouraged, and at the same time the FDA has made the regulatory environment for new submissions tougher. A quote:
". . .the FDA policy of requiring additional testing for antibiotics is a fairly bizarre policy and makes no sense. . .A much more cost-effective alternative would be to approve the drug in the normal manner (or even provide an accelerated approval) and spend additional resources on...post-approval surveillance."
He's probably right about this, but (and here's the usual problem) it makes sense only if you ignore the tort lawyers. If your new antibiotic goes out and causes trouble in some subset of the patient population, it's no use telling the attorneys that, hey, the FDA approved it. They're not going to get money out of the FDA; they're going to get it out of you. Nope, it was your willful, stupid, perverse, dare I say evil negligence that led to this completely avoidable tragedy, and. . .aargh, you can write the rest as well as I can.
That's the thing: the FDA requires that we show safety and efficacy. We can prove the presence of efficacy, but safety is merely the absence of harm. No one can prove a trial lawyer's definition of safety. A clinical trial can tell us that in the population that participated in the trial, X adverse events took place. Whether X is a greater or lesser number than we'd expect in the general population is a question that can be answered statistically, but whether our drug caused those X events isn't a question that can usually be answered at all.
In such cases, our best chance is to see if the affected patients had something in common, or if the problem increased in proportion to the dose. Often enough, neither is the case - does that make the compound safe, or not? Even if there weren't any signs during the trials, what will happen when our drugs hit the orders-of-magnitude larger population of paying customers? We don't know. We can rule out what our clinical trials were powerful enough to see, but we will never see the one-in-fifty-thousand kinds of trouble. Not until the lawsuits start flying.
There's yet another problem with Rubin's argument, scientific rather than regulatory, which I'll address tomorrow. . .
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+ TrackBacks (0) | Category: Infectious Diseases
April 13, 2004
Posted by Derek
You've probably heard of the hypothesis that a reasonable amount of dirt is good for you, especially in childhood. (My kids are certainly taking no chances.) The idea is that the immune system needs a certain amount of challenge to develop properly, so trying to live too antiseptic a life is a mistake. I think that this is very likely correct, and it turns out that it's especially correct if you're a zebrafish.
Not many of my readers are zebrafish, at least as far as I can tell from my referral logs, but they're an influential demographic. Danio rerio isn't as well known outside biology as say, the fruit fly, but it's a workhorse model organism for vertebrate development. Zebrafish are small, fast-growing, and the embryos are nearly transparent in their earlier stages. (Xenopus frogs share these characteristics, and have their partisans, too.)
The March 30th issue of the Proceedings of the National Academy of Sciences, with a Warholian zebrafish cover, features a study from Washington U. where the fish were raised under strictly aseptic (gnotobiotic) conditions. That's not easy to do, but if you make absolutely sure that no bacteria are present, it turns out that the embryos don't even develop properly. The defects are in the gut, which makes a lot of sense.
It turns out that colonization by normal intestinal flora is vital - zebrafish and their bacteria have become evolutionarily entangled. The bacteria actually induce some crucial gene expression by their presence, and the developmental program just doesn't have an aseptic default setting. There hasn't been an aseptic zebrafish since the beginning of biological time.
OK, these guys swim around in tropical pools, floating in a bacterial soup. But we're floating in one, too, just at a slightly lower density. Every part of a human body that can be easily (benignly) colonized by bacteria already is. Are there similar developmental effects in man? It wouldn't surprise me at all. No one's going to be running that exact embryo experiment, needless to say, but there are probably ways to sneak up on the answer using cell cultures. There's never been an aseptic human baby, either. . .although this is enough to make a person wonder about situations where a pregnant mother has had to take a long course of powerful antibiotics.
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| Category: Biological News | Infectious Diseases
March 7, 2004
Posted by Derek
I see that Steven den Beste linked to me as a general source of med-chem info, which was good of him. He was discussing resistance in treatment of tuberculosis (on the way to a broader point about current events), so I thought I'd say a few words about antiinfective drugs.
As I've mentioned in the past, it's not an easy area. At least, not any more. This was one of the first frontiers for medicinal chemistry (think Salversan for syphilis, sulfa drugs, penecillin and so on.) But it's clear that no one realized the long-term consequences of the free use of those early drugs. And even if they had, I doubt if much would have changed. There wasn't much incentive for restraint, not when people who were marked for death suddenly getting up and walking around.
It's easy to forget how serious infectious disease was back then. People are horrified now when there's a death like, say, Jim Henson's: a rampaging septic reaction that kills within a few days. But go back a hundred years, and that sort of thing happened all the time. Earaches could kill you, things that we'd consider bad colds might end up killing you. A toothache could signal that the end of your life was a week or two away. No, once drugs came around that could fight this sort of thing, no one felt like holding back.
But now we've burned out a lot of the easy targets. There are, broadly, two classes of drug targets against bacteria and other infectious agents. The first are enzymes and pathways unique to the pathogen, and those are naturally the best. Penecillin and all the related drugs fall into this category. They mess up the synthesis of the bacterial cell wall, leaving the affected organisms naked to the world and thus easy prey for the immune response. Cells of higher organisms don't make such walls, so you can beat on that pathway all day long without much risk.
The second group are targets that are present in humans as well, but with enough variation in the protein that you can hope for a selective compound. This takes more work, most of the time, and sometimes you can't separate the activity enough to be useful. Many bacterial enzymes are distant cousins of their human equivalents, but many others are too close to work against.
And with either class of drug, you have resistance. That's what they didn't appreciate in the early decades - and if they did, they underestimated it. Bacteria have such short life cycles, and there are so many of them. They're an ideal laboratory for evolution, and when humans came in and put the selection pedal down, the changes started and haven't stopped.
One common mechanism is for the target protein to end up mutating. There's a good amount of genetic variation in the bacterial population, and some of the group you're trying to hit might have a form of the protein that doesn't bind your drug. Given enough bacteria or enough time, there are bound to be some. So you treat with the drug, everyone else dies, these naturally resistant organisms have the whole field to themselves, and they run wild.
Sometimes the bacteria whip out another protein to take care of your drug all by itself. That's what happened to penicillin. Some bacteria turned out to have an enzyme to defend against such compounds (which are, after all, found in nature as antibiotics.) The enzyme, beta-lactamase, cleaves the crucial four-membered ring at the heart of the whole drug class. Naturally enough, this enzyme is all over the place now. (Thus the drug Augmentin, which contains a penicillin derivative and another drug, clavulinic acid, which inactivates beta-lactamase. But as you could guess, organisms have appeared whose beta-lactamase isn't affected by it.)
Yet another resistance mechanism is an active-transport pump. These are membrane-spanning proteins that physically expel the drug molecule once it enters the bacterium, pumping it right back out before it can do its job. (Cancer cells do the same thing, by the way.) What makes all of these such a problem is the habit many bacteria have of swapping DNA segments like trading cards. It's hard to measure, but I'm sure that over the years we've selected for accelerated DNA transfer. Under stress, the active traders have an edge, since they have a better chance of swapping in some DNA to code for the necessary inactivating enzyme or pump.
It's a battle. And from all appearances, it's never going to end. We're fighting tenacious, adaptable organisms that pull out all the stops all the time. They don't sit around fretting about the younger generation and their DNA-swapping ways, or worry that they're losing their essential staphylococcusness by taking on all these new characteristics. There are no spirochetes grousing that an arginine at that position was good enough for their granddads, and it's good enough for them. No, they'll do whatever it takes. It's life or death for them. Just like it is for us.
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| Category: Infectious Diseases
September 2, 2002
Posted by Derek
There's a rather weird legal fight going on between Glaxo SmithKline and the rest of the world. Like everyone else, GSK is fighting to hold on to profitable drugs that are losing patent protection. A lot of. . .creative. . .arguments are being deployed in these efforts, and I can't figure out if this is one of them or not.
The drug is Augmentin, which is actually two drugs in one. (For those readers old enough to remember it, you can now cue up the voice-over to the old Certs ad.) The antibiotic ingredient is plain old amoxicillin, a beta-lactam warhorse that's been generic for a long time now. Unfortunately, plenty of bacteria can chew right through amoxicillin and others of that era. I mean that literally: they use an enzyme called beta-lactamase to break open the four-membered ring at the core of all the penicillins.
That's where the second ingredient comes in, clavulinic acid (actually, its potassium salt.) It's a natural product that has a roughly similar structure, similar enough to fit into the active site of the beta-lactamase enzyme and gum up the works. Using the enzyme inhibitor leaves the amoxicillin free to do its work, and the combination is quite effective.
Well, amoxicillin you can order by the drum. But clavulinic acid is another matter. It's not economical to synthesize, not from the ground up (and neither are the beta-lactam antibiotics themselves, for that matter.) All these compounds are made (at least partially) by fermentation, which is just short of being a black art. You have to find strains of organisms (fungi for the 'cillins, bacteria for clavulinate) that produce unusually high amounts of the material, and you have to make them do it reproducibly. That means keeping them happy, but not so happy that they decide to give up the hard biochemical work of synthesizing your compound. And you have to find a good way to purify your stuff from the reeking fermentation broth - ideally in a continuous-feed mode so you don't have to run batch after batch. It's not trivial.
Perhaps you can guess where this is heading. GSK claims that they spent a lot of time and money developing a particular bacterial strain that produced clavulinic acid better than anything else known. And they're now claiming that some of these bacteria walked out of their facilities and are being used by their competitors (specifically Novartis as well as the generic companies Ranbaxy and Teva.) They seem to have a particular employee in mind, and a particular transaction history for the theft.
Problem is, that all happened starting in 1988. You wonder why GSK sat back for this long if they knew all this. . .and there are generic Augmentin formulations in Europe which don't figure into the suit. How'd they make their clavulinic acid? You do have to wonder if this isn't a desperation move.
On the other hand, this sort of theft isn't unknown. About twelve years ago, a New Jersey drug company had a former employee walk out with some of their engineered bacteria, which he later tried to sell to at least one small biotech outfit. They went to the Feds. The employee was caught on tape, thinking that he was selling the material to a Middle Eastern government, when he was really selling it to the FBI on two camera angles.
So GSK could be on to something, too. It'll be fun to watch.
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+ TrackBacks (0) | Category: Infectious Diseases | Patents and IP
August 8, 2002
Posted by Derek
Roche and their partner, Trimeris are developing an anti-HIV compound (called T-20) that has some remarkable features. It's the first to target a cell protein (gp-41) that is a key binding step in HIV's mode of infection, for one thing. But to be more precise, it has 106 more interesting things about it - that's the total number of synthetic steps in the manufacturing process.
My synthetic-organic readers are probably saying just what everyone in the field does when they first hear about that one - it's usually a variation of "no (procreating) way," followed by laughter. Those of us who've done natural product synthesis get the shivers, remembering those 20- or 30-step build-the-pyramids projects from our pasts. Trying to extrapolate those experiences up the asymptotic curve of awfulness to 106 steps is a scary exercise.
Fortunately, the compound is a peptide (36 amino acids,) which means that the chemistry is well-established and can be done largely by machine. It also means that you don't do all 106 steps in a row. Well, you could try, if you had a good excuse like having had a big recent dose of LSD or something, but it's not recommended.
For starters, it probably wouldn't work. Peptide synthesizers work by hanging one end of the chain off a solid resin support. As the molecule gets longer and snakier, it tends to ball up on you. Eventually, the far end, the one that is getting new amino acids added to it, isn't sticking out into the solution any more, but is tucked back into its own folds. End of synthesis, by default. The second problem with having that many linear steps is a mathematical one. A to-the-hundredth-power term in an equation is a bomb waiting to go off, and if your synthetic yields aren't just about perfect, you're going to be in bad shape.
For example, if every step works in 95% yield (which would be a mighty fine result across 106 steps,) then you're going to come staggering across the finish line with a 0.4% overall yield. What if you average an 85% yield? Admittedly, a peptide synthesizer will beat that, but it had damn well better, because that pace will leave you with 3-millionths of a percent yield. Ugly things, those exponents.
Roche, not being a gang of idiots, will certainly be making T-20 in small chunks, then stitching those together. The tricky part is figuring out where to break up a molecule that size. What combination of fragment assembly schemes has the best chance of high reproducible yields? The life expectancies of humans being what they are, you can't try all the permutations and pick the best. Some educating guessing using known pitfalls of protein design has apparently given them a route that works.
But it's going to be a honker of a synthesis, no matter how well it goes, because it's going to have to be done on monstrous scale. Peptides, as I never tire of pointing out, have every chance of making crappy drugs, and this is worse than most. You can't take a 36 amino-acid peptide orally and expect much to happen; your digestive tract will rip it to shreds like it does every other protein. T-20 has to be injected, twice a day, 100 mg per shot. Roche is going to have to make thousands of kilos of this stuff, which should handily break any records for peptide synthesis. It already looks like it'll be tough, at least at first.
While T-20 works quite well, it's going to be extremely costly to produce. Roche has reportedly already spent nearly $500 million on the manufacturing facility in Colorado. T-20, then, is also going to be extremely costly to take. There's room to doubt how long it'll take to pay off, especially for Trimeris. If resistance to the drug shows up ahead of expectations, it could never pay off at all. (The companies are developing some related peptides that might get around this problem, which is a good strategy.)
I'm still in awe of the decision to go ahead with this drug. It's a major risk, and I can only hope that it has major rewards for both the patients and the companies. And I can also be glad that I'm not having to keep those peptide synthesizers out in Boulder stocked with solvents!
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+ TrackBacks (0) | Category: Infectious Diseases
July 17, 2002
Posted by Derek
The business news has been on top of the science news recently, that's for sure. Maybe we can go a week or so without accounting issues, mergers, and whatnot.
I wanted to call people's attention to a good article in July 8 issue of The Scientist (free, but registration required.) It's a history of a recently developed vaccine for the common bacterium Staphylococcus aureus, a common cause of adventitious infections and septic shock. "Recently developed" isn't too accurate, though, since the research has been going on since the mid-1960s.
I won't go into all the twists and turns of the story, but there are plenty of them. At every step, there were good reasons to think that the entire idea wasn't going to work. Some of these were: Staph aureus doesn't have a polysaccharide capsule, need for a vaccine - wrong. The ones that people cultured didn't have much of one, but the real-world organisms do, of a tricky and complex kind. You can't raise good immunity to that kind of polysaccharide, then - wrong. It took some doing, but an antibody response was seen. OK, but they won't be protective, because people have them already - right, but wrong, for various intricate reasons.
The end result was reported earlier this year in the New England Journal of Medicine, showing a statistically significant decline in S. aureus infections in dialysis patients who received the vaccine. It wasn't a knockout blow, but it was pretty effective for something that was long thought impossible. More trials are underway.
I'm not beating the drum for the vaccine (although I wish it, and its licensee, a company called Nabi, well.) I am beating the drum for sticking with projects through bad patches, as long as there are experiments to run that can get you out of them. There's no point in flogging a project that's come to a dead end, of course, and there's always some useless thing you can think of to try to keep working. But I'm talking about definitive experiments. You should never give up until you've run the best make-or-break tests you can think of.
It's a truism in the pharmaceutical industry that every great drug project has come close to dying at some point. This vaccine effort faced termination more than once, but stayed alive because it passed crucial tests at the crucial times. Maybe having near-death research experiences is actually helpful. They concentrates the mind on key data and key experiments, on the stuff that could be the most convincing evidence to keep things going.
Many projects come to those points and fail, of course. But the projects that I'd mourn are the ones that got killed off before they even got a chance to redeem themselves. Most of them would have failed, as well. Most projects do. But some of them could have been contenders.
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+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
July 11, 2002
Posted by Derek
The big science story at the moment seems to be the SUNY-Stonybrook polio virus synthesis.
To tell the truth, I thought this sort of experiment had already been done. I'm not at all surprised that it worked, and only a bit surprised that it worked as well as it appears to have. Viruses (especially the smaller ones) are rather simple things. Synthesizing the needed genetic material isn't a big obstacle (easier, again, for the smaller viruses.) The Stony Brook team worked out a good system to go from the naked RNA of the polio virus to functioning viruses themselves, and that step is to me the main novelty.
Anyone who uses this as a platform to rant about creation of life is going to have to defend the notion that viruses are alive. And that's a tough one - how can something that doesn't eat, doesn't excrete, and can be disassembled and reconstituted count as alive? A virus is a little von Neumann machine, emphasis on machine.
Using this as a platform to rant about bioweapons is a bit more excusable. The sequence of polio virus has been a matter of public record for a long time now, though, and the road to this experiment could have been taken by any number of competent researchers. Here is a report from 1997 pointing out that very thing. The report (from Columbia U) stated:
"Even if total virus destruction could be accomplished, the small size of the poliovirus genome, whose sequence is known and whose complementary DNA is infectious, would make it possible for a terrorist to synthesize a new stock."
That's five years ago, folks, which is a long time in molecular biology. If this experiment serves to show people how hard containment of knowledge is, then the lesson has been worthwhile. Since genies don't go back into their bottles, it's better if we find out all we can about the ones that are running around.
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+ TrackBacks (0) | Category: Infectious Diseases
March 20, 2002
Posted by Derek
As I mentioned yesterday, Viropharma's compound Picovir (pleconaril) was turned down unanimously by an FDA panel. This could be the end for an interesting compound that's been kicking around for many years, going back to the days (1990 or so) when Sterling-Winthrop still existed as a drug company.
Kodak took over Sterling in 1988, looking to get into the high-margin drug industry (they already had a chemicals business, the Eastman side of things.) As it turned out, you couldn't have paid a gang of saboteurs to do a worse job running Sterling, and the whole deal was a costly disaster that lasted some six years. The pieces of Sterling were sold off (at a mighty loss) to the French firm Sanofi, among others. During the chaos, some of the Sterling people left to form Viropharma, negotiating with Sanofi for the rights to pleconaril.
It's an interesting compound, with a mechanism that (to my knowledge) isn't shared by any other antiviral candidate. It binds to a site on the surface of the virus, keeping it from infecting cells. Viropharma kept plugging away at it, trying it out for meningitis and respiratory infections, but without notable success.
The last couple of years were a particularly wild ride. If you go back and look at the stock chart, you can see a huge run-up, followed by an equally hair-frizzing decline. What happened was some media reports in December of 1999 convinced various clueless investors that VPHM had, yes, the cure for the common cold. That was indeed what Viropharma had started trying pleconaril against, the meningitis data having proven unimpressive. The compound was far from a miracle cure.
But try telling that to the notorious stock promoter Tokyo Joe. Remember Joe? Viropharma stock was one of his calls during this period, and his people piled into it hugely, followed by a swarm of tag-along momentum players. They had a real fiesta for a while there, but NASDAQ was in all-fiesta mode back then, anyway.
Momentum investing means, of course, buying stocks just because other people are buying them. It's the Bigger-Fool theory in action, and it's always struck me as similar to the way some jackrabbits dart in front of 18-wheel trucks. (This is coming from someone who shorted Imclone at what turned out to be their low point, so I'm no stranger to risk.) In this case, the 18-wheeler appeared in the form of new clinical data showing that pleconaril wasn't particularly effective against colds, which led to the roll-off-the-table section of the stock chart.
I'm happy to say that I was short VPHM when that happened. Of course, I'd shorted them at about 50 and promptly watched the stock jump like it had been hit with a cattle prod, right up over 100, and mighty quickly, too. Swallowing hard, I shorted some more. I just couldn't see the drug working that well based on the clinical data the company had already shown. Meanwhile, Tokyo Joe's people on the stock message boards were already making VPHM out to be the next Pfizer. That's a quote from some guy - another table-pounder kept going on about how you'd have liked to have bought into penicillin in 1940, wouldn't you? Right? Here's the chance of a lifetime, again! Some other maniac saw the compound as basically the savior of the human race. Then the bad news hit. I'd like to have a videotape of me trying to dial my broker right after I saw the stock quote that morning (down 43 5/8 or something like that.) I kept missing the buttons on my phone; it took three tries before I successfully dialed my broker to take my profits.
The data that came out of those studies helped keep the compound from being recommended yesterday. Pleconaril, taken three times a day, starting very early in the course of a cold, reduces the duration of cold symptoms by a day or two. And that's about it, and that's just not enough. That's an awful lot of drug to load your system with for a relatively minor disease, and it would presumably involve spending a fair amount of money that an HMO might not be keen on reimbursing.
Viropharma kept making their case, of course. One point was that dosing with the drug reduced what's descriptively called "virus shedding," which could make you less infectious to others. To the best of my knowledge, no clinical data was ever collected to put that idea to the test, though. They got a big company to buy into the compound, namely Aventis (known to longtime pharmaceutical people by its heritage, as Hoechst-Marion-Merrel Dow-Roussel-Rhone-Poulenc-Rohrer, which sounds like a white-shoe law firm.)
But, in the end, the combination of lackluster efficacy with some extra safety concerns (possible interactions with the menstrual cycle in a few women, for example) doomed the compound. The effects they saw would have meant nothing for a compound that treated, say, pancreatic cancer, which is otherwise a death sentence. But for a cold?
To their credit, you can see that Viropharma realized all this. That's why they started trials on viral meningitis. When that didn't work out, they went to serious respiratory infections. No dice. Finally, they were left with colds. They did the best with what they had, but it wasn't enough.
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February 26, 2002
Posted by Derek
Megan McArdle points out the recent news (which has shown up in Tuesday's NY Times and other outlets as well) about new HIV treatments with possibly fewer side effects. She asks if the same technique can be applied to other diseases, and I thought for the benefit of the non-pharma audience that I'd go into some detail on that.
Actually, there's no particular new technique involved - just good ol' drug development. These compounds work by different mechanism than the stuff we've had so far. Here's a (fairly) quick explanation, centering around one of the therapies highlighted in the press reports, the one from Schering-Plough.
The specific target of that compound is a protein called CCR5, which sits straddling the outer membrane of some types of cells. Part on the outside, part loops to the inside. It's one of a huge class of proteins called receptors, whose lot in life is to latch onto specific other molecules if and when they come by. When they do, that binding event sends a signal into the cell, and these signals can be tied into just about every cell process you can think of. This is one general way that you can enable some molecule floating outside the cells to set off changes inside them.
The subject, like most molecular pharmacology, rapidly reveals its career-worthy godawfulness on closer inspection. All those things in the above paragraph vary hugely and interrelatedly. To give you an idea, various receptors are a key step in the actions of things as important (and as unrelated) as insulin, cocaine, growth hormone, and caffeine. They're still counting up how many different receptors there are from the human gene sequences, but it's probably going to be in the low thousands when the dust settles.
In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.
This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. So far, it seems to work, and congratulations to the Schering-Plough team for it. Although I haven't talked to them about it - not that they'd tell me anything, either - I know several of the chemists who worked on this project. They and their biology colleagues deserve the success.
But will this lead to a marketed HIV drug? Good question. It's obviously made it through the animal toxicity testing I spoke about the other day, because the compound has shown efficacy in humans. Those are both big steps. Now come more studies, with more patients, to make the case to the FDA. It's not an early-stage drug any more, and the odds are fairly good that it'll make it, but there are still several places where it could banana-peel and slip off the tightrope.
If it does, will it have fewer side effects than the protease inhibitor cocktails? Another good question. Right now the only thing you can be sure of is that the side effects will be different. All drugs, every single one of 'em, have side effects. Some are major, some are minor, and some are minor only relative to the disease that's being treated. Since this doesn't work on HIV protease, it presumably will avoid the problems of those drugs, which is good news. But there could always be others out there waiting.
There could mechanism-based tox, for example. We really won't know until larger, longer trials are conducted what might happen when you block CCR5 for an extended period, what happens when you block it while you're taking other drugs at the same time, or if there's some subset of the patient population that will react unusually.
Or there could be non-mechanism-based tox, which is what happened with the protease inhibitors: keep in mind that (when the research began) no one expected the body-fat remodeling and the other side effects of that class. Those seem to have nothing to do with blocking HIV protease, and arguments rage as we speak about what causes them. Is there some other protease that you can't avoid hitting when you go after the one in HIV? Could be. Is there some totally unrelated thing with (by sheer bad luck) a similar-looking binding site, so that most anything that binds HIV protease will hit it, too? Can't rule it out.
None of these arguments are specific to the HIV therapy field, of course. Investigative drugs go down the tubes all the time for just these sorts of reasons. And sometimes even the large trials aren't enough to catch bad side effects that occur at very low frequency, and you get the serious bad news after the stuff has gone to market. That seems to be what happened with the diabetes drug Rezulin (troglitazone,) and it's not the only example. When that happens, so many lawsuits start flying that it looks like it's snowing.
Am I a gloomy researcher or what? Nah, just realistic. I'm actually fairly perky most of the time, so I'll end on an optimistic note:. What we have now are some new ways to treat a terrible disease. The more routes of attack we have, the better. Along the way, we're learning a lot that can help out in other fields as well. The great thing about drug discovery, about science in general, is that nothing's ever really in vain, and no good work is ever really wasted. It all adds up, and keeps adding up. And what we're building, I truly believe, is the greatest work of the human race.
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