22 
Unremarkably, I was totally stuck at O’Hare last night until midnight waiting for a flight that was supposed to take off around 6:00. This being the second time in less than 30 days that O’Hare made me want to die. I mean… Fuck O’Hare. Anyway, given my late arrival and sleeping in later than normal, I’m sitting around with little to nothing to do waiting for mummy Finchsigmate to arrive home with delicious scrambled caviar and figured I’d do a little post on a drug most people probably haven’t heard of.
Cerezyme is freeze dried imiglucerase, a recombinant (and modified) form of the enzyme Glucocerebrosidase and it costs about $200,000 a year for life. It’s one of three treatments for Gaucher’s disease which doesn’t involve scooping organs out with a spoon before they explode or topping the ‘ol femurs off with some new bone marrow. (The others are Miglustat, a small drug and Ceredase, an enzyme derived from leftover placenta… fuckin’ gross.) In general, you don’t have to worry if you aren’t an Ashkinazi Jew or a Sweed from Norrbotten, as they are the ones that seem to be afflicted.
The drug is made inside CHO cells, which are just Chinese hamster ovary cells that have been transfected to produce imiglucerase. Imiglucerase is not the real deal; since they do not produce the actual Glucocerebrosidase, 15% of patients develop antibodies to the drug and of those about half have an allergic reaction. My understanding is that the modifications, specifically the Mannose sugars on the terminus of the existing polysaccharide chain, lead to a selective uptake of the enzyme by macrophages that are resent in liver, spleen and skeleton. Without this modification the drug does not work effectively.
The drug works just like the natural protein by catalyzing the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide as part of the normal degradation pathway for membrane lipids.
If you want to make your own, here is the sequence:
ARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANH
TGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNIIR
VPMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWT
SPTWLKTNGAVNGKGSLKGQPGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGL
LSGYPFQCLGFTPEHQRDFIARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPE
AAKYVHGIAVHWYLDFLAPAKATLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRG
MQYSHSIITNLLYHVVGWTDWNLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQPMFYHL
GHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDPAVGFL
ETISPGYSIHTYLWRRQ + manoses
Why is it $200,000 a year? Maybe more, depending on your dosage needs? Certainly not all recombinant drugs are this expensive. Insulin has been grown in bugs for almost a decade and it’s dirt cheap in comparison.
The answer is that, quite simply, there are probably only 10,000 people in the world with this disease and 5,000 of them are already on it. To recoup that investment they needed to put the price point higher. But it’s an orphan drug! They already got a shitton of money back from the gubment for just making it, why do they need to sell it for such a shitton of money it actually has sales in excess of a billion dollars a year?
Well, that’s one of them sticky ethical questions that the ChemBlog is running out of time to answer… Caviar is almost ready.
Back to top
Yes, yes – standard Genzyme business protocol. Their treatments will take care of that oh-so-rare disease of yours, while costing you the proverbial arm-and-a-leg and the same time.
YOUR RIGHT I GUESS WE SHOULD JUST LET THEM DIE LOL SO THE DRUG COMPANIES DONT MAKE MONEY.
tard
Apostrophes are out of work. Employ them.
Damn it all, Kyle, when will you allow us to edit our comments!?
It occurred to me that you might think my former comment was referring to your usage of tard as opposed to ‘tard.
If so, rest assured that it was directed to whomever the tard is that posted as TOD.
Or TOM, even. See?
I’m slinking off now.
It’s alright. ‘Tard.
You have gone linkastic in this post!
Let me reiterate the old joke about the Czech man regarding the sequence (with obviously no offense to Czech people of course…this is an old affectionate one).
Opthalmologist: Can you read the sequence ARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALG
Czech man: Read the sequence?! I KNOW him!
True. I love my “link” button.
Two things that factor into the cost of enzymes like these are folding – it’s likely you can’t express this enzyme in E. Coli and get the same activity, and optimizing mammalian expression is much tricker than bacterial expression – and process work to get rid of the endogenous retroviruses (typically 5-6 additional purification/neutralization steps) that are rampant in CHO cells and that the FDA doesn’t like to see injected into patients.
It’s less an issue of cerezyme in particular and more an issue of just expressing mammalian proteins as replacement therapies – there isn’t any way to do it cheaply.
Retroviruses? You can’t purchase retrovirus free CHO cells? Or is that how they transfect mammalian cell?
CHO cells are fucking crazy-expensive to make drugs in, although humanized antibodies apparently come out in rediculous yield (I heard from someone in amgen kilograms/liter of continuous culture). Media alone can run you many, many, times the amount it costs over sac. cereveisae, which is what insulin and insulogs are made in. Not to mention handling and process chemistry to make sure that it’s not misfolded. Actually what probably happens is that they make a bunch of batches and clear the ones with enough activity. If you’re curious, I have a connection to the company involved in the production of Cerezyme, and I can find out for you exactly why it costs so much.
Bacteria are also no walk in the park– you have to get rid of endotoxin, especially for drugs going into immunocompromised patients.
Interestingly insulin lyspro, is made with one less amino acid than it should have, which is tacked on later using reverse proteolysis. Has to do with cerevisiae’s KEX1-protease only being able to cleave at certain dibasic sites, leaving an extra lysine on the end. Which seems like it should be shitty but apparently works like gangbusters.
I would be interested. Though the answer a company gives usually isn’t the actual answer.
There are hundreds (possibly thousands) copies of *endogenous* retroviruses in the CHO genome (and for that matter, ours), and, no, no one has gone through and deleted them all and sells a ‘retroviral free’ CHO line. I’m not sure that much genome surgery is even possible with our current tools.
Unfortunately, this is something that drives up the price of all mammalian biologics, especially recombinant antibodies..
Your genome probably also containst thousands of endogeneous, usually silenced retrovirii, which will take a tiny mutation to reactivate.
Fuq that noiz. The FDA has approved a series of qualifications on protein purity coming from CHO cells (and for biopolymer pharmaceuticals in general). Doubtful any retrovirus would get through the gauntlet of purifications anyways.
Dear Kyle,
Cerzyme is not made in ecolie it is made in a mammarian overy that takes up to a month to harvest and is mutated frequently to prevent antibodies from forming. Cerazyme is essentiall Ceradase which is not ued to treat patients anymore due to AIDS and HIV infections in paitents, stronger more antibodies, and over exposure to large quantities of estrogen. Dosage is regulated by weight of the patient. The rate for most gauchers patients is 60 units per kilogram. In addition the development of the drug was established at the National Institute of Health and took over 65 years of research to develop Ceradase. The goverment does not allow itself to produce drugs therefore a bidding war was established for a company to manufacute and make the drug. Genzyme having made this was than automatically awarded and orphane patent which would allow a set drug company to recoup the money spent on devleoping a drug. The law was passed in the early 80’s so that drug companies would actually attempt to work on drugs for rare disease but would not because they would not see any financial gain. In order for another drug to compete with cerazyme they would not simply need to show chemical structure but complete a full 6 year clinical trial which would cost billions of dollars because it is an injection made from an animal protein and not pill or made from a bacteria. The drug also once unfrozen has a shelf life of 20 hours after mixture with steril water and cannot be shaken. It also takes up to three hours to admininster at specific rate per that patients matabolosim or it will nto be abosorbed by the body. In addition I am neith an Ashkinazie Jew nor am I from Norbotten Switzerland and I have Gauchers diseae. Your tone is offensive you should consider this when your write a blog.
Sincerly,
Your friendly dying person
Cerezyme is not made in Coli it is made in CHO cells. These are cultured chinese hamster ovary cells. . Basically it’s a replacement therapy that replaces absent glucocerebrosidase (which normally resides in the lysozyme). This works because cells uptake proteins naturally — and the protein happens to have all of the localization motifs built in, resulting in efficient trafficking to the lysozyme — a strategy which does not generally work for biopolymer therapeutics with targets inside the cells.
Since Gaucher’s is an orphan disease, Genzyme got the patent on an orphan disease program. .
In order for another drug to compete with cerazyme they would need to show chemical structure, complete a full 6 year clinical trial which would cost billions of dollars, revalidate their culturing techniqe and culturing strategy, show efficacy, and safety, like all drugs, whether made in bacteria, or on the tonscale in huge petrochemical feedstocks.
In addition I got really unlucky and have one of the other 120 mutations identified (or possibly not identified) that cause Gaucher’s besides N370S or L444P, which are the predominant Ashkenazi or Swiss mutations.
It’s okay though. Several research groups are looking at pills which will cure gaucher’s, either by stabilizing the native protein, or by tricking the body into accepting a slightly defective mutant. This will kick the ass of administering protein by injection, and will not have the broadscale side effects of substrate deprivation. That is, unless those research groups are observing artefact and giving Gaucher’s patients false hope.
that was supposed to be a translation of the above, edited to correct for scientific content.
Hello, FDP!
I, too, am neither Jewish (Ashkenazi or otherwise) nor am I descended from the Swiss. I was diagnosed w/ Gaucher’s at 23 … 8 yrs ago now. I just happened to stumble across Kyle’s blog here, which I personally found fairly spot on. While I see where his nonchalant tone and critical questioning of Genezyme’s motives could seems crass and insensitive, I personally didn’t read it to the same result.
In fact, there’s not a week that goes by that I don’t growl a little and being somewhat ‘indebted’ to an industry that can hold my very life over my head simply if they feel their profit margins just aren’t ‘quite’ high enough this year.
Realistically though, I recognize I’m damned lucky to have access to this treatment. I know my daughter is pretty grateful too considering she wouldn’t have many yrs left w/ dear ol’ mom if it weren’t for the piles of cash changing hands on my behalf every 10 days.
I also think that even bigger a concern than the drug corps these days, for me anyway, are the insurance sharks. If the profit maximizing trend of eliminating fixed copays on meds in favor of 10, 20, or even 30% of cost copays continues at this rate … well, how much Genzyme is making off us will diminish quite quickly. =)
If anyone gets that answer from Genzyme about pricing structure, I’d be interested in hearing it. Oh, and FDP, my ERT takes 4.5 hrs for drug alone … which means typically 6 hrs in clinic each time.
Thanks for an interesting discussion on this, guys. It’s rare to find anything new to read on this.
From clinic,
Dawn
friendly drug orphan, optimist, general all-around hippie
I see this string is a little old, but contrary to some of the implications in the comments, there are other drugs being created for Gaucher’s. Made by Shire PLC, the drug is velaglucerase alfa and is in Phase III testing. If I understand correctly, this may be accelerated because of a shut down at the Genzyme plant in Boston. I have no idea what the cost is but I competition usually leads to lower costs in a properly operating market. Of course, given the high average cost to produce the drug, the use of subsidies, and insurance, we are not in that type of market. Still, Genzyme is making a great deal of money and competition could eat into that. (Just a note, I am a Gaucher’s patient and am on Cerezyme. I am very happy that insurance pays the cost of the medication.)
WHAT IS EVERYONE DOING ABOUT THEIR INFUSIONS? WHAT A DISASTER