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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: Twitter: Dereklowe

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August 24, 2009

Arzoxifene: Not the Road to Big Profits?

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Posted by Derek

Eli Lilly announced some bad news last week when they dropped arzoxifene, a once-promising osteoporosis treatment (and successor to Evista (raloxifene), which has been one of the company's big successes).

If this drug had been found ten or fifteen years ago, it might have made it though. But the trial data showed that while it made its primary endpoints (reducing vertebral fractures, for example), it missed several secondary ones (such as, well, non-vertebral fractures). And the side effect profile wasn't good, either. That combination meant that the drug was going to face at hard time at the FDA for starters, and even if it somehow got through, it would face a hard time competing with generic Fosamax (and Lilly's own Evista).

So down it went, and it sound like the right decision to make. Unfortunately, given the complexities of estrogen receptor signaling, the clinic is the only place that you can find out about such things. And there are no short, inexpensive clinical trials in osteoporosis, so the company had to run one of the big, expensive ones only to find out that arzoxifene didn't quite measure up. That's why this is a territory for the deep-pocketed, or (at the very least) for those who hope to do a deal with them at the first opportunity.

One more point is worth emphasizing. Take a look at the structures of the two compounds (from those Wikipedia links in the first paragraph). Pretty darn similar, aren't they? Arzoxifene is clearly a follow-up drug in every way - modified a bit here and there, but absolutely in the same family. A "me-too" drug, in other words, an attempt to come up with something that works similarly but sands off some of the rough edges of the previous compound. But anyone who thinks that development of a follow-up compound is easy - and a lot of people outside the industry do - should consider what happened to this one.

Comments (14) + TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Drug Development | Toxicology


1. FormerMolecModeler on August 24, 2009 9:02 AM writes...

I find it interesting that they decided to make the follow-up compound more lipophilic. I wonder how many analogs they made before they settled on that one, which I bet is one among the first set of derivatives they made.

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2. Lucifer on August 24, 2009 9:19 AM writes...

Signal transduction differences between cell types and organs can be a problematic.

Has anybody made a less toxic version of clozapine without reducing it' efficacy?

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3. CMCguy on August 24, 2009 10:14 AM writes...

This to me illustrates how if Pharma companies become overly specialized, as per recent post, there is more risk of failure. Even though a "me-too" certainly the objective was to create something that "worked better" than existing drug (sand off edges good statement) and because Lilly had a previous drug in this area one would argue they should know how to do that. We always come back to the complexities of Biology where our level of understanding frequently is more limited than we wish to accept and I think that indeed is the message public does not comprehend,

Hard to get a read if this was a Science or Marketing driven halt but even today if this was coming from a small Pharma/Biotech more than likely would have been pushed forward regardless of the apparent poor side effects profile.

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4. cookingwithsolvents on August 24, 2009 1:07 PM writes...

Ouch, those are pretty close to my un-drug candidate eye.

Isn't clipping off the anisole Me a pretty big change from a physical properties standpoint, though? Or does the liver just do that anyways?

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5. bayarea on August 24, 2009 2:06 PM writes...

The bis-phenol is necessary to mimic estradiol, the natural ER ligand. However, it was found that the compound's phenolic hydroxyls are prone to glucuronidation (not much of a surprise there). So, one of the phenols is capped with a Me (prodrug). Interestingly, the hydroxyl that was glucuronidated in the monkey is different than the one glucuronidated in humans.

Pfizer's Fablyn, another SERM antagonist, did not fare too well either.

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6. FormerMolecModeler on August 24, 2009 2:27 PM writes...


The differential glucoronidation between monkeys and humans, which is about as close as you can get, just makes me despair. It's amazing anythinig gets through the clinic when you're up against something like that.

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7. Kismet on August 24, 2009 3:51 PM writes...

I don't get why a company would design a me-too of one of their own drugs, even though the raloxifene patent apparently does not expire in the near term.
Even if the drug succeeded it would it eat into sales of raloxifene, no?

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8. Crazed_modeler on August 24, 2009 3:59 PM writes...


Arzoxifene is indeed a pro-drug. Depending on how it is measured, desmethylarzoxifene is from 8 to 300 more potent than arzoxifene:

Cancer Research 61, 8412-8415, December, 2001

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9. PorkPieHat on August 24, 2009 7:53 PM writes...

Hey, does this thing generate p-quinone metabolites?

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10. TX Raven on August 24, 2009 9:22 PM writes...

Must be the cLogP....

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11. Incha on August 25, 2009 8:52 AM writes...


'I don't get why a company would design a me-too of one of their own drugs, even though the raloxifene patent apparently does not expire in the near term.
Even if the drug succeeded it would it eat into sales of raloxifene, no?'

Thats because pharma companies are not (always) the money grabbing evil giants some people want you to believe.

Lilly thought they could make a better drug, that would help more people, more efficiently and with fewer side effects - that is what we do!

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12. Alig on August 25, 2009 9:04 AM writes...

"Lilly thought they could make a better drug, that would help more people, more efficiently and with fewer side effects - that is what we do"

That's nice, but doesn't make business sense unless it opens up a larger market. Actually, I believe they thought other companies could make a better drug, and they would lose market share to the competitors. To counter the anticipated competetion, they made what they thought would be a better drug, unfortunately it failed to be better. "Me-too" drugs often drive competition which causes improvements to be made in the standard of care.

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13. Ed on August 25, 2009 1:46 PM writes...

Well I think Nexium is a case in point regarding 'me-too' drugs. Debatable improvement over its predecessor Losec, but still one of the biggest selling drugs in the world.

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14. milkshake on August 27, 2009 11:50 AM writes...

I really dislike the switch from diaryl ketone in raloxiphene to diaryl ether in arzoxifene. With hydroxy-substituted benzothiophene the molecule already looks like a metabolic liability waiting to happen, so electron-withdrawing substituent like benzoyl can be an useful thing to have. Aryloxy- I don't think so.

Electron rich ring systems like naphtalene and thiophene are not nice even though you see them in drugs.

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