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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Where Drugs Come From, and How. Once More, With A Roll of the Eyes | Main | Wasted Money, Wasted Time? »

August 3, 2009

Savient Feels The Pains of Gout

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Posted by Derek

Well, here's a nasty surprise for you: your new drug gets a 14 to 1 "Yes" vote from an FDA advisory committee, but the agency turns you down, anyway. That's what's just happened to Savient and their new biologic product for gout, Krystexxa (pegloticase).

The FDA isn't required to say why they do such things, at least not to anyone else other than the company that submitted the drug. And they're aren't talking this time, either, but it looks like there's a manufacturing issue involved. The process for making Krystexxa seems to have changed a bit since the clinical trial batches, and the agency apparently wants to make sure that this hasn't altered anything. If all goes well, then, you'd expect the company to get things straightened out sometime next year, but for Savient, that's an awful long time to wait.

People who follow the company (and the gout market) have been arguing for the last few years about its prospects. Krystexxa is a pegylated form form of an enzyme called uricase (urate oxidase) that clears out uric acid (crystals of which are the proximate source of trouble in gout). Interestingly, this is one of those enzymes that's found all over the various phyla, and in mammals up to primates - but it stops there. We have the gene for the enzyme, but it appears to have been mutated to an inactive form at some point (rather like our gene for the last step in endogenous Vitamin C synthesis - I always wonder what the Intelligent Design people have to say about such things, although I'm pretty sure that it's some variant of "Because it was Designed that way for some good reason that's not immediately clear to us right now").

Bringing in this enzyme, then, isn't a case of replacing something that we already have. This is adding a function that we lost back in the early primate days, so we're talking "foreign protein" here. The pegylation is partly there to help with that, and partly just to give the protein a chance to survive the usual metabolic processes. For those who don't know the term, "Peg" is short for "polyethylene glycol", so a pegylated protein has long polymer chains of this hanging off it at various points. The total effect is rather like spraying the thing down with a coat of clear varnish - it changes the solubility, slows down metabolism and clearance, and changes the immune response to the protein. Pegylation is useful indeed, but something of a black art, since it's difficult to predict just what'll happen each time you try it.

Well, I wish Savient luck in getting things straightened out. And I wish their shareholders luck today. The company's stock has not been a place for the easily alarmed over the last year or two, and I'll bet that a lot of people thought that the fear had been cleared by that 14-1 advisory committee meeting. But that's the thing about this whole industry: you can never quite breath easy. . .

Comments (13) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs


COMMENTS

1. ANON on August 3, 2009 9:38 AM writes...

This isn't such a suprising result if they've changed their method, though the timing was possibly poorly handled. It is more usual for method development to have been sorted before the trials, or the old route will be run alongside the new to take the product to market, while allowing the FDA to run it's checks on the new one, allowing a swift change over.
As you allude to Derek, this highlights the problems with biologicals where a modified route can lead to the possiblity of significant changes in post-translational modifications. Small molecules will always have a home!

Permalink to Comment

2. Sili on August 3, 2009 10:24 AM writes...

I always wonder what the Intelligent Design people have to say about such things
The Fall. Everything can be explained by Original Sin. Or post-Diluvian hyper-evolution.

Ah yes, PEG. The "anti-freeze and ether" in vaccines making all our poor kids autistics.

Sorry - Just been reading Respectful Insolence.

Permalink to Comment

3. CMCguy on August 3, 2009 10:44 AM writes...

I see two possibilities for the denial:

As you state "Pegylation is useful indeed, but something of a black art, since it's difficult to predict just what'll happen each time you try it" and Savient have not demonstrated adequate control via manufacturing process validation or analysis methods both of which are extremely difficult relative to small molecules and most biologics.

Another consideration is that FDA is using to make a statement indirectly about "biosimilars or biogenerics" and signaling that again process and methods need to be controlled very very well before agency will be willing to approve any such products. Such messages seem to be a common mode that makes a single company suffer to provide lessons for others.

Permalink to Comment

4. emjeff on August 3, 2009 10:56 AM writes...

After reading this, the first thing I thought of was bio-similars. FDA is going to have to do a lot of back-pedaling if they want generic biologics. Imagine, the same company makes some changes in their process and the Agency needs more data, data that may take a year of more to generate. What's going to happen when several comapnies are trying to make the same protein?

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5. Muruga on August 3, 2009 10:58 AM writes...

Here is a point to note. While FDA refused Savient to market the biological, Krystexxa, the same regulator has approved the small molecule drug, Colcrys (Mutual Pharma) to treat gout last week. The potential safety issues, associated with Krystexxa, and to a small extent, manufacturing defect, could have contributed to the rejection by FDA. No doubt, Krytexxa is clearly efficacious. However, Krystexxa seems to have the potential for increasing CV risk and developing severe allergic responses. It has caused anaphylaxia in 5% of patients in Phase III trials, which were of small sample size.

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6. TOSG on August 3, 2009 11:22 AM writes...

Wow, Nicholas Cage must be hard up for work these days...

Permalink to Comment

7. Hap on August 3, 2009 12:02 PM writes...

Why couldn't he just do another mediocre action movie instead of turning to spamming to pay his tax debt? It would have been much more honest and less detrimental to his reputation and soul to do porn or sell used cars, time shares, or even supplements than to become a drug spammer.

Wave bye-bye, (ex-)#6.

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8. d on August 3, 2009 3:08 PM writes...

Hopefully they will sort out the manufacturing issue. DSCO had a similar problem and it has gone on for quite a while now

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9. Linnea on August 3, 2009 4:06 PM writes...

If it's any consolation, it has been postulated that urate may act as an antioxidant in human blood, so in theory the relative hyperuricemia may be beneficial (up to a point, of course).

Ann Intern Med 2005;143:499-516

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10. milkshake on August 4, 2009 1:18 AM writes...

if its any consolation, the antioxidant properties of elevated urate will not objectively make your live longer but it can make your feel like your misery lasted for eternity

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11. srp on August 4, 2009 3:14 AM writes...

I'm not qualified to judge its accuracy, but the "molecular varnish" explanation of pegylation is first-class from a vividness perspective.

Permalink to Comment

12. Greg Q on August 21, 2009 8:12 PM writes...

rather like our gene for the last step in endogenous Vitamin C synthesis - I always wonder what the Intelligent Design people have to say about such things

Actually, I wonder what the "survival of the fittest" people have to say about the loss of that gene. It would seem like at least as big of a problem for them, no?

Permalink to Comment

13. Pariente on February 25, 2013 9:52 AM writes...

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