Act Now, Supplies Are Limited
May 5, 2009 5:26 PM Subscribe
Raptiva, an immunosuppressant used to treat severe plaque psoriasis, caught the attention of the FDA as triggering the activation of the John Cunningham virus. Present in 70% to 90% of human beings, the virus, once activated, inflames the white matter of the brain - a condition known as progressive multifocal leukoencephalitis (PML) - which has no cure and is almost always fatal. Although the FDA recognized the link between Raptiva and PML last autumn, it wasn't until last month that Genentech, the manufacturers of the drug, issued a voluntary withdrawal, and even then, are still allowing people who use Raptiva to continue to get refills until June 8.
When you're immune system is taking you apart in it's spare time, you're probably a lot more willing to take chances. TNFα antagonists will also scare the hell out of you, but if you were spending your life on your back in pain, it might not seem like too much of a risk.
It's the immune stimulants that scare me, but they're mostly designed for things that are busy killing you anyway like metastatic melanoma (that one died in phase three).
posted by Kid Charlemagne at 5:44 PM on May 5, 2009 [1 favorite]
It's the immune stimulants that scare me, but they're mostly designed for things that are busy killing you anyway like metastatic melanoma (that one died in phase three).
posted by Kid Charlemagne at 5:44 PM on May 5, 2009 [1 favorite]
At least it's somewhat more likely that someone taking Raptiva for Psoriasis will recognize early symptoms of PML.
Multiple Sclerosis was the indication for which Tysabri was approved. The scariest thing about the Tysabri PML link was that the initial PML symptoms could be mistaken for a particularly bad MS exacerbation.
posted by Pliskie at 6:00 PM on May 5, 2009
Multiple Sclerosis was the indication for which Tysabri was approved. The scariest thing about the Tysabri PML link was that the initial PML symptoms could be mistaken for a particularly bad MS exacerbation.
posted by Pliskie at 6:00 PM on May 5, 2009
Yeah, and Tysabri is back on the market.
That's not really fair, assuming I'm reading your subtext properly. I believe something like 7 people have gotten PML while taking Tysabri. Out of something like 50,000. Given that Tysabri appears to be the single most effective treatment for multiple sclerosis, those don't strike me as bad odds at all.
I'll be pissed if the FDA pulls Tysabri unless the risk of developing PML turns out to be a lot higher than it appears to be. 7 out of 50,000 is a pretty decent risk/reward ratio for a serious disease.
posted by Justinian at 6:04 PM on May 5, 2009 [2 favorites]
That's not really fair, assuming I'm reading your subtext properly. I believe something like 7 people have gotten PML while taking Tysabri. Out of something like 50,000. Given that Tysabri appears to be the single most effective treatment for multiple sclerosis, those don't strike me as bad odds at all.
I'll be pissed if the FDA pulls Tysabri unless the risk of developing PML turns out to be a lot higher than it appears to be. 7 out of 50,000 is a pretty decent risk/reward ratio for a serious disease.
posted by Justinian at 6:04 PM on May 5, 2009 [2 favorites]
Yeah, I was curious about the rate of PML in Raptiva patients. This is what turned up in a quick search. This drug brought in 108 million dollars in 2008, if I recall correctly. Which might just cover the lawsuits.
Here is a timeline.
posted by Xoebe at 6:27 PM on May 5, 2009 [1 favorite]
Here is a timeline.
posted by Xoebe at 6:27 PM on May 5, 2009 [1 favorite]
When you're immune system is taking you apart in it's spare time, you're probably a lot more willing to take chances.
Absolutely, people who have severely disabling/disfiguring psoriasis or psoriatic arthritis may quite rationally conclude those risks are well worth it.
What worries me is the (purely anecdotal) sense that immunosuppressants in general, like so many heavily marketed pharmaceuticals, are possibly being WAY overprescribed. For about the past decade, my psoriasis has been ludicrously mild and easily controlled, practically non-existent. But for two years, my DIP psoriatic arthritis, which first cropped up when I was 12 and then more or less subsided, has become rather active. However, the worst you could call it is moderate. And yeah, since not only my day-to-day activity and hobbies but my profession depends on manual dexterity, I'm having to make adjustments and am bit by bit encountering more noticeable deficits.
The thing is, I am absolutely not an appropriate candidate for Humira, Enbrel or methotrexate, but when my psoriasis-specializing dermatologist learned that the rhematologist had prescribed the boring old-school hydroxychloroquine (which seems to be mainly holding off the inevitable progression for now), he scoffed and said I should just go straight to Humira, which is apparently his go-to utility player these days -- and he is quite a reputable, veteran practitioner, not some fly-by-night goofball.
Oh, really? You seriously think I'm going to take intravenous meds whose known side effects include, oh, lymphoma just because my fingers are chronically painful and fucked up? It's one thing to roll the dice on this scarifying if miraculous stuff because you're in a very bad way, but dermatologists ought not to be passing out major immunosuppressants like Pez, at least not until after they've at least explored the more conservative approaches.
posted by FelliniBlank at 6:35 PM on May 5, 2009 [7 favorites]
Absolutely, people who have severely disabling/disfiguring psoriasis or psoriatic arthritis may quite rationally conclude those risks are well worth it.
What worries me is the (purely anecdotal) sense that immunosuppressants in general, like so many heavily marketed pharmaceuticals, are possibly being WAY overprescribed. For about the past decade, my psoriasis has been ludicrously mild and easily controlled, practically non-existent. But for two years, my DIP psoriatic arthritis, which first cropped up when I was 12 and then more or less subsided, has become rather active. However, the worst you could call it is moderate. And yeah, since not only my day-to-day activity and hobbies but my profession depends on manual dexterity, I'm having to make adjustments and am bit by bit encountering more noticeable deficits.
The thing is, I am absolutely not an appropriate candidate for Humira, Enbrel or methotrexate, but when my psoriasis-specializing dermatologist learned that the rhematologist had prescribed the boring old-school hydroxychloroquine (which seems to be mainly holding off the inevitable progression for now), he scoffed and said I should just go straight to Humira, which is apparently his go-to utility player these days -- and he is quite a reputable, veteran practitioner, not some fly-by-night goofball.
Oh, really? You seriously think I'm going to take intravenous meds whose known side effects include, oh, lymphoma just because my fingers are chronically painful and fucked up? It's one thing to roll the dice on this scarifying if miraculous stuff because you're in a very bad way, but dermatologists ought not to be passing out major immunosuppressants like Pez, at least not until after they've at least explored the more conservative approaches.
posted by FelliniBlank at 6:35 PM on May 5, 2009 [7 favorites]
Genentech? Raptiva?
I guess the 21st Century turned out to be exactly as predicted by 80s sci fi flicks, at least in terms of corporate marketing.
posted by Kattullus at 6:40 PM on May 5, 2009 [7 favorites]
I guess the 21st Century turned out to be exactly as predicted by 80s sci fi flicks, at least in terms of corporate marketing.
posted by Kattullus at 6:40 PM on May 5, 2009 [7 favorites]
I guess the 21st Century turned out to be exactly as predicted by 80s sci fi flicks, at least in terms of corporate marketing.
An easy prediction in this case, since Genentech's been around since the mid 70s...
posted by mr_roboto at 6:55 PM on May 5, 2009
An easy prediction in this case, since Genentech's been around since the mid 70s...
posted by mr_roboto at 6:55 PM on May 5, 2009
These things are never as simple as you have portrayed them here. You portray this as a big scam by Genentech to hurt people. This is an immunosupressant. These are very dangerous drugs, but drugs for which people with immune disorders have a great need. There have been very few cases of this virus flaring up. There have been very many people getting good treatment with the drug. Yes, pulling it is probably the right thing, but if you had the condition that this drug treats you might feel otherwise. You might be so miserable that you are willing to take the risk. Anyway, this post is a big piece of scare crap.
posted by caddis at 6:57 PM on May 5, 2009 [7 favorites]
posted by caddis at 6:57 PM on May 5, 2009 [7 favorites]
You know, I have no problem with these drugs being on the market, as long as the risks and benefits are made very explicit to prescribers and patients. If you are being slowly murdered by MS, you may well choose a medication like Tysabri, even if there is a chance it might eat your brain, because that's one of the things that MS will do, left to its own devices.
Powerful drugs like this are always going to have side effects, and their use should be reserved for the most gravely ill patients.
posted by Mister_A at 7:10 PM on May 5, 2009 [6 favorites]
Powerful drugs like this are always going to have side effects, and their use should be reserved for the most gravely ill patients.
posted by Mister_A at 7:10 PM on May 5, 2009 [6 favorites]
Yes, pulling it is probably the right thing, but if you had the condition that this drug treats you might feel otherwise.
See, to me this is contradictory. Provided that the efficacy of the drug has been proven (and it has), it should be up to the patients and their doctors to decide whether the side effects are worth it, not the FDA. Even if one of those side effects is "death".
posted by Justinian at 7:12 PM on May 5, 2009 [2 favorites]
See, to me this is contradictory. Provided that the efficacy of the drug has been proven (and it has), it should be up to the patients and their doctors to decide whether the side effects are worth it, not the FDA. Even if one of those side effects is "death".
posted by Justinian at 7:12 PM on May 5, 2009 [2 favorites]
Repeat after me. JCV is not "activated" by Raptiva. Saying otherwise is editorializing.
JCV is a virus that is kept at bay by your immune system. When you suppress the immune system the virus can start taking control. If you are immunodeficient (i.e. have AIDS or, surprise surprise, taking immunosuppressant drugs) there's a good chance that getting JCV will start you down the path of contracting PML. A non-negligible number of AIDS patients end up contracting PML and quite a few end up succumbing to it.
The drug is working as intended and does exactly what it says on the box. It's not some grand conspiracy that Genetech is out to make their fortune while killing off the human race. The simple fact is that what it does on the box is a precursor to a chance of some other disease is a risk you have to take as a consumer. If you've got an ongoing struggle between a deadly virus kept at bay and your immune system overzealously attacking your own body then you're stuck between a rock and a hard place not the victim of an evil drug company.
posted by Talez at 7:23 PM on May 5, 2009 [11 favorites]
JCV is a virus that is kept at bay by your immune system. When you suppress the immune system the virus can start taking control. If you are immunodeficient (i.e. have AIDS or, surprise surprise, taking immunosuppressant drugs) there's a good chance that getting JCV will start you down the path of contracting PML. A non-negligible number of AIDS patients end up contracting PML and quite a few end up succumbing to it.
The drug is working as intended and does exactly what it says on the box. It's not some grand conspiracy that Genetech is out to make their fortune while killing off the human race. The simple fact is that what it does on the box is a precursor to a chance of some other disease is a risk you have to take as a consumer. If you've got an ongoing struggle between a deadly virus kept at bay and your immune system overzealously attacking your own body then you're stuck between a rock and a hard place not the victim of an evil drug company.
posted by Talez at 7:23 PM on May 5, 2009 [11 favorites]
(yes, this was a "voluntary" withdrawal, I was speaking in general about things like Tysabri. The calculus is different for degenerative or terminal illnesses than with non-degenerative or non-terminal conditions).
posted by Justinian at 7:23 PM on May 5, 2009
posted by Justinian at 7:23 PM on May 5, 2009
Justinian: I agree with one caveat, that doctors and their patients pass a basic statistics exam before they are allowed to make these kinds of decisions.
posted by dirty lies at 7:25 PM on May 5, 2009 [2 favorites]
posted by dirty lies at 7:25 PM on May 5, 2009 [2 favorites]
I neither said nor implied that this was a "big scam by Genentech to hurt people" or that it was a "grand conspiracy that Genetech is out to make their fortune while killing off the human race" and I find both charges hyperbolic. Please read the FPP again. The main thrust is a) the time that past between the FDA bringing these side effects to light and Genentech pulling the product, and b) letting people continue to get refills even while contending the product is dangerous enough to warrant a recall.
posted by Marisa Stole the Precious Thing at 7:37 PM on May 5, 2009 [1 favorite]
posted by Marisa Stole the Precious Thing at 7:37 PM on May 5, 2009 [1 favorite]
You seriously think I'm going to take intravenous meds whose known side effects include, oh, lymphoma just because my fingers are chronically painful and fucked up?
Not that I disagree with your assessment, FelliniBlank, but from the research I've done and from talking to my doctor when trying to decide whether or not to go on another of the TNF inhibitors, it's not actually clear to what extent they're responsible for increased incidence of lymphoma. People with psoriasis are already at increased risk of it anyway (a fun fact I hadn't known until I started my research!), and that may be what's causing the cases that have been seen in people on the drugs.
It's one thing to roll the dice on this scarifying if miraculous stuff because you're in a very bad way, but dermatologists ought not to be passing out major immunosuppressants like Pez, at least not until after they've at least explored the more conservative approaches.
No argument there.
posted by asterix at 7:42 PM on May 5, 2009
Not that I disagree with your assessment, FelliniBlank, but from the research I've done and from talking to my doctor when trying to decide whether or not to go on another of the TNF inhibitors, it's not actually clear to what extent they're responsible for increased incidence of lymphoma. People with psoriasis are already at increased risk of it anyway (a fun fact I hadn't known until I started my research!), and that may be what's causing the cases that have been seen in people on the drugs.
It's one thing to roll the dice on this scarifying if miraculous stuff because you're in a very bad way, but dermatologists ought not to be passing out major immunosuppressants like Pez, at least not until after they've at least explored the more conservative approaches.
No argument there.
posted by asterix at 7:42 PM on May 5, 2009
Marisa Stole....(OK, your user name is too long, that is my one big criticism) I really like you, you are one of my favorite posters here. Please do not take my comments too personally. Nevertheless, this delay is all part of trying to make a rational decision on risk. I think pulling the product is the right thing to do for Genentech, but if I were a patient I would be pissed. Sometimes companies will continue a program of limited availability for people willing to assume the risk. Our product liability laws discourage this, but when companies do it rest assured it is for altruistic reasons as the profit has been killed by that point yet the risk remains.
posted by caddis at 7:46 PM on May 5, 2009
posted by caddis at 7:46 PM on May 5, 2009
letting people continue to get refills even while contending the product is dangerous enough to warrant a recall
Well, based on the last two links in the FPP, going off the drug carries its own risks, so I can see an argument for taking precisely that course of action. I'm not inclined to grant Genentech complete benefit of the doubt, but I think the situation is a little more complicated than you're making it out to be.
posted by asterix at 7:48 PM on May 5, 2009
Well, based on the last two links in the FPP, going off the drug carries its own risks, so I can see an argument for taking precisely that course of action. I'm not inclined to grant Genentech complete benefit of the doubt, but I think the situation is a little more complicated than you're making it out to be.
posted by asterix at 7:48 PM on May 5, 2009
I didn't take it personally; I was just baffled by the interprettation.
Our product liability laws discourage this, but when companies do it rest assured it is for altruistic reasons as the profit has been killed by that point yet the risk remains.
I thought about this as well. It made me wonder how the entire decision-making process works at drug companies, what prompts the FDA to step in, at what point the FDA trumps a drug company and steps on the brakes, as opposed to a voluntary withdrawal, in this case, and how a drug company can simultaneously say "Yeah, we're pulling it off the shelves because it could kill you" and "You can still get refills until X date."
posted by Marisa Stole the Precious Thing at 7:51 PM on May 5, 2009
Our product liability laws discourage this, but when companies do it rest assured it is for altruistic reasons as the profit has been killed by that point yet the risk remains.
I thought about this as well. It made me wonder how the entire decision-making process works at drug companies, what prompts the FDA to step in, at what point the FDA trumps a drug company and steps on the brakes, as opposed to a voluntary withdrawal, in this case, and how a drug company can simultaneously say "Yeah, we're pulling it off the shelves because it could kill you" and "You can still get refills until X date."
posted by Marisa Stole the Precious Thing at 7:51 PM on May 5, 2009
Holy hell,
I'm a new-generation super-mutant myself, (I have psoriasis! My skin can grow ten times faster than yours! Kneel before me, weakling!) and I can't begin to imagine how badly the people who are taking this level of treatment are suffering.
It's simply tragic that for their condition the risks of treatment are so high. I really have to agree with Caddis' comment above.
posted by Catch at 8:06 PM on May 5, 2009 [1 favorite]
I'm a new-generation super-mutant myself, (I have psoriasis! My skin can grow ten times faster than yours! Kneel before me, weakling!) and I can't begin to imagine how badly the people who are taking this level of treatment are suffering.
It's simply tragic that for their condition the risks of treatment are so high. I really have to agree with Caddis' comment above.
posted by Catch at 8:06 PM on May 5, 2009 [1 favorite]
a) the time that past between the FDA bringing these side effects to light and Genentech pulling the product, and b) letting people continue to get refills even while contending the product is dangerous enough to warrant a recall.
They did it voluntarily after making damn sure they could be involved. Pulling a drug off the market is a huge disruption. Patients have to see doctors to find alternate treatments (you can't just go off immunosuprressants unless you fancy your condition flaring up and possibly putting you in a hospital), they may need to fight with insurance companies, find ways to afford different/more expensive co-pays and, worst of all, do this multiple times before they find a way to control their psoriasis in a way that worked as good as Raptiva.
You want a damn good reason before taking an otherwise effective drug off the market. If anything it should be put back on the market since immunosuppressants will let dormant viruses run wild by definition. The patient is stuck between a rock and a hard place and IMHO they should be the one to choose which they go for.
posted by Talez at 8:11 PM on May 5, 2009 [2 favorites]
They did it voluntarily after making damn sure they could be involved. Pulling a drug off the market is a huge disruption. Patients have to see doctors to find alternate treatments (you can't just go off immunosuprressants unless you fancy your condition flaring up and possibly putting you in a hospital), they may need to fight with insurance companies, find ways to afford different/more expensive co-pays and, worst of all, do this multiple times before they find a way to control their psoriasis in a way that worked as good as Raptiva.
You want a damn good reason before taking an otherwise effective drug off the market. If anything it should be put back on the market since immunosuppressants will let dormant viruses run wild by definition. The patient is stuck between a rock and a hard place and IMHO they should be the one to choose which they go for.
posted by Talez at 8:11 PM on May 5, 2009 [2 favorites]
what prompts the FDA to step in, at what point the FDA trumps a drug company and steps on the brakes, as opposed to a voluntary withdrawal, in this case, and how a drug company can simultaneously say "Yeah, we're pulling it off the shelves because it could kill you" and "You can still get refills until X date."
Like I said, it is not an easy decision. People are adversely affected when drugs are taken away. Surely, the company is loathe to give up the profits, yet they are also loathe to take on the liabilities. I think in a perfect world these medicines would still be available somehow. We haven't figured out how to make that possible, or perhaps cared to make that possible. No one really thinks about the patient, it is mostly about the company or the agency. The key would be full transfer of risk information. I would like to see a company be able to offer such meds at essentially 10% profit (which is super low for drug companies) with a full disclosure and also fully without risk of suit, except for failure to disclose the risk fully. Let people have the freedom to make their own informed decision, but let it be really informed. They get everything, all risks, all negatives. Maybe the profit doesn't matter, unless the system of offering these drugs becomes a profit center with its own abuse potentials. The real key is letting patients have access. There are many drugs gone which some patients would still like to take, even with the risk. Every drug, every single one, carries a risk profile. Never take one without reading the full risk profile in the PDR. That would be foolish. Yet, with these drugs with high risk, I would prefer that freedom prevails and it is the person who might benefit who decides (yet with full information) rather than some government agency or a company afraid of suit. For many of these drugs, certainly not all, these benefits are really quality of life issues.
posted by caddis at 8:27 PM on May 5, 2009 [4 favorites]
Like I said, it is not an easy decision. People are adversely affected when drugs are taken away. Surely, the company is loathe to give up the profits, yet they are also loathe to take on the liabilities. I think in a perfect world these medicines would still be available somehow. We haven't figured out how to make that possible, or perhaps cared to make that possible. No one really thinks about the patient, it is mostly about the company or the agency. The key would be full transfer of risk information. I would like to see a company be able to offer such meds at essentially 10% profit (which is super low for drug companies) with a full disclosure and also fully without risk of suit, except for failure to disclose the risk fully. Let people have the freedom to make their own informed decision, but let it be really informed. They get everything, all risks, all negatives. Maybe the profit doesn't matter, unless the system of offering these drugs becomes a profit center with its own abuse potentials. The real key is letting patients have access. There are many drugs gone which some patients would still like to take, even with the risk. Every drug, every single one, carries a risk profile. Never take one without reading the full risk profile in the PDR. That would be foolish. Yet, with these drugs with high risk, I would prefer that freedom prevails and it is the person who might benefit who decides (yet with full information) rather than some government agency or a company afraid of suit. For many of these drugs, certainly not all, these benefits are really quality of life issues.
posted by caddis at 8:27 PM on May 5, 2009 [4 favorites]
Seconding the importance of allowing patients time to switch treatments in a safe manner (hence the refills until June); these are serious drugs, and abruptly stopping could likely put a person in a hospital if their condition flares up suddenly. Also this kinds of drugs may be the first thing that has actually worked for severe cases; some people have spent years experimenting with different treatments before they got the results they did with immunosuppressants that have become available recently (which doesn't mean the other treatments shouldn't be tried and used first). Instead of blaming the drug companies, hope they find something just as effective without the side effects...
posted by ejaned8 at 9:20 PM on May 5, 2009
posted by ejaned8 at 9:20 PM on May 5, 2009
It made me wonder how the entire decision-making process works at drug companies, what prompts the FDA to step in, at what point the FDA trumps a drug company...
I'm worked for a drug company (or three or four depending on how you count - I've only had the one phone number) for 15 years now and I have some of your answers:
1) God only knows. Every so often we in-license something that was produced by some start-up somewhere (who may have just got wacked on the nose with a rolled up newspaper by the FDA). Sometimes these aren't too terrible. Sometimes, well, I've seen other people's specifications that made me cringe*. And when I hear how much we payed for the privilege of making this train wreck suitable for clinical testing I cringe some more.
In the trenches, where I live, we look at our data, hold it up to our past experience and what information we have from the agencies and other drug companies and try to go from there. Teasing apart signal and noise is often the biggest stumbling block.
2) About the time you want to start doing animal testing. That's CDER and I'm from the world of CBER, but it's more or less the same.
3) Any time they damn well feel like it. The different regulatory agencies have different characters. The MHRA in the UK and EMEA in Europe tends to hire from industry** so it's people like me who know all the dirty little secrets and where incompetence likes to hide. The FDA hires people out of college and tries to train them from the ground up a la the army.*** The real problem is the FDA is so damn stripped down you have to schedule everything years in advance and God help you if you're not ready. (I've brought this up before.)
The agency whose reputation sound the most like what I'd want if I was a government auditor is the TGA's from Australia. They're your best buds and show up at your site for your audit assuming you're doing everything right and they're just there for a quick look-see, "You know mate, just to make sure. We can all pop down to the pub for a quick pint after." May God help you if you disappoint them. (Or so I've been told.)
*Me at my most cynical: "They wanted to inject this into people? Who was going to let them do that, Joseph Mengele memorial?!?!"
**So obviously they're in bed with the industry, just like the FDA who does the exact opposite.
***The FDA apparently likes to look at your documentation more than you labs, so everyone sets up a little suite with a staff of runners and what not to get the auditor whatever piece of paper they want next. If you have a plate of doughnuts and a pot of coffee in there, apparently the FDA guy will wait until about a third of them are gone to avoid the impression of impropriety. It kind of disturbs me that somewhere in FDA command someone thinks we might think we could bribe them with doughnuts and coffee.
posted by Kid Charlemagne at 9:26 PM on May 5, 2009 [5 favorites]
I'm worked for a drug company (or three or four depending on how you count - I've only had the one phone number) for 15 years now and I have some of your answers:
1) God only knows. Every so often we in-license something that was produced by some start-up somewhere (who may have just got wacked on the nose with a rolled up newspaper by the FDA). Sometimes these aren't too terrible. Sometimes, well, I've seen other people's specifications that made me cringe*. And when I hear how much we payed for the privilege of making this train wreck suitable for clinical testing I cringe some more.
In the trenches, where I live, we look at our data, hold it up to our past experience and what information we have from the agencies and other drug companies and try to go from there. Teasing apart signal and noise is often the biggest stumbling block.
2) About the time you want to start doing animal testing. That's CDER and I'm from the world of CBER, but it's more or less the same.
3) Any time they damn well feel like it. The different regulatory agencies have different characters. The MHRA in the UK and EMEA in Europe tends to hire from industry** so it's people like me who know all the dirty little secrets and where incompetence likes to hide. The FDA hires people out of college and tries to train them from the ground up a la the army.*** The real problem is the FDA is so damn stripped down you have to schedule everything years in advance and God help you if you're not ready. (I've brought this up before.)
The agency whose reputation sound the most like what I'd want if I was a government auditor is the TGA's from Australia. They're your best buds and show up at your site for your audit assuming you're doing everything right and they're just there for a quick look-see, "You know mate, just to make sure. We can all pop down to the pub for a quick pint after." May God help you if you disappoint them. (Or so I've been told.)
*Me at my most cynical: "They wanted to inject this into people? Who was going to let them do that, Joseph Mengele memorial?!?!"
**So obviously they're in bed with the industry, just like the FDA who does the exact opposite.
***The FDA apparently likes to look at your documentation more than you labs, so everyone sets up a little suite with a staff of runners and what not to get the auditor whatever piece of paper they want next. If you have a plate of doughnuts and a pot of coffee in there, apparently the FDA guy will wait until about a third of them are gone to avoid the impression of impropriety. It kind of disturbs me that somewhere in FDA command someone thinks we might think we could bribe them with doughnuts and coffee.
posted by Kid Charlemagne at 9:26 PM on May 5, 2009 [5 favorites]
I'll be pissed if the FDA pulls Tysabri unless the risk of developing PML turns out to be a lot higher than it appears to be. 7 out of 50,000 is a pretty decent risk/reward ratio for a serious disease.
posted by Justinian at 6:04 PM on May 5 [2 favorites +] [!]
Just a heads up from : Tysabri Wikipedia page (last line of second to last paragraph)
"The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months."
posted by smartypantz at 11:15 PM on May 5, 2009
posted by Justinian at 6:04 PM on May 5 [2 favorites +] [!]
Just a heads up from : Tysabri Wikipedia page (last line of second to last paragraph)
"The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months."
posted by smartypantz at 11:15 PM on May 5, 2009
Justinian: I agree with one caveat, that doctors and their patients pass a basic statistics exam before they are allowed to make these kinds of decisions.
This seems to assume that the FDA is making better decisions than doctors and patients, which doesn't appear at all clear to me.
posted by Justinian at 11:21 PM on May 5, 2009
This seems to assume that the FDA is making better decisions than doctors and patients, which doesn't appear at all clear to me.
posted by Justinian at 11:21 PM on May 5, 2009
For many forms of arthritis, taking TNF-a inhibitors in the early stages of the disease is highly recommended because it may prevent the more serious effects of the disease from even beginning. For me, my arthritis had not yet become disabling, but I take Enbrel because research suggests it may prevent my spine from fusing, not to mention preventing the many side effects of life-long chronic inflammation, like heart disease.
Unlike PML, research suggests that the correlation of TNF-a inhibitors with cancer was due to the correlation of auto-immune disease with cancer. Suppressing inflammation may even reduce the risk of some cancers.
Also, it's really nice to be able to get out of bed in the morning, feel good, work all day, hang out with friends in the evening, and not crash with fatigue or be in horrible pain. The drugs sounds scary to those who don't have to make that choice. Quality of life, right now, is worth some uncertain future risk.
posted by hydropsyche at 4:18 AM on May 6, 2009 [2 favorites]
Unlike PML, research suggests that the correlation of TNF-a inhibitors with cancer was due to the correlation of auto-immune disease with cancer. Suppressing inflammation may even reduce the risk of some cancers.
Also, it's really nice to be able to get out of bed in the morning, feel good, work all day, hang out with friends in the evening, and not crash with fatigue or be in horrible pain. The drugs sounds scary to those who don't have to make that choice. Quality of life, right now, is worth some uncertain future risk.
posted by hydropsyche at 4:18 AM on May 6, 2009 [2 favorites]
You know, June 8 is more or less a month away. That really isn't a terribly long time to switch medication for a chronic condition.
posted by jester69 at 6:59 AM on May 6, 2009
posted by jester69 at 6:59 AM on May 6, 2009
That third link implies that JC virus normally exists in the brain, and that it is reactivated within the CNS after immunosuppression. But I'm not sure that that has been definitively shown. Since JC virus can infect tonsils and the gastrointestinal tract, it remains possible that the brain becomes infected due to viral escape from these sites rather than reactivation within the brain itself. It may seem like a pedantic point, but it might explain why the occurrence of PML is relatively higher in natalizumab patients, since the antibody blocks alpha-4 integrin, which is used by T cells to enter mucosal sites (such as the GI tract) and mucosa-associated lymphoid tissue (such as the tonsils).
As a side note: Since the same drug (natalizumab) has a remarkable capacity to reduce relapses in MS, and more than 90% of all T cells reside within gastrointestinal lymphoid tissue, it makes you wonder about where exactly the stimulating agent for RRMS is coming from. I know where my money's at!
posted by kisch mokusch at 7:59 AM on May 6, 2009 [1 favorite]
As a side note: Since the same drug (natalizumab) has a remarkable capacity to reduce relapses in MS, and more than 90% of all T cells reside within gastrointestinal lymphoid tissue, it makes you wonder about where exactly the stimulating agent for RRMS is coming from. I know where my money's at!
posted by kisch mokusch at 7:59 AM on May 6, 2009 [1 favorite]
It may seem like a pedantic point, but it might explain why the occurrence of PML is relatively higher in natalizumab patients, since the antibody blocks alpha-4 integrin, which is used by T cells to enter mucosal sites (such as the GI tract) and mucosa-associated lymphoid tissue (such as the tonsils).
Well, the alpha-4 beta-7 integrin pairing is certainly mucosal and gut-directing, binding MadCAM, but alpha-4 beta-1 pairings bind VCAM, which is much more widely expressed, including on inflamed vessel walls of the CNS. The gut is a neat place, with some unique relationships with the immune system, but it seems most likely that nataluzimab works in MS by directly blocking access of T cells to the CNS.
As a side note: Since the same drug (natalizumab) has a remarkable capacity to reduce relapses in MS, and more than 90% of all T cells reside within gastrointestinal lymphoid tissue, it makes you wonder about where exactly the stimulating agent for RRMS is coming from. I know where my money's at!
A relapsing-remitting form of EAE, the mouse model of MS, can be reliably induced in susceptible mouse strains by immunization with peptides derived exclusively from components of myelin. Inflammation in this model is characterized by progressive 'spread' in future relapses to new epitopes in these myelin-associated proteins. Granted, this model is quite distinct from human disease, requiring a healthy dose of Freund's adjuvant to get things going. The intiating phenomenon, and the targeted proteins, in human disease are much less clear, but in the mouse model at least the antigenic source seems to be exclusively CNS-associated.
posted by monocyte at 8:30 AM on May 6, 2009 [3 favorites]
Well, the alpha-4 beta-7 integrin pairing is certainly mucosal and gut-directing, binding MadCAM, but alpha-4 beta-1 pairings bind VCAM, which is much more widely expressed, including on inflamed vessel walls of the CNS. The gut is a neat place, with some unique relationships with the immune system, but it seems most likely that nataluzimab works in MS by directly blocking access of T cells to the CNS.
As a side note: Since the same drug (natalizumab) has a remarkable capacity to reduce relapses in MS, and more than 90% of all T cells reside within gastrointestinal lymphoid tissue, it makes you wonder about where exactly the stimulating agent for RRMS is coming from. I know where my money's at!
A relapsing-remitting form of EAE, the mouse model of MS, can be reliably induced in susceptible mouse strains by immunization with peptides derived exclusively from components of myelin. Inflammation in this model is characterized by progressive 'spread' in future relapses to new epitopes in these myelin-associated proteins. Granted, this model is quite distinct from human disease, requiring a healthy dose of Freund's adjuvant to get things going. The intiating phenomenon, and the targeted proteins, in human disease are much less clear, but in the mouse model at least the antigenic source seems to be exclusively CNS-associated.
posted by monocyte at 8:30 AM on May 6, 2009 [3 favorites]
This may sound dumb, but does JCV have a greater chance of mutating to become more dangerous with the use of Raptiva, and does that mutated JCV become more likely to harm other people without some sort of induced immunodeficiency? I just wonder whether the withdrawal of the drug might have anything to do with protecting to public at large, as opposed to affecting only those with plaque psoriasis.
posted by jabberjaw at 9:17 AM on May 6, 2009
posted by jabberjaw at 9:17 AM on May 6, 2009
I fucking hate psoriasis drugs. Every one of them has a negative impact. Methotrexate killed my mother. My grandmother bled at the slightest touch from the corticosteroids she took to control her psoriasis. I myself take corticosteroids (as rarely as I can) to avoid my face looking like I just stepped out of zombie film. I'm afraid of the effects they have on me, but I pretty much have to in order to not be shunned by the regular populace.
Not sure what else I have to say...I'm just sick of the disease and the treatments as well.
posted by Kickstart70 at 9:27 AM on May 6, 2009
Not sure what else I have to say...I'm just sick of the disease and the treatments as well.
posted by Kickstart70 at 9:27 AM on May 6, 2009
Well, the alpha-4 beta-7 integrin pairing is certainly mucosal and gut-directing, binding MadCAM, but alpha-4 beta-1 pairings bind VCAM, which is much more widely expressed, including on inflamed vessel walls of the CNS. The gut is a neat place, with some unique relationships with the immune system, but it seems most likely that nataluzimab works in MS by directly blocking access of T cells to the CNS.
I wasn't planning on derailing the thread into a conversation about MS pathogenesis. I merely wanted to point out that how exactly PML develops during immunosuppression is incompletely understood (and I then proceeded with some idle speculation about the true mechanism of action of natalizumab in MS). The other theory that's floating around is that this antibody actually weakens the BBB, enabling better entry of JC virus.
That being said (and since there haven't been any new comments here for few hours, so it's not really a derail), I'm sure that natalizumab ameliorates the extent of inflammation during a relapse though it's reduction of T cell entry into the CNS. But it also seems to prevent relapses, and I therefore wonder whether the reduction of T cell entry into the CNS is the only means by which this drug is working in MS. Especially since it has other known effects in changing T cell recirculation via MadCAM-a4b1.
One of the catches is, as you pointed out, that VCAM is expressed on inflamed vessels. In EAE models*, the effector T cells are activated within a peripheral site (CFA+Ag s.c.), but still manage to gain entry to the CNS, even though at that point, the CNS isn't inflamed. Most EAE (and EAN) models use activated T cells to break the BBB down, which really suggests that they can get in there without VCAM-binding (although upregulation of VCAM is surely an important factor in the subsequent inflammation).
Of course, if you subscribe to the theory of MS pathogenesis which hypothesises that some event occurs in the CNS (such as apoptosis of an oligodendrocyte, I know this one is gaining popularity) leads to microglial activation and upregulation of VCAM on blood vessels, thereby enabling autoreactive T cell infiltration and further inflammation then yes, it would be likely that natalizumab acts primarily by preventing T cell entry to the CNS itself. But MS patients also frequently have relapses following flu/adenovirus infections, suggesting that the precipitating event needn't be in the CNS itself, but rather an activation of autoreactive T cells in a completely separate lymph node.
What actually occurs in in MS, and what the precipitating agents actually are, as you said, pretty much completely unknown, but I'm more inclined to think that an external factor, rather than an internal one, is precipitating relapses. Which means I'm more inclined to believe in the molecular mimicry theory (as is believed to occur in Guillain-Barré syndrome). If this was true, then natalizumab could very well be preventing the initial T cell activation in MALT, thereby preventing relapses through a separate mechanism.
But neither model of disease initiation has been definitively demonstrated, so it's pure speculation at this point.
*I have serious reservations about how much EAE can be applied to MS. AFAIK, MBP and Mog have not been shown to be autoantigens in MS. Interestingly enough, the factors in involved in the initiation of acute disseminated encephalomyelitis (the human version of EAE) are generally viral, bacterial and/or parasitic in origin.
posted by kisch mokusch at 5:22 PM on May 6, 2009 [2 favorites]
I wasn't planning on derailing the thread into a conversation about MS pathogenesis. I merely wanted to point out that how exactly PML develops during immunosuppression is incompletely understood (and I then proceeded with some idle speculation about the true mechanism of action of natalizumab in MS). The other theory that's floating around is that this antibody actually weakens the BBB, enabling better entry of JC virus.
That being said (and since there haven't been any new comments here for few hours, so it's not really a derail), I'm sure that natalizumab ameliorates the extent of inflammation during a relapse though it's reduction of T cell entry into the CNS. But it also seems to prevent relapses, and I therefore wonder whether the reduction of T cell entry into the CNS is the only means by which this drug is working in MS. Especially since it has other known effects in changing T cell recirculation via MadCAM-a4b1.
One of the catches is, as you pointed out, that VCAM is expressed on inflamed vessels. In EAE models*, the effector T cells are activated within a peripheral site (CFA+Ag s.c.), but still manage to gain entry to the CNS, even though at that point, the CNS isn't inflamed. Most EAE (and EAN) models use activated T cells to break the BBB down, which really suggests that they can get in there without VCAM-binding (although upregulation of VCAM is surely an important factor in the subsequent inflammation).
Of course, if you subscribe to the theory of MS pathogenesis which hypothesises that some event occurs in the CNS (such as apoptosis of an oligodendrocyte, I know this one is gaining popularity) leads to microglial activation and upregulation of VCAM on blood vessels, thereby enabling autoreactive T cell infiltration and further inflammation then yes, it would be likely that natalizumab acts primarily by preventing T cell entry to the CNS itself. But MS patients also frequently have relapses following flu/adenovirus infections, suggesting that the precipitating event needn't be in the CNS itself, but rather an activation of autoreactive T cells in a completely separate lymph node.
What actually occurs in in MS, and what the precipitating agents actually are, as you said, pretty much completely unknown, but I'm more inclined to think that an external factor, rather than an internal one, is precipitating relapses. Which means I'm more inclined to believe in the molecular mimicry theory (as is believed to occur in Guillain-Barré syndrome). If this was true, then natalizumab could very well be preventing the initial T cell activation in MALT, thereby preventing relapses through a separate mechanism.
But neither model of disease initiation has been definitively demonstrated, so it's pure speculation at this point.
*I have serious reservations about how much EAE can be applied to MS. AFAIK, MBP and Mog have not been shown to be autoantigens in MS. Interestingly enough, the factors in involved in the initiation of acute disseminated encephalomyelitis (the human version of EAE) are generally viral, bacterial and/or parasitic in origin.
posted by kisch mokusch at 5:22 PM on May 6, 2009 [2 favorites]
Most of the reasons for pulling drugs with severe side-effects really seem to be the fault of doctors who misprescribe, or who aren't doing a good job explaining the risks to their patients before prescribing, rather than of the drugs themselves, or really even of the drug companies. Of course the drug companies have a profit motive to sell drugs. That's obvious, and it ought to be obvious to doctors; if they're not smart enough to take a sales pitch with a grain of salt, they should try a career where their stupidity won't kill anyone. That's not to say that we shouldn't be rigorously enforcing truth-in-advertising on the part of the drug companies, but the fact that a drug has side effects — even severe ones — shouldn't be cause to pull it from the market, as long as those side-effects are communicated to doctors.
I know several people with MS, and also several people at Biogen-Idec (the maker of Tysabri). An 1:1,000 chance of death is not unreasonable to people with severe MS that's not responding to other medication, or who can't tolerate anything else. Forcing a recall is the worst kind of overbearing parentalism. The only circumstances under which a drug should get recalled is if the information surrounding it is wrong, meaning that doctors and patients aren't making informed decisions; and even then, the preferred course of action should be to update the information provided to prescribers and patients, notify current users and change the drug's labeling, and let patients and their doctors decide whether to continue treatment in view of the newly-understood risks.
Before anyone strawmans me: I'm not arguing in favor of a totally unregulated pharmaceutical marketplace; we've seen that before and it sucks. Some regulation is obviously necessary to make sure that drug makers are honest about the efficacy of their products, and punish those who are not. But the current system punishes patients and seems to operate on the assumption that the are too stupid to decide whether to take a potentially dangerous drug. That's a terrible attitude when it comes to government and a worse one when it comes to medicine.
posted by Kadin2048 at 5:47 PM on May 6, 2009 [2 favorites]
I know several people with MS, and also several people at Biogen-Idec (the maker of Tysabri). An 1:1,000 chance of death is not unreasonable to people with severe MS that's not responding to other medication, or who can't tolerate anything else. Forcing a recall is the worst kind of overbearing parentalism. The only circumstances under which a drug should get recalled is if the information surrounding it is wrong, meaning that doctors and patients aren't making informed decisions; and even then, the preferred course of action should be to update the information provided to prescribers and patients, notify current users and change the drug's labeling, and let patients and their doctors decide whether to continue treatment in view of the newly-understood risks.
Before anyone strawmans me: I'm not arguing in favor of a totally unregulated pharmaceutical marketplace; we've seen that before and it sucks. Some regulation is obviously necessary to make sure that drug makers are honest about the efficacy of their products, and punish those who are not. But the current system punishes patients and seems to operate on the assumption that the are too stupid to decide whether to take a potentially dangerous drug. That's a terrible attitude when it comes to government and a worse one when it comes to medicine.
posted by Kadin2048 at 5:47 PM on May 6, 2009 [2 favorites]
It's always interesting, listening to a new dermatologist. The one before last told me I was bound for lymphoma if I kept injecting Enbrel, and the new one told me that Enbrel would protect me from lymphoma. Derm A wants to take my blood every three months now (before, he saw me once a year); Derm B just wanted a tb skin test, and "yeah, you can phone that result in."
One in between - he just did referrals - said he never dealt with biologics at all.
I've had psoriasis since I was five years old, and it got to what they call severe a couple decades ago. I refused to take methotrexate. Oh my, have I spent tons of time in cold baths and PUVA and UVA and using all those fucking topicals. I never spent time in the sacks filled with tar - I never had health insurance that would cover that, and who knows if it would have worked?. When I lost my health insurance, I couldn't move without breaking the crust of a lesion and bleeding. I had to wear two layers of clothing at my job, and even then, I'd be bleeding through my clothes, fingernails and toenails detaching.
Enbrel was my biologics savior. If it gives me lymphoma eventually, shit, that's fine. It cleared my skin well enough that I stopped staying at home, scratching and bleeding, lonely as could be. It cleared me up enough that this severe psoriatic went out and found a lover.
posted by goofyfoot at 8:24 PM on May 7, 2009 [3 favorites]
One in between - he just did referrals - said he never dealt with biologics at all.
I've had psoriasis since I was five years old, and it got to what they call severe a couple decades ago. I refused to take methotrexate. Oh my, have I spent tons of time in cold baths and PUVA and UVA and using all those fucking topicals. I never spent time in the sacks filled with tar - I never had health insurance that would cover that, and who knows if it would have worked?. When I lost my health insurance, I couldn't move without breaking the crust of a lesion and bleeding. I had to wear two layers of clothing at my job, and even then, I'd be bleeding through my clothes, fingernails and toenails detaching.
Enbrel was my biologics savior. If it gives me lymphoma eventually, shit, that's fine. It cleared my skin well enough that I stopped staying at home, scratching and bleeding, lonely as could be. It cleared me up enough that this severe psoriatic went out and found a lover.
posted by goofyfoot at 8:24 PM on May 7, 2009 [3 favorites]
kisch mokusch -
Would you be able to summarize your comments regarding MS and the potential debatable causes in layman's terms (as it were)?
Pretty please?
I was recently diagnosed with MS and a lot of the newer articles and research are somewhat impenetrable to someone such as myself, and I find it frustrating to kind of get what's going on, but knowing I am missing many years of education that would enable me to actually understand the language.
I am particularly interested in ideas surrounding viruses being some sort of potential trigger as I have had oral herpes (cold sores) since I was a child. In recent years I have fought off outbreaks almost monthly, sometimes multiple sores in a month (like 9 one time) - almost certainly partially due to high stress and (I have since discovered) a sensitivity to chocolate :(
I have since found great relief in L-Lysine and Lysine rich foods.
But yeah.
Help me understand?
posted by smartypantz at 5:47 AM on May 27, 2009
Would you be able to summarize your comments regarding MS and the potential debatable causes in layman's terms (as it were)?
Pretty please?
I was recently diagnosed with MS and a lot of the newer articles and research are somewhat impenetrable to someone such as myself, and I find it frustrating to kind of get what's going on, but knowing I am missing many years of education that would enable me to actually understand the language.
I am particularly interested in ideas surrounding viruses being some sort of potential trigger as I have had oral herpes (cold sores) since I was a child. In recent years I have fought off outbreaks almost monthly, sometimes multiple sores in a month (like 9 one time) - almost certainly partially due to high stress and (I have since discovered) a sensitivity to chocolate :(
I have since found great relief in L-Lysine and Lysine rich foods.
But yeah.
Help me understand?
posted by smartypantz at 5:47 AM on May 27, 2009
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posted by dilettante at 5:31 PM on May 5, 2009