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Recombinant Human Antithrombin – Milking Nanny Goats for Big Bucks

Antithrombin deficiency is a hereditary disease causing low levels or defects of antithrombin, a blood protein required for controlling clot formation. Patients are at risk of blood clots, organ damage, and death. They usually have to take oral anticoagulant drugs like warfarin for life.

During high-risk procedures like surgery or childbirth, oral anticoagulants must be discontinued to minimize the chance of bleeding complications. While patients are off oral anticoagulants, they are given preventive treatment with antithrombin derived from pooled human blood. With any human blood product there is a small risk of infection with diseases like hepatitis C. And human antithrombin supplies are not plentiful.

Clever researchers found an ingenious solution. Put a human antithrombin gene in goats, milk them, isolate the human antithrombin protein from the milk, and voila! An udderly safe and plentiful source. A Brit might call it bleatin’ brilliant.

Yes, transgenic goats. No, they are not human/goat hybrids, despite a recent report that a goat had given birth to a human faun in Zimbabwe.

Sex between humans and animals does happen, but it can’t result in pregnancy because of the chromosome differences and other factors. 28% of men with bestial desires are attracted to goats. Goats come fourth after canines, equines and bovines.

You probably don’t know anyone who practices bestiality, but that doesn’t mean it doesn’t happen. I was e-mailed a video clip filmed by a Marine unit in Iraq, a light magnified night image (Improved Thermal Sight System). The marines were monitoring a known Taliban safe house. When they saw a suspect acting strangely, they thought he might be emplacing an IED. As they filmed him, they realized he was copulating with a donkey. They caught the whole thing on video. The best part is their comments as they watch the blurry images and gradually realize what they are seeing. It was apparently on YouTube briefly before it got banned. There is a similar clip with two Iraqis, one holding the donkey, that hasn’t been banned yet.  Of course, I can’t guarantee this isn’t video trickery. But in 2005 there was a well-documented case of a man who died after having sex with a horse just a few miles from where I live. Washington State is one of 17 states where sex with animals is not against the law. Instead of choosing a receptive female equine, this unfortunate man chose a stallion. The man died of a perforated colon; the horse suffered no physical damage, although I suppose we could speculate about possible psychological damage…  The whole thing was caught on videotape. Now there is even a movie. I report the facts without judgment: humani nihil a me alienum puto.

Pardon the prurient diversion. Back to the subject. Transgenic goats can’t be created by such “natural” methods: they require complicated tricky maneuvers in the lab. They are just like normal goats in every respect except that they produce one human protein, antithrombin. Still, it’s a wonder the religious fundamentalists haven’t been denouncing the evil scientists and bombing goat labs. Do they even know about this?

The recombinant human antithrombin is marketed under the brand name ATryn. It has been approved by the FDA for patients with antithrombin deficiency who are undergoing surgery or childbirth. Two clinical studies were done with 5 and 14 patients, respectively. Small studies, but it didn’t seem to call for a lot of investigation since it only amounted to replacing one of the patients’ own deficient proteins. No serious adverse events were reported.

The Medical Letter has evaluated ATryn (Volume 51, issue 1323, October 19, 2009. pages 83-63) and concluded it is a safe and effective source of replacement that may well turn out to have additional therapeutic applications.

Only one problem. It costs $2.34 per international unit, and patients in one study received anywhere from 39,200 IU to 294,000 IU. That adds up to $91,728 to $687,960 for one course of treatment for one patient. The manufacturer has a patient assistance program, but WOW! That’s a lot of money to protect one patient during childbirth! We don’t yet know how many patients will need to be treated to prevent one blood clot or save one life.

I can’t stop thinking about this. I am constantly amazed at the cost of some of the new drugs with limited applications, especially chemotherapy. And it’s not just the new, limited-use drugs. I recently got a prescription for what I thought was a cheap old antibiotic long available as a generic, and I was appalled at the price. It was more than ten times what I would have guessed.

It’s wonderful that science can accomplish such feats, and I have no ethical qualms about using goats as factories to help humans, but I wonder about the ethics of saddling society with unaffordable bills for treatments that provide only a small advantage. As we develop more of these expensive drugs, we could go bankrupt trying to provide them for every patient. It’s a dilemma that bears thinking about before it happens. One of the 4 basic principles of medical ethics is justice, or fair distribution of medical services to society.

However you look at it, our technical ability will eventually outrun our ability to pay.

Posted in: Pharmaceuticals, Science and Medicine

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14 thoughts on “Recombinant Human Antithrombin – Milking Nanny Goats for Big Bucks

  1. kill3rTcell says:

    Not necessarily. You cannot judge the future affordability of the intervention based purely upon current costs. Pharming has various advantages over other protein-production systems, including the low level of additional modifications required to get the protein you want (bacterial, yeast and plant expression systems often have quite different post-translational modification systems to mammals), easy scalability and the prior existence of the infrastructure required to keep pharm animals, especially cows.

    While I agree the price is exorbitant I feel that it is a side-effect of the newness of the technology. I also agree that new, expensive technology will be unfortunately limited to those who can pay or be subsidised, however a key feature of such things is that they become less-expensive over time as the technology develops (I am sure you yourself would have seen such progressions in technology over the course of your medical career). Pharming may very easily be one such example (factors mentioned in first paragraph).

    This is why I don’t feel the specific example of the current high cost of proteins produced from transgenic animals is a solid example to support your conclusion.

  2. windriven says:

    Amplifying kill3rTcell’s thoughts, the high current cost may well owe to this being essentially prototype technology. As the market becomes aware of availability and as the herd grows and isolating the protein is scaled out of the lab and into an industrial process, cost should go down.

    Further, there are huge costs to be amortized (R&D, regulatory, etc.) and a limited number of years during which the technology will be protected by patents. And the pool of patients needing the therapy is relatively small.

    It amuses me when I hear wackaloons bash ‘Big Pharma’ as some monolithic money printing enterprise. If that was true why aren’t pharmaceutical stocks a slam-dunk investment? Pfizer, as I write this, is selling at $18.72 a share with a P/E of 15. Not exactly breathtaking.

  3. Certainly technologies generally get cheaper in time, but that applies primarily to technologies with strong demand. Specialized technologies tend to remain costly.

    Perhaps manufacturers have already picked all the low-hanging pharmaceutical fruit, and now must pursue profits from drugs with limited applications … and limited markets.

    p.s. “Humani nihil a me alienum puto” is my favourite new scrap of Latin, and I will be looking for every possible excuse to use it.

  4. hatch_xanadu says:

    Huh.

    Fascinating!

  5. Geekoid says:

    Why were the antibiotics more expensive then expected? If they were generic I would suspect it has to do with the market, or they have recently shot of to generate some temporary revenue increase to prepare for the impeding Universal Health care reforms bill.

    When driven by an educated market, expensive technique tend to drop in price with time. In the medical industry, most of the market isn’t educated about true price. Meaning they pay there co-pay and don’t really pay attention to the actual price.

  6. qetzal says:

    I skimmed some of GTC’s SEC filings. (GTC is the company that developed Atryn). No doubt they have hopes of making big bucks from this product, but they seem to be a long ways from that so far.

    Although Atryn was only recently approved in the US, it’s been approved in Europe since 2006. Yet GTC’s total revenue from Atryn was only $4.2 million in each of 2007 and 2008.

    It’s also interesting to note that Atryn competes against plasma-derived antithrombin (i.e. stuff that’s purified from human plasma, which carries the risk of exposure to viruses like HIV, HBV, & HCV). There’s apparently only one such brand approved in the US, and it only sells $12-15 million a year. However, there are multiple brands approved in Europe, and worldwide sales are said to be ~ $250 million/year.

    Doesn’t look like Atryn has made many in-roads on that market. Of course, GTC claims that Atryn has other applications that could result in billions/year. Good luck to them, but I’m not holding my breath (or investing).

    In fact, a number of companies have tried to develop biopharmaceuticals using transgenic animals. It sounds like a great idea: get a cow, goat, or even rabbit to make lots of some human protein in its milk, breed up a bunch of animals, and make tons of the stuff. Animals are cheaper to house and maintain than bioreactors, there are plenty of sophisticated milking systems, and it’s supposedly easier to purify proteins from milk (vs. recombinant production in bacteria, yeast, or mammalian cells).

    In practice, none of those companies has really been successful to date. Some have gotten out of the business. Finding a biopharma product where this really makes sense from all angles turns out to be much harder than initially advertised.

  7. micheleinmichigan says:

    Harriet Hall ” An udderly safe and plentiful source. A Brit might call it bleatin’ brilliant.”

    One could say you are milking that pun for all it’s worth. hehe

  8. momkat says:

    nnnnnaaaahhhh

  9. kill3rTcell says:

    qetzal, I don’t think that’s a truly fair assessment. While the true test of the technology will be in its application, I don’t feel the failures of previous ventures due to harsh restrictions on GMOs in the EU or due to partner companies pulling out (cough cough Bayer cough cough) are fair assessments of the sensibility of the applications of the technology. While they may indicate that currently it is not an ideal method of producing molecules of interest on a wide scale, this does not mean that all applications of it are not commercially viable. It seems that while it will definitely not work for all molecules of interest, there are going to be niches that this technology can fill (I’ve enjoyed watching the recent trials on recombinant antibody and interferon production to treat cancers and Heps).

    It may also just turn out to be a big dead end. Either way I’m curious as to any novel applications of GM technology to help people, the ingeniousness of some of the ideas always intrigues me.

    (and purification is easier than in bioreactors – gotta love existing infrastructure – the path of least resistance :P)

  10. qetzal says:

    kill3rTcell,

    Don’t get me wrong; I love these kinds of things. It would be great to see them succeed, and some day, they almost certain will.

    But the fact remains that no one’s been successful with this so far. Sure, regulatory issues have played a role, as have partnering problems. But those are all part of the overall package. Bio-farming can’t succeed unless it overcomes those issues (along with all the others).

    Besides, the fact that big pharma doesn’t want to partner on these projects is pretty telling in itself. They’re clearly skeptical of the profit potential for the reasonable future. Big pharma can be wrong, of course, but they’re not amateurs at this stuff. Their opinions (as expressed by where they invest their partnering dollars) shouldn’t be lightly dismissed.

    All IMHO, of course.

  11. sanjiva86 says:

    There’s a paper in this week’s JAMA that’s talking about diminishing returns and how it will affect innovation (http://jama.ama-assn.org/cgi/content/extract/302/20/2254)

    I haven’t had time to read the full paper, but I think it could be relevant to the discussion here. The problem with many new treatments is that the clinical benefit they offer over existing treatments is usually small, yet they are typically more expensive. This is particularly relevant in cancer, where some of the new biologics and oral chemotherapy agents have exorbitant prices, yet many of them don’t even have any proven overall survival benefit or only have a demonstrated benefit of a few months. Even though Avastin has been shown to have a fairly decent overall survival benefit when added to FOLFOX for stage IV colorectal cancer, NICE (in the UK) decided not to give it the green light because they determined it cost more than $50,000 per quality-adjusted life year. Avastin was studied in large trials in combination with anti-EGFR agents like Erbitux and Vectibix, but unfortunately(?) there was no difference in overall survival. I shudder to think what the cost of such a combination would have been!

    On the one hand, giving a cancer patient even an extra month to live seems worthwhile, but at some point society has to ask at what cost they are willing to do this. It’s an issue that is bound to come repeatedly in the future – with aging populations and many pharma companies focuif there will be a point at which the payors’ reluctance to pay for expensive cancer medications will hamper innovation in oncology.

  12. kill3rTcell says:

    qetzal (Arg! So hard not to put a ‘u’ in there!) – I completely agree. Current issues and assessments with/of a product or technology are still issues, and could easily be indicative of future problems.

    sanjiva86 thanks, that article’s really food for thought.

  13. yeahsurewhatever says:

    humani nil a me alienum

    Publius Terentius Afer is generally given credit for this, but the play it comes from is actually just a translation of a preexisting Greek play (Εαυτόν Τιμωρούμενος / Heauton Timorumenos) by Menandros of Athens, which is largely lost. I know nothing of the Greek language (it’s all Greek to me…), so I can’t attempt to translate it back to the original.

    Also, in this case, alienum doesn’t actually mean ‘weird’, but something closer to ‘outside my purview’. Literally, in perfect fullness, the word means ‘belonging to someone else and thus definitely belonging not to me’. The words ‘alien’ and ‘strange’ have taken on meanings in English that their Latin roots can’t actually support. In the old meaning, someone from another country is strange (extraneus), regardless of how well you understand them and regardless of how similar their customs may be to yours.

    So the phrase doesn’t mean something along the lines of “I don’t consider anything humans do to be weird anymore” but rather more along the lines of “There is no facet of humanity which can’t equally be applied to me as well”. It’s not a stoic observation of human diversity. It’s an admission that ego, the person saying it, is just as culpable as anyone.

  14. jmorrison says:

    If only there were some way to monetize prevention or at the very least prioritize and fund public health research. There’s no incentive for prevention, so maybe pharma profits should be taxed (and tax credited) to fund prevention. A bit like the soda/sugar tax (e.g. let’s keep the corn syrup for our ethanol fueled SUVs, not for empty calories).

    Surely there’s low hanging fruit on the prevention side? It would be nice to know with some certainty whether the Garlands over at UCSD are right about vitamin d and cancer prevention (perhaps now that Framingham is finding associations with cardiovascular disease, it might get more study)

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