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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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March 20, 2007

AGI-1067: Dead or Alive?

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Posted by Derek

Pfizer's enormous torcetrapib failure last fall wasn't the only time a company has come to grief in the cardiovascular area, and it's not going to be the last one, either. That's been proven this week by a much smaller company, Atherogenics, and their lead drug, AGI-1067 (partnered with AstraZeneca).

The company is targeting expression of the VCAM-1 protein in blood vessels. That's an immunoglobin that seems to be involved in the adhesion of various blood cell types to the vessel walls, and as such is considered a very interesting target for atherosclerosis. AtheroGenics has been working on a series of drug candidates that interfere with the expression of VCAM-1 (through blocking an oxidative pathway in the endothelial cells) and could thus slow the development of arterial plaques (or reduce the size of plaques that had already formed).

Such is the hope, anyway. AGI-1067 behaved well in animal models, and went through numerous Phase I trials in combination with other cardiovascular agents. That link will also take you through the Phase IIa and IIb trials, which showed some real effects in reduction of plaque volume. Those results led to this Phase III trial (with the acronymn ARISE), which expanded the number and variety of patients while looking at real-world endpoints.

That's just how things should work. You see if the drug is tolerated, alone and with the therapies it's going to be given with. Then you check some primary endpoints, to see if the mechanism you're targeting is really being affected. Finally, you see if that's actually going to do a real number of patients any good: I, II, and III. And, unfortunately, III is where the Atherogenics drug ran into trouble.

They missed their primary endpoint, which was a composite score of cardiovascular adverse events - death, heart attack, stroke, angina, etc. Overall, AGI-1067 was no better than placebo when given along with the standard drugs for this patient population. There's no way to call that good news, and no one's even trying. At the same time, though, the company claims to have seen positive effects in some disease states. What subgroups those are, and how positive those effects were, won't be known until next week's meeting of the American College of Cardiology in New Orleans. It's impossible to say if this is just wishful thinking, or a drug worth salvaging.

That's just what the people at AstraZeneca have to decide. The company's pipeline could use some help (not that this distinguishes them very much these days), so they don't want to walk away from something promising. At the same time, they can't afford to throw good development money after bad, either. But the stakes are much, much higher for AtheroGenics, since this physiological pathway is basically the platform for the entire company. There are doubtless some very difficult and unpleasant meetings in progress, not the tiniest bit of fun for anyone involved. My. . .well, heart, goes out to everyone involved. . .

Comments (7) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development


1. Al on March 21, 2007 4:47 AM writes...

Derek, Master of Understatement! I think that makes it five failures in a row from AZ - Iressa, Exanta, Galida, Cerovive, and now this latest one. Their late stage pipeline could indeed "use some help".

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2. CR on March 21, 2007 8:06 AM writes...

It's a shame--although, not surprising--that this drug failed for both AZ and Atherogenics. After the smallish mid-west Pharma company that I was working for decided to close shop on their discovery efforts last year I was job searching and interviewed at Atherogenics. Nice, small company in a desirable--for my wife at least--area. I had doubts regarding the fact that all their eggs were in one basket--AGI-1067. I inquired what would happen if this failed and the overall consensus was the company would have a hard time continuing--their market cap diminished from ~310 million to ~110 million when their stock dropped nearly 60%. It would have been nice--AZ was pledging up to $1B in support for AGI-1067. As it stands now, most analysts are saying AZ will simply walk away from the deal--only putting in ~50M. Other analysts are saying even though Atherogenics is trying to spin this into some good--that they will have a hard time gaining FDA approval for these other "positive" outcomes. Such is life at a small company.

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3. Wavefunction on March 21, 2007 2:20 PM writes...

Derek, any thoughts on the interview with William Haseltine about the 'State of the Pharma Sector' in the February 5, 2007 issue of C & EN? Haseltine says that in his opinion, the current model of US pharma is flawed and is facing problems, because it is obsessed with blockbusters, thus neglecting drugs which would bring in less revenue with say a 70% profit margin, but could be valuable for special diseases and cases nonetheless. He says that pharma should capitalise on all the good stuff, blockbuster or otherwise, if it wants to remain successful.

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4. Wavefunction on March 21, 2007 2:26 PM writes...

Apart from QT interval issues, what are the other standard CV problems encountered in these trials?

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5. Anonymous on March 21, 2007 6:09 PM writes...

is this the compound that was some sort of bisthio methylene compound (kind of like a thioacetal of an aromatic compound)? I always thought it was kind of odd looking for a drug-this opinion was just structure based. I never looked at the pharmacology.

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6. anon on March 21, 2007 10:45 PM writes...

Sorry Derek,
VCAM isn't an immunoglobulin (check your spelling, too). It has an Ig fold, but it's not an immunoglobulin (you can trust me or ask Gerry Edelman who won the prize for work on Ig's then later determined that his favorite neurobiology molecules were pretty similar to Ig's).

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7. Johnny Stettin on March 22, 2007 1:01 PM writes...

These results are interesting as AGI-1067 could essentialy be considered as a prodrug of probucol. Probucol presumably works well enough to be launched (I haven't looked in detail). Its lipophilicity enables it to associate with LDL and it seems that addition of structual elememts in AG-1067 that increase water solubility may have changed the drugs tissue distribution. Perhaps this no longer occurs with the more hydrophilic derivative. Either way, once some digging is done on reasons for failure, this may become another lesson on how prodrugs may not be the 'slam-dunk' many think they are.

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