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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

« Fat Rats Make Poor Test Subjects? | Main | Flowing, Not So Gently »

March 3, 2010

Dimebon Comes Crashing to Earth

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Posted by Derek

Earlier this month I wrote about Medivation and their Russian-derived clinical candidate for Alzheimer's disease, Dimebon (latrepirdine). At the time, I wrote that "A lot of eye-catching numbers from small Phase II trials tend to flatten out in the wider world of Phase III, and if forced, that's the way I'd bet here."

Unfortunately, that's just what appears to have happened. The results are out today, and Dimebon has not showed any efficacy at all versus placebo. From the data given in the press release, the comparison is just absolutely flat; you could have been giving the study patients breath mints and seen the same numbers. Since the design of this trial was similar to the smaller Phase II trials that showed such interesting results, there's clearly something going on that we don't understand. But that's the motto for all central nervous system research, isn't it?

I'm really not sure if there's a way forward for this drug. When you go to a larger, more well-controlled trial and revert back to baseline, it's hard to make a case for continued development. Pfizer (Medivation's partner here) still has a lot of money and a lot of desire to find a good Alzheimer's drug. But I don't think they'll be in the mood to spend much more of it here.

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. David Formerly Known as a Chemist on March 3, 2010 11:02 AM writes...

Alzheimer's is such a horrendously complex, poorly understood disease. Shorting the stock of companies with products in Phase III for AD is unfortunately an excellent investing strategy.

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2. The Pharmacoepidemiology on March 3, 2010 11:50 AM writes...

Unfortunately, if I bought companies on the basis of Phase II results alone, I'd be very rich indeed. However, Phase III data are requisite. There's a reason why they're requisite--large numbers, statistical differences, etc. Medivation is just another example of those reasons. I feel bad for the employees of Medivation. Between Pfizer likely giving the drug back wholesale and the lack of positive data appealing to potential investors from whom it could raise some cash, there are going to be a lotof people laid off: Certainly everyone in the nascent marketing and medical affairs departments, maybe in the clinical development group too. Just what we need on the peninsula south of SF--more biotech people looking for jobs.

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3. Cialisize me on March 3, 2010 12:01 PM writes...

The "Good Phase II / Bad Phase III" story is a common theme in biotech. The reward is tremendous for a biotech with good phase 2 results, so there is a great incentive to produce positive data. Just sayin.

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4. anchor on March 3, 2010 12:05 PM writes...


When it is too good to be, do not believe it. A cardinal "rule #1" for any scientist. Must be true also in clinical studies.

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5. You're Pfizered on March 3, 2010 12:07 PM writes...

Medivation's stock started the day at $40 and is now down in the $13 range. Ouch!

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6. anchor on March 3, 2010 12:08 PM writes...

When it is too good to be, do not believe it. A cardinal "rule #1" for any scientist. Must be true also in clinical studies.

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7. Wage Slave on March 3, 2010 12:34 PM writes...

that is worth saying twice.

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8. Skeptic on March 3, 2010 12:54 PM writes...

"The "Good Phase II / Bad Phase III" story is a common theme in biotech. The reward is tremendous for a biotech with good phase 2 results, so there is a great incentive to produce positive data. "

Too bad Jan Hendrik Schon didn't discover biotech. He'd still be pumping out great Phase II data, never missing a meal.

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9. Ty on March 3, 2010 1:01 PM writes...

It's so clear in the hindsight, just wondering what Pfizer people were thinking when they bought in...

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10. Anonymous on March 3, 2010 2:01 PM writes...

I once went on a course where a scenario was laid out for us - having closed a disease area and laid off the scientists a couple of years later one of the guys let go comes back with a "great drug" that can cure the disease. Should you a) continue to work on what you know or b) change direction and throw everything you've got at this new opportunity ?

I voted for option a while almost everyone else voted for option b. Quite simply I've seen us fall all too often for the next miracle cure that some great external scientists have developed, only to discover that we brought snake oil instead.

I was wrong apparently. The course leader went on to greater and better things. While the disease in our hypothetical scenario was cancer it all seems the same to me. A compound that seems to work in Phase II trials with no idea of the mechanism. No thanks. And most "colleagues" didn't think it was that smart either.

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11. Me on March 3, 2010 2:03 PM writes...

We know that Pfizer managers who decided to buy Dimedon with a lot of cash are MBAs. They should learn from history about this Alzheimer's disease and the successful rate of other research. These managers are over-rated.

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12. David, Health Blogger on March 3, 2010 2:20 PM writes...

The second I read this news I thought

a) that really sucks
b) another great call by Derek Lowe

The problem is that everything is clear in hindsight; the process of drug discovery is capricious and many blockbusters have emerged from dubious beginnings.

Poor Medivation. At least Pfizer has some interesting tricks up its pipeline.

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13. SPRITY on March 3, 2010 2:29 PM writes...

Another example of placebo effect, or spiritual effect or pyscological effect, whichever suits you. It is especially prominent in PII of CNS drug since the selected group of patients get a lot of attention. The human mind is pretty powerful.

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14. SPRITY on March 3, 2010 2:33 PM writes...

Another example of placebo effect, or spiritual effect or pyscological effect, whichever suits you. It is especially prominent in PII of CNS drug since the selected group of patients get a lot of attention. The human mind is pretty powerful.

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15. Pharma Conduct Guy on March 3, 2010 4:16 PM writes...

So for all those smart analysts at Morgan-Stanley who predicted that outsourcing discovery will result in a 3x ROI compared to current in-house research, how do they factor in this kind of phase III failure?

As I and many others have said many times before, identifying and rejecting which leads will undergo late stage attrition is the real challenge, not generating leads in the first place. Hiding the warts on leads is much easier when they aren't developed in-house.

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16. Skeptic on March 3, 2010 4:28 PM writes...

"b) change direction and throw everything you've got at this new opportunity ?"

Actually its:

c) Buy stock in Company A with your own money when its beaten down, then acquire Company A with someones else money (shareholders) and then short your own stock until the "unexpected" bad news in phase III trials is announced. Then give yourself a golden parachute when the dumb money figures out your pipeline is dry and its time to leave.

End result: Insiders retire on tropical island

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17. Wow on March 3, 2010 5:25 PM writes...

Worked on this compound at blue P. Sorry to hear the news but it was a fishy candidate from the very beginning.

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18. partial agonist on March 3, 2010 6:04 PM writes...

Maybe bad news like this is why Pfizer CEO Jeff Kindler had to settle for a $14.9 million pay package, a 4% dropoff from last year (reported today at Pharmalot).

Times must be tough for him, tightening the belt. It is probably beans and rice or mac and cheese night, every night at the Kindler household.

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19. Hap on March 3, 2010 6:29 PM writes...

1) (#15) Why would they, exactly? If drug companies follow their advice, they get a share of the bump in pharma stock price for laying off bunches of salary, get a cut of the partnership trade from pharmas that now have no products and have to make deals with companies that have excellent P2 data (and need to someone to run the sales), and then the shorts on the smaller firms when their licensed drugs perform the dreaded "controlled flight into terrain" bit (which will probably happen even more often than it does for insourced research, because of the incentives to push research to the point where it can be cashed out). I don't think the productivity of the companies themselves actually matters - it's not a part of their incentive structure.

2) (#18) Only for his employees, and the house staff. If they have to keep that diet up, they might need more of his company's drugs. A win-win.

Permalink to Comment

20. Skeptic on March 3, 2010 7:22 PM writes...

US Biological Science can be summed up as:

Stock Machination Scoundrel + Self-Absorbed PHD

Its a dysfunctional system that is becoming irrelevant due to the gorilla in the room: The fast moving online electronic herd of investors who are now being presented with options.

From the perspective of speculators, all you see is relatively small sized, overlapping, transient, and unfocused efforts scattered about the landscape. Its like the mining company scene, junior and seniors. Find your mineral deposit, with the minimum fuss. Fine for mining perhaps (not really because of the weak environmental accountability) but in biology, the follosing is lacking:

1. Biological know-how is severely lagging chemical mechanism.
2. Technology development is too slow

I blame both parties equally...because neither has any motive. Rapid technology development obsoletes PHD careerism and the stock scoundrels just want the hopes/dashes of a end product to move the stock price violently.

Permalink to Comment

21. Chris P on March 4, 2010 11:00 AM writes...

The last company with a Phase 3 Alzheimer's failure was Myriad Genetics (7/2008); MYGN is the ticker. The stock went up after the P3 failure from about 23 to about 45 six months later. Sometimes the market puts the right amount of skepticism into the pricing of a clinical program.

Permalink to Comment

22. E on March 4, 2010 2:35 PM writes...

My understanding is that the Phase II studies were done in Russia, where the medical sciences are not always ... uh ... aligned with Western medicine. Was there any indication that the Phase II study was not appropriate by Western standards?

Permalink to Comment

23. bbooooooya on March 4, 2010 3:02 PM writes...

"Was there any indication that the Phase II study was not appropriate by Western standards?"

Results of the study were published in The Lancet, so it at least got by the peer-reviewers. I don't belive that publishnigin Lancet is that easy

Permalink to Comment

24. nikita on March 5, 2010 3:15 AM writes...

Do you think II phase was fraud?

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25. Anonymous on March 5, 2010 3:28 PM writes...

#23 "I don't belive that publishning in the Lancet is that easy"

Unless you have some funny annecdotes about autism and MMR and you want to start a scare that down the line leads to measles outbreaks across the UK.

Permalink to Comment

26. Imike on March 11, 2010 2:42 PM writes...

Perhaps the dose of dimebon was too low and in other trials at higher dose it will work

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27. dd on May 3, 2010 9:23 PM writes...

Does anyone know if enternacept is fish oil too?

To people with the disease, fish oil is very tempting as there isn't much else out there.
If you know anything about enternacept pls let me know: dds35day@netscape.net

There is a lot more at stake here than biotech stock... by the way.

Permalink to Comment

28. JO on May 19, 2010 3:55 PM writes...

If you go to this link......http://www.alzheimersreadingroom.com/2010/05/dimebon-experience-marions-view_18.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+TheAlzheimersReadingRoom+%28Alzheimer%27s+Reading+Room%29

You will see stories of folks who have had big improvements on Dimebon. You will notice that right questions aren't being asked when caregivers are trying to give feedback on how effective the drug has been for their loved one. I say even if it's the placebo effect it's better than nothing!

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29. retread on June 1, 2010 1:01 PM writes...

Before going to reunions last weekend, I'd have thought this was the end of the story. But I met a classmate there whose wife (and a few of his friends) was convinced that he was better than a year previously on Dimebon. These are solid people. You can read more about it, in the current post on Chemiotics II.

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30. mahjong connect games on June 20, 2013 9:33 AM writes...

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