About this Author
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: Twitter: Dereklowe

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December 13, 2012

Rheumatoid Arthritis Wins A Couple of Rounds

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Posted by Derek

No one told me that it was "Rheumatoid arthritis clinical disaster day for companies that have enough to worry about already", but apparently that's what it is. AstraZeneca doesn't have an awful lot in its late-stage pipeline, but one of the things in it is a Syk inhibitor licensed in from Rigel, Fostamatinib. (More accurately, that's a phosphate ester prodrug of the Rigel compound - check out the structure and you'll see why a prodrug approach might have been necessary).

That's positioned as an orally active anti-inflammatory, to go up against Humira and the like. Back in Phase IIa it looked promising, although there have been concerns about blood pressure effects (disclosure of which has led to some hard feelings among some investors). But a new trial head-to-head against Humira in rheumatoid arthritis patients, it definitely comes up short. A Phase III trial will report next year, but what are the odds that it'll turn this one into a success?

And Eli Lilly is another company that doesn't need any more bad news, but they're stopping an RA therapy, too. Tabalumab, an antibody against B-cell activating factor, is also targeting the TNF pathway. This trial was in RA patients who were not responsive to methotrexate therapy, and was halted for sheer lack of efficacy, which is disturbing, since the antibody had (up until now) shown reasonable data. Lilly says that they're suspending enrollment in the clinic until they see the results (next year) of their ongoing trials.

Comments (6) + TrackBacks (0) | Category: Clinical Trials


1. Anonymous on December 13, 2012 10:58 AM writes...

And Rick Gonzalez smiles.

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2. Calvin on December 13, 2012 11:02 AM writes...

Kudos to a former coworker for this observation but while AZ "strives" to be best in class or first in class, what it actually does is be "never in class"

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3. jimmy on December 13, 2012 12:04 PM writes...

OK I'll bite. Why was a phosphate ester prodrug needed in this case? Parent compound doesn't look so bad for a kinase inhibitor. Was it solubility? And is the active compound the amide or the N-hydroxymethyl amide? Sometimes those aminal-type structures can be stable if one of the N's is acylated or otherwise electron poor.

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4. Innovorich on December 13, 2012 12:47 PM writes...

jimmy - the amide - it's called tamatinib. And don't really know - don't think Rigel/AZ know/knew either. As stupid as it sounds, maybe they didn't even know it was a pro-drug?!

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5. Anonymous on December 13, 2012 3:46 PM writes...

@ Innovorich: You are correct, what you wrote does sound stupid. The hydroxymethyl phosphate moiety is a known prodrug ( ). There is no need to insult the medicinal chemists at Rigel.

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6. Anonymous on December 14, 2012 7:06 AM writes...

I am curious if Pfizer did the same head-to-head trial for their Tofacitinib?

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