'You need to maintain the factory, you need to do the paperwork...'

November 19, 2018 10:31 AM

The Million Dollar Drug :: Glybera is a miracle cure for people born with a genetic mutation that causes lipoprotein lipase disorder (LPLD), but at a cost of one million dollars per dose, it is a cure nobody can afford. The drug works. It is safe. But it's no longer available anywhere in the world.
posted by anastasiav (37 comments total)

In a perfect world, van Deventer says, Glybera would still be on the market.

"It's a shame because it does work and I think people accept that it works and it should have been a product for sure."

But he said the costs for uniQure were too high.

"You need to maintain the factory, you need to do the paperwork, you need to test the product, you need to make new product batches all the time because product expires," he said.

At some point we need to transition to a system where the components of gene therapy delivery are preapproved and ready to use, off-the-shelf. Then there would be one factory that made the treatments for a whole slew of rare diseases and the costs would be reasonable. My personal view is that in order for this to work, it needs to be not-for-profit and run by a government or university. It also needs a new regulatory framework. The FDA has demonstrated that it can facilitate transfer of massive amounts of our money to drug companies by allowing patents on dirt cheap generic drugs grandfathered in years ago (see colchicine). They have no incentive (and probably no mandate) to manage genetic therapy except on a case-by-case basis.
posted by Emmy Noether at 11:04 AM on November 19, 2018 [14 favorites]

Company forms a charity for disease X. Donates a few thousand doses of the drug to the charity each year, which gives it to patients for free. Pharma company benefits from huge tax write-off to set against its profits from its other drugs.
posted by w0mbat at 11:13 AM on November 19, 2018 [14 favorites]

Just a reminder that Jonas Salk never patented the polio vaccine, because he felt potentially eradicating that much-feared disease was more important than making a profit.
posted by TedW at 11:13 AM on November 19, 2018 [83 favorites]

But, TedW, that made sense to manufacture because of economies of scale - every person on earth basically needed it. That's different than the drugs we are talking about here, that only impact a few hundred patients a year - and they only need one dose. I don't know what it costs to create and maintain the medicine for something specific like this but I think one of the points in the article is that the incentive for manufacturers to continue making a drug is in the profit. Without it, they don't provide the money for research and development. Although it sounds like all the research here is academic, so I'm not sure about that.

This isn't going to change until we stop treating healthcare and medicine like regular commercial industries, at least in the US.
posted by dpx.mfx at 11:17 AM on November 19, 2018 [13 favorites]

Tax write-offs on things manufactured by the company are related to basis rather than market value. Which means it actually has to cost to make what you are writing off. That's not an attractive proposition. Especially for a company without a lot of assets or taxable income to write off. It's a 1.1 billion market cap for uniqure. Either someone will buy them and produce the drug along with a whole bunch of other gene therapy drugs and economies of scale will bring down the price slightly, or the patents will expire in 2034 or so and generics will come into the picture.
posted by BrotherCaine at 11:22 AM on November 19, 2018 [1 favorite]

the incentive for manufacturers to continue making a drug is in the profit. Without it, they don't provide the money for research and development. Although it sounds like all the research here is academic, so I'm not sure about that.

The issue blocking Glybera presently is an issue of patents/intellectual property. The original company folded because they couldn't sell the drug until the long approval process was completed. Another company swooped in like scavengers and bought up the rights. They're the ones who settled on the million-dollars-a-dose idea, to satisfy the investors who ponied up the money to buy the rights -- the only way to satisfy said investors would be to extract that level of profit. They couldn't. So no one gets Glybera because some rich people had a tantrum over insufficient ROI, basically.
posted by halation at 11:22 AM on November 19, 2018 [55 favorites]

Van Deventer says the company never considered lowering the price.
"Why would we? Pricing shouldn't be a political decision.

We could make so, if you’d like.
posted by Thorzdad at 11:23 AM on November 19, 2018 [52 favorites]

Orphan drugs like this should be manufactured and sold at cost by the government.
posted by rockindata at 11:26 AM on November 19, 2018 [31 favorites]

The pricing makes sense in comparison to a lifetime of ongoing treatment for pancreatitis etc... The primary villain in this piece seems to me like it should be insurance companies.
posted by BrotherCaine at 11:28 AM on November 19, 2018 [4 favorites]

I had the outraged feelings but then began mulling if there were rational sides to the story. If I understand, the disease is generally not fatal and there are dietary methods of managing symptoms. It was not clear but it sounds legitimately very expensive to manufacture as well as the regulatory hurdles, most of the patients were test subjects.

What the article did not address is the more general issue of where and how the lines should be drawn, dedicate all resources, could that be done legislatively? Should research be funded purely by taxes, thus raising what you pay significantly? If not how, ask researchers to work for lower pay? Then who decides what research, the government? Should we all vote on a new drug?
posted by sammyo at 11:28 AM on November 19, 2018

As for reducing regulatory costs, don't forget Thalidomide.
posted by sammyo at 11:33 AM on November 19, 2018 [6 favorites]

Not to thalidomide derail, but I was cleaning out a desk a couple of weeks ago and found a DVD for doctors about prescribing thalidomide. Apparently it's a second-line TB treatment.
posted by elsietheeel at 11:37 AM on November 19, 2018 [3 favorites]

What the article did not address is the more general issue of where and how the lines should be drawn, dedicate all resources, could that be done legislatively? Should research be funded purely by taxes, thus raising what you pay significantly? If not how, ask researchers to work for lower pay? Then who decides what research, the government? Should we all vote on a new drug?

Why would state-funded research raise drug prices? Currently it does exactly the opposite.

In the US, the government actually funds quite a lot of the research which generates new drugs. "We" don't "vote" on new drugs; the NIH is overseen by the federal government and sets research priorities based on its own internal deliberations. NIH is actually able to do things a lot cheaper than the private sector for a variety of reasons - they don't need to make a profit, for one, and for another they tend to pay academic salary rates rather than corporate. (So you might be a staff scientist in a university lab making $60,000 a year, with 2/3 of your salary from grants and 1/3 from the school itself, rather than a corporate researcher making a lot more, all of which would have to be recuperated from drug prices.)

I don't see any reason other than "political" why, in the US, the vast majority of medical research should not be NIH-funded. In any situation, you have to pick what you research - maybe you make a hard decision to focus more effort on a condition that affects hundreds of thousands and less on a condition that affects hundreds. But it would be far better to make that decision based on necessity rather than the profit motive.
posted by Frowner at 11:58 AM on November 19, 2018 [10 favorites]

99% Invisible recently did an episode on orphan drugs, including the amazing story about how the Orphan Drug Act came to be.
posted by Foci for Analysis at 12:06 PM on November 19, 2018 [12 favorites]

The primary villain in this piece seems to me like it should be insurance companies.

$1mil/dose is also too expensive for health programs in countries which don't operate on private insurance models, though. Hell, one of the biggest populations which could benefit from this specific drug is in Quebec, in Canada, the country which developed the treatment. They have provincial healthcare systems rather than US-style insurers.

The villains here are uniQure and Chiesi Farmaceutici and their management and shareholders, who based their pricing not on production costs (and who had no losses related to research and development to recoup since they bought a drug that was ready to go), but solely on the level of profit they felt they deserved. The primary villain here is, as usual, greed.
posted by halation at 12:28 PM on November 19, 2018 [41 favorites]

The issue blocking Glybera presently is an issue of patents/intellectual property. The original company folded because they couldn't sell the drug until the long approval process was completed.

To my mind, the IP stuff is secondary (though important). What killed the ability of getting this drug to market was, and continues to be, the cost of the approvals process. The academics can't do it. Public grant money will never cover it, so private investors have to. So enter the speculators.

Is there regulatory capture and other industry pressure to keep approvals costs astronomical? You betcha. Are countries far too unwilling to accept data from other reputable jurisdictions? Absolutely.

However, the best remedy in my mind in these unusual cases is a compulsory license in the national interest. Canada has used threats of that in the past. It hasn't been actually done for decades, though threats were made during the SARS crisis of 2003. (It was also floated as a nuclear option during the recent NAFTA renegotiations---Canada expropriating drug patents with the implication that a blind eye would be given to generics being resold into the US). Expropriation once or twice would probably be enough to take the wind out of the speculators sails.

A really limited drug like this would be ideal in a couple of ways. It would solve an immediate problem, but it also would not be a large enough market to cause to many ripples with other governments. But it might call the stock market bluffs.
posted by bonehead at 12:48 PM on November 19, 2018 [3 favorites]

One million is too much for a lifetime cure when it costs $300000+ per year to treat with alternatives? When people are hospitalized for days and weeks of agonizing pain from pancreatitis? Maybe Canada has successfully bargained down the alternate treatments to pennies on the dollar? If you can't point to a cheap gene therapy that's been successful I'd be more inclined to buy your point.

I do appreciate that the pharma biz is full of price gougers. Don't get me started on what I pay for insulin now. But how do you tease apart real costs from oligopoly/monopoly extortion? Once you start taking property from pharma does that cause a drop off in R&D? I really think it's irrelevant who did the research, but it didn't stop when uniqure bought the assets if the patent dates are accurare.
posted by BrotherCaine at 1:04 PM on November 19, 2018 [5 favorites]

Another way to cool rampant speculation could be to tax the value of patent protected assets. It woukd force the companies to either attempt to realize a profit or write down the asset until it could be acquired for a reasonable cost and opened to public domain.
posted by BrotherCaine at 1:06 PM on November 19, 2018 [6 favorites]

If I understand, the disease is generally not fatal and there are dietary methods of managing symptoms.

I'd let the people with the actual disease decide what their risk tolerance is. "Managed symptoms" may reflect a life that is a continual running of the gauntlet.
posted by benzenedream at 1:23 PM on November 19, 2018 [14 favorites]

If I understand, the disease is generally not fatal and there are dietary methods of managing symptoms.

From the article:
All her life, Turcotte has had to follow a strict diet. She can't eat cheese or chocolate or any food that contains fat. And she can't drink even a drop of alcohol.
...
But the worst part was learning that she could never have children. Women with the disease are warned to avoid pregnancy because there is a high risk of miscarriage.
posted by snofoam at 1:29 PM on November 19, 2018 [16 favorites]

So no one gets Glybera because some rich people had a tantrum over insufficient ROI, basically.

That I don't believe. Right now, the price is set at a level where there is no return on investment. Any return is going to be better than none.

The costs of development are a sunk cost. They've been written off. What exists right now is a chunk of IP and a licence to use that IP. The IP is only worth the the income from the use of that IP, ie selling the cure. If the start-up and running costs are too high to be covered the income from sales of the cure, then that's not a commercial play.

Instead, it's a public good opportunity. Government should take back ownership of the IP and produce the drug at a loss, because that loss looks to be less than the cost of health care for the sufferers.

What price should the government pay? Well, the current value of the IP is zero, so that's a good starting point for the negotiation with the owners.
posted by happyinmotion at 1:55 PM on November 19, 2018 [10 favorites]

That I don't believe. Right now, the price is set at a level where there is no return on investment. Any return is going to be better than none.

Boy, I wonder why all those storefronts in busy and prosperous urban areas are vacant! You'd think any rent would be better than a vacancy for the landlord!

(In other words, there's such a thing as market failure.)
posted by praemunire at 1:59 PM on November 19, 2018 [11 favorites]

Of course there's such a thing as market failure. What we've got here is market friction, with low deal flow and sticky pricing. This is likely an options play from the IP owner, where they are presuming that at some point, there'll be enough social pressure on government or other potential buyers that there'll be a deal and the current owners will be able to sell their currently-worthless IP for more than zero dollars.

What's why government when negotiating about the price should start with an initial offer of "we pay you $1 and you like it coz the other offer is we take it for $0".

If you want to be truly cynical, then you could note that the original article is going to increase the demand for a deal that makes this cure available. Hence this article is going to increase the value of the IP in the drug and enable an outcome where the current IP owners don't end up completely out of pocket. Which is where they are right now.

(As for any rent being better than none, look at mattress stores, pop-up shops, temporary art galleries, and all the other ways that landlords get income between having prosperous clients.)
posted by happyinmotion at 2:39 PM on November 19, 2018 [1 favorite]

It was not clear but it sounds legitimately very expensive to manufacture as well as the regulatory hurdles, most of the patients were test subjects.
I work in viral gene therapy (non-clinical research, formerly in academia but these days for a small and fairly obscure biotech company), and the cost of manufacture of these products is huge, orders of magnitude higher than normal small-molecule or even antibody-based drugs.

Recombinant viruses aren't chemically synthesized, but grown. Let's say you've been through all the standard efficacy and toxicity testing in animals already (hellishly expensive and slow, but that's true for all drugs) and all you need to do is manufacture the stuff. First you need large quantities of DNA, produced to levels of purity and documentation similarly stringent to actual drugs, which will cost you many thousands of dollars. Then you grow up tens or hundreds of litres of (characterised, quality controlled, probably expensively licensed) cells in specialised medium, and add your DNA to them. A few days later, you take this soup to purify your virus from it in a process that can be horrifically expensive, labour-intensive, or both (expensive if you like chromatography, labor-intensive if you're unlucky or mad enough to be still be working with ultracentrifugation, both if your protocol requires both).

Then the fun starts because, unless the European Medicines Agency have changed their mind since I looked a couple of years ago, they like to see you do new (slow, expensive) efficacy studies in your animal model for every batch of virus you make, in addition to the relatively quick molecular biology-based assays to check what you have in the tube. Because they have a limited shelf-life even at -150°c, for rare diseases you don't get much economy of scale because it just goes off in the freezer while you wait for the next patient, so you're always in a treadmill of making and assaying new batches.

I don't have any special insight into uniQure's processes. But while of course they'll be turning a profit at $1MM/dose, the cost of manufacture per dose is plausibly measured in hundreds, not tens, of thousands.

This is currently a huge problem for the field of gene therapy generally. The literature is littered with papers saying "We can cure [disease caused by mutation of a known gene] in [model animal] with a single dose of gene therapy", to the point where "I've cured this rare disease" is a not terribly remarkable claim for a PhD student's poster presentation at a gene therapy conference. But translating this into a clinical product that health services (or, I guess, insurance customers?) can afford, even on a non-profit basis, is extremely difficult.

Healthcare should be socialised and free at the point of delivery, and big pharma has a history of getting up to some truly shady shit. But it's not *just* greed that results in this class of drug having such a huge price point.

(This also applies to the awesome ex-vivo stuff, using lentiviruses to "reprogram" T-cells to attack lukaemia: there you need to make the recombinant virus and then the extra step of growing and checking the patient's T-cells, a well established but nevertheless finicky process).

(Disclosure: I work on a commercial project whose aim is to make a stage of the virus manufacture process much cheaper. Which is not identifying information because offhand I can list ten companies from international behemoths to scrappy startups working on varying approaches to the same problem, never mind all the academic labs. )
posted by metaBugs at 2:42 PM on November 19, 2018 [34 favorites]

30 people and a couple cats[1] got cured by provision of the drug through non-market mechanisms, and one person got cured by provision of the drug through the market, so that looks to me like non-market is the way to go here. Cost effectiveness versus continual treatment aside, given the ability to cure people of such a deadly and life impacting disease, we, as a society, have a moral obligation to do so.

[1] given the history mentioned, the cats involved didn't really sounds like lab animals so much as some rando cats a veterinarian encountered so I'm choosing to believe they were some beloved pets who got the chance of a lifetime to get cured in a clinical trial before returning home to New Zealand and you should absolutely not provide evidence to the contrary if it exists
posted by vibratory manner of working at 2:49 PM on November 19, 2018 [7 favorites]

for that matter I'm increasingly of the opinion that free universal health care for family pets should be made available as well but like that we haven't even managed that for people is horrifying
posted by vibratory manner of working at 2:51 PM on November 19, 2018 [5 favorites]

> This is currently a huge problem for the field of gene therapy generally. The literature is littered with papers saying "We can cure [disease caused by mutation of a known gene] in [model animal] with a single dose of gene therapy", to the point where "I've cured this rare disease" is a not terribly remarkable claim for a PhD student's poster presentation at a gene therapy conference. But translating this into a clinical product that health services (or, I guess, insurance customers?) can afford, even on a non-profit basis, is extremely difficult.

is this a problem that's solvable by a group of grad students who've done research in the appropriate fields, who have good infosec practices, and who have the appropriate level of respect for bourgeois law (i.e. nil)? Or does manufacture require access to tools or infrastructure outside of reach for your standard anarchist collective?
posted by Reclusive Novelist Thomas Pynchon at 2:57 PM on November 19, 2018

Orphan drugs like this should be manufactured and sold at cost by the government.

The gov't fixed this with the Orphan Drug Act!
posted by 922257033c4a0f3cecdbd819a46d626999d1af4a at 2:58 PM on November 19, 2018

This is likely an options play from the IP owner, where they are presuming that at some point, there'll be enough social pressure on government or other potential buyers that there'll be a deal and the current owners will be able to sell their currently-worthless IP for more than zero dollars.

No. The problem is not that they can't sell it at any profit, it's that they can't sell it at the profit they want (and may have promised creditors). The IP is not valueless. If there is a market for a good at a price that ensures a profit but the good is still not being made, there is market failure. Since they can't get the margin they want manufacturing it for sale, they're hoping to inflict enough suffering by not manufacturing it that some less market-oriented entity will license or buy the patent from them and thereby give them more of a return on it than they could manufacturing it at a price insurers and/or healthcare systems would pay for.

(Why people insist on trying to give corporations the benefit of the doubt in this day and age, I will never understand. Capitalism hates you.)

(As for any rent being better than none, look at mattress stores, pop-up shops, temporary art galleries, and all the other ways that landlords get income between having prosperous clients.)

You are really not clear on retail blight in the relevant cities. There are seven or eight stores in my neighborhood alone that have been completely vacant for the two-years-plus I have lived there. None of your little dreams of how this is actually not happening. It really is.
posted by praemunire at 3:25 PM on November 19, 2018 [8 favorites]

The gov't fixed this with the Orphan Drug Act!

As mentioned in the 99% Invisible episode that Foci for Analysis linked above, the Orphan Drug Act doesn't adequately address the problem, and doesn't solve the issue of extortionate pricing:

Abbey Meyers has mixed feelings about her legacy. “Thirty to thirty-five years later, the Orphan Drug Act has been responsible for the most miraculous treatments in many diseases,” she says, “but it’s also been a major economic problem, because some of the companies that make these drugs have put a price on them that make the drugs absolutely unaffordable.”

posted by Lexica at 4:30 PM on November 19, 2018

Yeah I listened to the 99% episode too. The Act is doing exactly what it was meant to do. Get cures out there and to make sure a private company makes bank.
posted by 922257033c4a0f3cecdbd819a46d626999d1af4a at 5:51 PM on November 19, 2018

Or does manufacture require access to tools or infrastructure outside of reach for your standard anarchist collective?

Yes. We're talking about ultrcentrifuges, liquid N2 tanks, and reagents that cost multiple dollars per microliter. A reasonably wealthy academic lab could do some early work but scaleup and safety testing are unavoidable $100k+ experiments.
posted by benzenedream at 7:07 PM on November 19, 2018 [10 favorites]

Well, I guess it depends on your risk tolerance? A huge proportion of the cost comes from safety precautions, mostly a combination of Good Manufacturing Practice (double-checking and keeping meticulous records of all your ingredients, equipment, and processes, which can include checking your suppliers' labs and records) and quality control of the produced batches. Plus licensing agreements for various patented bits of tech which are free for early research but become enormously expensive to use in clinical trials or commercial products.

A small volunteer team with a background in engineering (to (re)build and calibrate second-hand equipment) and virology could probably get doses made for costs in the order of thousands of dollars, plus startup costs in the high tens of thousands. But only if they were willing to roll the dice on some of their patients dying from preventable contaminations or mis-dosing, and then not being able to work out why or which other batches are affected.
posted by metaBugs at 1:05 AM on November 20, 2018 [4 favorites]

In April 2017, just two years after it first went on the market, Chiesi announced it was abandoning Glybera. The company allowed the European marketing licence to expire.

Three doses left on the shelf were basically given away. A patient in Italy was treated for 1 euro, and two German patients also received doses for 1 euro each after Dr. Steinhagen-Thiessen asked Chiesi for the leftover product.

A $1 million drug sold for 1 euro? The exchange rate is worse than I thought!

(There is surely an interesting economics paper to be had here.)
posted by clawsoon at 6:21 AM on November 20, 2018

Oh, hi! My kid takes the most expensive drug currently on the market, and I worry about health insurance, specialty pharmacy access, deliveries of tiny glass bottles, and making sure he takes it three times per day with food (and his other, less expensive, specialty medication) every day. My kid’s dosage has a list price of about $400,000 per year (dosage is calculated by body surface area, so it will grow as he grows), and we’ve well surpassed the $1,000,000 mark over the years.

One thing I don’t worry about (but maybe I should, because America?) is its ongoing existence and production, since it is officially FDA-approved and protected by the Orphan Drug Act. Due to this, unlike Glybera, the pharma company gets to rip off the entire US health industry for at least 7 years due to exclusivity rights. And they bought the predecessor drug, which was used as a cheaper but more awful alternative for people who couldn’t tolerate or get their hands on the new drug, jacked that price up as well, and now they own and get to set prices for the whole pipeline! Amazing market cap, pharma bros! The drug is just starting to be made available in the EU and in the UK, which bodes well for ongoing availability here, though Canada has approved the drug but has been negotiating pricing for the past two years. I am really rooting for Canada because if Gilead happens here we are leaving ASAP.

The key difference between this drug and Glybera, though, is that it is a maintenance medication and not a cure. My son will be on this medication every day of his life until a better medication comes along, and big pharma knows it and is making bank while they can. I fully anticipate a $1+ million price tag for whatever gene therapy drug comes along, though my kid may be an adult by then and choose to get it for free (but with risk) via a clinical trial. I am so sad for the families affected by LPLD who could not get Glybera during the brief window in which it was available, and who know that the science that could cure them is out there and sitting on an inaccessible shelf.
posted by Maarika at 6:55 AM on November 20, 2018 [8 favorites]

rockindata: Orphan drugs like this should be manufactured and sold at cost by the government.

They used to be. (At least, here in the UK. A third of a century ago I was a trainee pharmacist working in an NHS district general hospital that had an attached aseptic manufacturing suite, for producing low-cost/high-demand products that no generics manufacturer would touch. Like peritoneal dialysis fluid—each dialysis patient[*] needed about 40 litres per week of what was basically sterile-to-injectable-standards isotonic saline, in big-ass infusion bottles, and the stuff was too cheap for trad manufacturers to make and ship profitably. (Basic ingredients cost less than the equivalent volume of Coca Cola, but had to be prepared with i/v pharmaceutical levels of quality control and sterility.)

I'm pretty sure that over the past three decades NHS England closed all those district manufacturing suites, probably as a "cost saving measure" ...

[*] I'm way out of touch but AIUI there is considerably lower demand for renal dialysis in the UK than the USA; efficient transplant services on the NHS, among other things. (Even in 1985 it was clear that a kidney transplant worked out cheaper than 15 months of dialysis per patient, so the NHS prioritized it.)
posted by cstross at 7:42 AM on November 20, 2018 [5 favorites]

But only if they were willing to roll the dice on some of their patients dying from preventable contaminations or mis-dosing, and then not being able to work out why or which other batches are affected.

Also note that with many types of gene therapy, you may only get one chance since the gene therapy agent may be seen and recognized by the immune system, which means if you underdose you may be robbing the person of a chance at a cure in the future.

Dosing in these treatments is also complicated by the fact of preexisting immunity to the viral backbone used as the delivery agent, so in the worst case every patient needs to have neutralizing antibodies tested for, and the dose is different for every patient based on the results.
posted by benzenedream at 5:56 PM on November 20, 2018 [2 favorites]