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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

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November 8, 2011

Targacept's Antidepressant Fails, And How

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Posted by Derek

Bad news yesterday from Targacept, a small company that's been developing an antidepressant with AstraZeneca. TC-5214 (the S enantiomer of the nicotinic ligand mecamylamine) missed its endpoints in a trial of 295 patients in Europe who had not responded to standard drug therapy - the trial started with more like 700 patients, who received open-label therapy with one of the usual agents, and then they picked out the tough cases for the real trial, adding this compound to the standard regimens.

Seeing results in such a population is a very tall order, but that's why AZ and others were excited about the earlier Targacept data. The Phase II numbers were extraordinary. A compound that followed through on that promise would be huge. This piece by Adam Feuerstein gets across the excitement - people really couldn't believe what they were seeing.

And maybe they shouldn't have. The grumbling today, though, is taking an interesting turn. What you might not realize from reading about those Phase II results is that they were the result of a clinical trial in India. That's added an extra layer of can-we-trust-this-stuff to the usual despairing comments about Phase II/Phase III disconnects. This is an unusually brutal disconnect, because the earlier data were unusually good. So the muttering is not going to go away any time soon.

AstraZeneca says that they're committed to further studies of TC-5214, so we'll see what happens then. Depression is a tricky illness, and getting solid clinical data isn't easy. It's possible that this latest study just had some confounding variable that messed up the numbers - but then, it's possible that the earlier one did, too, and that, sad to say, is probably the way to bet. This is bad news for AZ, a company that needs all the help it can get, and downright catastrophic news for Targacept, as I'm sure their stock price will reflect. And it might even be bad news for India, and Indian clinical research.

Update: to drive the point home, Adam Feuerstein has posted this under the heading of "My punishment for getting TRGT wrong".

Comments (26) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System


COMMENTS

1. Anon on November 8, 2011 9:32 AM writes...

Can we say, "layoffs to ensue?"

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2. max on November 8, 2011 9:47 AM writes...

Wow, people are super jaded. I`ve been through a significant lay-off and I see this as par for the course.

There`s a reason why we don`t stop at PhII.

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3. bbooooooya on November 8, 2011 10:02 AM writes...

There are a few more layers to this failure. The most important is the drastic improvement seen (in India) in going from the racemic mixture to the single enantiomer: seemed a little too big.

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4. anchor on November 8, 2011 10:20 AM writes...

Derek : My understanding of irrational excuberence previously was due to the fact that the depression patients were treated with the combination of TC-5214 + Celexa (marketed by Forest Labs) and this combo demonstrated a 6-point improvement on the Hamilton Rating Scale for Depression, or HAM-D, compared to patients treated with Celexa alone. Whereas under the present circumstances the clinical trial in Europe were for a stand alone drug. Correct me if am wrong. But, I do agree with your issue regarding the integrity of clinical data from India.

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5. Derek Lowe on November 8, 2011 10:32 AM writes...

Anchor: nope, this was not the stand-alone trial. Patients were either given their medication they'd been on, or that medication plus the Targacept compound. I think that the stand-alone version of things is still in Phase II.

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6. johnnyboy on November 8, 2011 10:40 AM writes...

I work in a preclinical CRO (in north america). Part of this work, practically every day, is to deal with the expectations of the sponsors for their product. More often than not you have to provide negative results, and the reaction of sponsors is variable; it can go from the philosophical ("oh well, we'll see if the next one works better"), to the pragmatic ("can you make the report wording a little less negative, like using this word instead of that one, and do we really need to show that scary data as a graph"), to the downright appalling ("what do you mean, negative results ? That can't be, YOU must have done something wrong - we're not paying you a dime"). The pressure that sponsors can apply can be very strong, and it takes a very sturdy ethical and financial backbone (as well as fear of the FDA) to resist giving in to unreasonable demands. Transfer this to India, where the main driver of their industry's growth is low price, where the regulatory landscape is probably underdeveloped, and where companies doing the testing are practically immune from serious FDA audits. What could possibly go wrong ?

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7. Hap on November 8, 2011 11:20 AM writes...

Is it possible that the trial was different because of dietary or genetic differences between the populations and not simply because of oversight/honesty errors?

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8. pete on November 8, 2011 11:41 AM writes...

@7 Hap
re: something special in the air/water over there
Maybe the generation of folks who journeyed to India to achieve a higher state really were on to something..?

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9. bbooooooya on November 8, 2011 11:47 AM writes...

"Is it possible that the trial was different because of dietary or genetic differences between the populations"

That's likely part of it: incidences of depression do vary by ethnicity and country.

Weight likely also an issue. Average weight in TRGT's phase 2 study was 60 kg, which will be closer to 80 in Europe (where the current study was done). Dosing was the same, so effective dose dropped by 1/3 right out the door.

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10. Anonymous on November 8, 2011 11:59 AM writes...

Reminds me of the Russion phase II trial data for Medivation's dimebon. Data also looked too good to be true and it was.

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11. IDTBMD on November 8, 2011 12:57 PM writes...

@Hap,

That is a valid argument. To a certain degree, depression is more or less a "Western"/"developed countries (e.g., Japan)" condition. In Chindia, depression is generally not considered a medical condition as far as I know, but a sign of weakness. I don't think that John Waynes and 49ers of the world in the good old days would feel depressed over a denied promotion, layoff, or rejected boy/girl-friend. They tough it out and move on. A bad idea to conduct a trial of an antidepressant in Chindia.

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12. anonymous on November 8, 2011 12:57 PM writes...

That's why the FDA recommends that a certain % of subjects exposed in clincial trials be representative of the intended US population.

It could this drug is only effective in vegetarians...

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13. DCRogers on November 8, 2011 1:02 PM writes...

Obviously they needed to conduct the Phase III trail in India, also.

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14. Anonymous on November 8, 2011 7:16 PM writes...

I was on a due diligence team for another Targacept molecule. We quickly discovered that the statistical analysis was botched, with the net result being much less evidence for efficacy than claimed by the company. I've no reason to suspect this was a factor here, but my experience certainly left me with a poor impression of the company.

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15. Just sayin' on November 8, 2011 8:37 PM writes...

@9 bbooooooya: "Weight likely also an issue. Average weight in TRGT's phase 2 study was 60 kg, which will be closer to 80 in Europe (where the current study was done). Dosing was the same, so effective dose dropped by 1/3 right out the door."

I thought Americans were on average heavier on average than Europeans. When Europeans get depressed, do they REALLY let their figures go?

Permalink to Comment

16. anon 3 on November 8, 2011 10:32 PM writes...

It's always, ultimately, in the outcome of the Phase 3 data----desptie any over-hype by stock pushers, VC's, talking heads, company hopefuls, market makers, Power-Point talkers,......Take Sirtris for example, please. Oh yeah, someone did....suckers.

Permalink to Comment

17. watcher on November 8, 2011 10:42 PM writes...

On one hand, we see functionally an excess of PhD chemists now in the US, and where quite a number of foreign-born, US educated, moving back to their home countries to find opportunities. On the other hand, we keep hearing from NIH and other government sources that the US does not train enough scientists and engineers. And so, which is closer to a real picture of reality?

While certainly not all "scientists" are interchangable (can a synthetic chemist design a bridge that won't fall down?), there seems to be a big disconnect between the government's view and projections compared with today's employment realities in the US.

It seems very similar to the recent news about NIH's multi-million dollar initiative in compound screening needing new sponsors, a new home, or being shut-down. Those in-charge coming largely from academic backgroungs, simply don't understand or appreciate the practical realities of real-world economics for individuals or corporations in the techincal arena. If they would have had to actually balance a budget with money earned, not simply given to them by the government, they'd have been in bancruptcy decades ago.

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18. Innovorich on November 9, 2011 7:13 AM writes...

This is not about not trusting India, this is about the ridiculousness of thinking that, given the cultural differences, that a trial of an anti-depressant in India would actually be relevant!

Permalink to Comment

19. watcher on November 9, 2011 7:23 AM writes...

#18: And what is the difference, if you could explain your logic?

Why should a trial conducted in India be untrusted, irrelavent, per se, when then you suggest that work coming from non-tradiational bacountries sed on cultural differnece is expected to be overall acceptable? The cultural differences, work ethics, maintenance of standards and quality, are present for any and all work done with local hands and minds. Your comment makes no sense.

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20. Hap on November 9, 2011 10:27 AM writes...

People in India are likely to differ genetically from the populations in the US (at least average-to-average). Their diets almost certainly differ, and the mixture of environmental challenges is also likely to be significantly different. In addition, the culture and its support (and method of support) for individuals is likely to differ significantly (and thus to generate a different set of people who have permission to claim depression and a different type of support from others). Also, the level of drug treatment for depression might reflect whether a drug is expected to do something for depression. All of these things impinge significantly on a depression drug trial and whether the outcome of a trial in India reflects the likely effect in a US population.

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21. pete on November 9, 2011 12:36 PM writes...

@20 Hap
Good points - and short of doing at least one PIII trial in India (@13 DCRogers) - AZ Clinical probably should have done ALL trials among their primary target consumers: NAmerica/Euro.

Permalink to Comment

22. Anonymous on November 9, 2011 12:49 PM writes...

Maybe there were a lot more smokers in the European trial?

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23. pandora on November 9, 2011 3:59 PM writes...

It's not a good time to run anti-depressant trial in EUROPE right now, especially in Greek and Italy.
Guess nothing will work. By the way, the ph2 trial was run in India AND U.S.

Permalink to Comment

24. Bbooooooya on November 10, 2011 11:57 PM writes...

Only 8% of PTA in the phase 2 study were in the us.

Smoking is another factor that killed the trial. In the Indian study o ly 8% were smokers: the average in Europe is much higher. Also problems with drugs used. Concomitant ly

Too bad for employees (and shareholders): layoffs are likely and shareholders lost capital due to a poorly thought out clinical strategy. No certainty the drug would have worked in well designed trials, but odds would have been greater.

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25. MIDNIGHT SCIENTIST on December 27, 2011 5:44 PM writes...

THE TRACK RECORD OF TARGACEPT IS POOR. SO MANY COMPOUNDS DEVELOPED SO FAST WITH LOT OF HYPE. MANY EMPLOYEES WHO LEFT THE COMPANY WILL ATTEST TO THE FAILURE OF TARGACEPT TO COME UP WITH LOGICAL RELIABLE CLINICAL STUDY. THE CLINICAL STUDIES IN INDIA WAS CERTAINLY CORRUPTED. INDIA IS A BAD PLACE FOR CLINICAL STUDIES ANY WAY. NONE OF THE COMPOUNDS DEVELOPED BY TARGACEPT SO FAR HAS GONE BEYOND PHASE 2.

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26. MIDNIGHT SCIENTIST on December 27, 2011 5:45 PM writes...

THE TRACK RECORD OF TARGACEPT IS POOR. SO MANY COMPOUNDS DEVELOPED SO FAST WITH LOT OF HYPE. MANY EMPLOYEES WHO LEFT THE COMPANY WILL ATTEST TO THE FAILURE OF TARGACEPT TO COME UP WITH LOGICAL RELIABLE CLINICAL STUDY. THE CLINICAL STUDIES IN INDIA WAS CERTAINLY CORRUPTED. INDIA IS A BAD PLACE FOR CLINICAL STUDIES ANY WAY. NONE OF THE COMPOUNDS DEVELOPED BY TARGACEPT SO FAR HAS GONE BEYOND PHASE 2.

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