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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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March 26, 2006

A Word to the Wise About TGN1412

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Posted by Derek

Here is the voice of someone who is under a great deal of stress and is not thinking clearly:

Thomas Hunig, the German professor who founded the TeGenero company, said he still hoped the drug, TGN1412, could be brought to the market.

He said he was devastated that the six men were taken ill but said that he was "not going to give up".

Professor Hunig said: "I do hope TGN1412 can come to the market. This tragic incident does not exclude the theoretical application of TGN1412 some time in the future.

Let me be one of the voices informing Prof. Hunig: there is an almost overwhelming likelihood that his drug will never again come near a human being, much less near the market. Pharmaceutical companies drop compounds all the time that show far less severe side effects than this in rats - a disaster like this in man is the end of the line. That's not to say that the whole idea of a CD28-derived drug is dead (although it's going to be slow going after this), but TGN1412 is not going to be it. Go look for a clinical supervisory board - outside of North Korea, that is - that would allow another dosing in humans. Good luck.

Says Prof. Hunig:

""I don't want to hurt anybody in any way. I don't want to come across as a crazy scientist who wants to save his baby despite the victims he has taken. Definitely not."

Someone needs to point out that he's doing a pretty poor job of not coming across like that. Talking about the wonderful science involved and all the work that's gone into the project doesn't help, either. Arguments about how much time and effort have been spent are irrelevent - that's a sunk cost if ever there was one. And the science is no doubt nifty in the extreme, but our scientific understanding of the drug and its effects is clearly a bit. . .incomplete, which places an upper bound on just how nifty it can be.

I feel like the guy in the Monty Python sketch: Dr. Hunig, your drug has ceased to be.

Comments (23) + TrackBacks (1) | Category: Clinical Trials


COMMENTS

1. Team player on March 26, 2006 8:30 PM writes...

I'm behind...what happened to his baby that he wants to solve?

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2. TWAndrews on March 26, 2006 9:37 PM writes...

Wow, the self-delusion is palpable...

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3. Robin on March 26, 2006 9:43 PM writes...

How can anyone think of this after such a serious adverse event on the drug?

I can understand the amount of time and money the company has invested in the development of the drug and the pre clinical studies. But using human life to exchange for such investment is definitely out of this world!

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4. Daniel Newby on March 26, 2006 11:36 PM writes...

I disagree. This drug seems like it might make a dandy vaccine adjuvant. Where would you find a review board that would allow it? Try it as an add-on for a terminal stage cancer vaccine.

What I want to know is why they started a dose-calibration study of a potential superantigen in anything other than homeopathic doses? Could they not find a single immune expert? I'm only a casual spectator for this industry, and even I know that intrinsic immune responses are highly idiosyncratic with respect to species.

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5. Alex Scouras on March 27, 2006 1:48 AM writes...

Is it not possible that the dosage given is simply too much and the drug might be effective at a concentration 1/1000 that which was administered?

Not that such a study would be approved until we knew far more about the pathway and what happened. But perhaps in 5 or 10 years?

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6. Dr Snowboard on March 27, 2006 2:07 AM writes...

Given the research term for a compound that is going nowhere is 'a useful pharmacological tool', is there a corresponding development term for something like TGN1412, other than 'landfill'?

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7. Petros on March 27, 2006 2:07 AM writes...

The comments are clearly unsound and suggest that the compnay may have great trouble surviving as well.

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8. Peter Ellis on March 27, 2006 2:55 AM writes...

Looks dead to me. They aimed for something that would damped the immune system by activating regulatory cells, instead they got something that superactivated inflammation.

Now, boosting inflammation might be useful in some *other* set of diseases. However, there's no way they're going to be able to effectively test it to find out what it *is* useful for, since the drug effects in animals and humans are so different. You'd have to do a buttload of testing on humans without any animal testing just to find out whan it *does*, let alone what it's useful for - all in the knowledge that it's already nearly killed six people, given at 1/500 of the expected dose, and with non-dose-dependent severity of the effects. (i.e. large variability between individuals).

This one's dead.

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9. Jack Friday on March 27, 2006 3:11 AM writes...

Dr Hunig reminds me of the coyote in the Roadrunner cartoons.

A true fanatic is someone who redoubles his efforts when he has lost his aim!

I would ask him if he plans to be the next human volunteer to have TGN1412 injected into him.

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10. LNT on March 27, 2006 8:36 AM writes...

Peter, that's a good point. If tox studies in animals are KNOWN not to be predictive of human tox, then there's just no reasonable way to have any confidence carrying forward, even at a much lower dose.
A related question/comment: I wonder what impact this will have on further development of other antibody based therapeutics? It seems to me that this "disconnect" between animal and human toxicity is much more of a problem with antibody therapeutics than with small-molecule therapeutics. Antibodies are fundimentally species specific -- dog tox data on a human antibody is worthless. Is it not?

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11. qetzal on March 27, 2006 10:51 AM writes...

LNT wrote:

"It seems to me that this "disconnect" between animal and human toxicity is much more of a problem with antibody therapeutics than with small-molecule therapeutics. Antibodies are fundimentally species specific -- dog tox data on a human antibody is worthless. Is it not?"

I wonder. Is the difference really that fundamental? After all, lots of small molecules work by binding to some target protein. That's also susceptible to differences across species, right? Are antibodies really qualitatively different?

I'm far from an expert here, but my impression is more similar to Daniel Newby's. I suspect this is more a problem related to targeting the immune system, than it is a problem of antibodies per se.

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12. LNT on March 27, 2006 12:43 PM writes...

Qetzal,
In principle, you are right. Small molecules can be species specific. But in my experience the binding differences between rat, dog, and human (for GPCRs) are negligable. In past projects, we would frequently test our compounds against the rat and dog targets just to make sure they bound before running rat or dog efficacy/toxicity studies. I only remember one case where there was much of a difference, and it was only 10-15 fold. For antibodies, my understanding is that the species selectivity is on the order of hundreds or thousands-fold. The reason for this is probably that the active site ("interior") of the enzyme/receptor is quite conserved between species. But the "exterior" is not. Antibodies generally recognize the "exterior" of a protein, while small molecules usually bind to the conserved "interior" (active site).

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13. Daniel Newby on March 27, 2006 8:38 PM writes...

The trouble with Peter Ellis's approach is that immune system membrane-bound proteins are under tremendous evolutionary pressure from parasites. Interspecies tests of those proteins will always have less predictive power than we'd like. If we want to develop drugs for those targets, and we definitely do, we have no choice but human testing with an appropriate level of caution.

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14. Peter Ellis on March 28, 2006 2:27 AM writes...

Daniel - I'd say rather that we should be developing a set of animal resources to let us test antibody drugs somewhat better. Mice with human CD28, for example.

I just can't see anyone, anywhere, doing what amounts to basic bluesky research on humans, and nor can I envisage the volunteers coming forward. Particularly for a drug which has already hit the press (accurately or not) as an insta-killer.

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15. MT on March 28, 2006 4:04 AM writes...

I'm sure the US Military will interested in dolphins with blow pipes, shooting darts containing TGN 1412

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16. Denni on March 29, 2006 10:23 AM writes...

Wow, your blog came up on Google News when I searched for the latest developments on TGN1412--in second and third place!

Good news at least that 2 of the men have been discharged, although one is still in a critical condition.

Permalink to Comment

17. Scott S. on March 29, 2006 2:34 PM writes...

This is a drug for chronic lymphocytic leukemia as well as autoimmune disease. I spoke to a CLL expert yesterday, and this trial came up.

He said that this trial would never have been approved in the United States. According to him, they would have tried it on patients, not healthy volunteers, and they would have done one patient, waited a day, then a second patient, and so on.

This doctor is involved in running many clinical trials, and I thought his comments were interesting.

He also said that they have enough problems getting patients to participate in trials as it is, and this disaster certainly won't help.

Permalink to Comment

18. ROBERT FIDDAMAN on April 6, 2006 3:56 AM writes...

MHRA - In whose Interests?

The recent TeGenero drug trial debacle was an accident waiting to happen. As long as the Pharmaceutical Industry continues to suppress clinical trial data the MHRA (Medicines and Healthcare products Regulatory Agency) will walk blindly and feed the British public false information.

News this week that GlaxoSmithKline knowingly withheld clinical trial data from the MHRA regarding the top selling anti-depressant drug Seroxat will add further fuel to the fire and hopefully push for an independent review into how the MHRA could be duped into believing that a drug they have reviewed on numerous occasions was safe.

The MHRA are made up of medical experts, some of whom are former employees and shareholders of the pharmaceutical companies they grant licenses to. Surely this is wrong and at the very least there is the suspicion of a conflict of interest?

For too long now the MHRA have been hoodwinked by the Pharmaceutical Industry. Lawsuits for damages in respect of harm caused to patients are popping up all over the place, but avoid media and public scrutiny because they are usually settled out of court on the proviso that evidence is not made public.

A public enquiry is needed to examine how the MHRA is run and why former Pharmaceutical Industry directors are allowed onto the board. Would a convicted drink driver be allowed to adjudicate on a road safety panel?

The MHRA need to pull the plug NOW on their close associations with the Pharmaceutical Industry. The British public expects and naively assumes impartiality and not a regulatory authority whose main interest seems to be one of ‘delivering jobs for the boys.’

Mr Robert Fiddaman (Group Moderator of the Online Seroxat Support Group)

Birmingham, UK

Permalink to Comment

19. Paul Dietz on April 8, 2006 12:33 PM writes...

The NY Times now has a story on the trial disaster:

http://www.nytimes.com/2006/04/08/world/europe/08britain.html

(free registration may be required). According to this story, by the time the sixth victim began receiving the drug the first had already begun to show serious symptoms. I can't imagine this is anything but gross negligence on the part of those who designed and conducted the test.

Permalink to Comment

20. Mike on April 11, 2006 7:43 AM writes...

The volunteers took an unknown risk and nearly died; it seems only fitting that the researchers, who were responsible for the volunteers, also suffer the consequences--their careers should be over. It's not like there aren't enough biomedical researchers to take their place.

In fact, perhaps the best thing to do would be if researchers just carried out "Phase 0" safety trials on themselves.

Permalink to Comment

21. Sandy Wilson on April 12, 2006 2:23 PM writes...

With respect to Robert Fiddaman I don't think this particular sad event had anything to do with lack of publication of clinical trials or with MHRA staff feeling some allegiance to the pharma industry. I do know that project managers (in this case the MD) in drug companies can deeply resent and question closely any adverse comments on their project. They wear rose coloured spectacles. Understandably, often it is their livelihood and several years' work at stake. But those of us reviewing the data have to stand up to that.

TeGenera knew that effects on the immune system were likely to occur at the doses given to volunteers but believed the effects would not be adverse (see the IB and IMPD published on the MHRA site). The evidence on which they based this was iffy - a primate study which had problems. So they disregarded the immunological effects when calculating the safety margin and the first dose. MHRA endorsed this thinking. Note, it is only relatively recently that the MHRA have been involved in approval of first administration to healthy volunteers so their experience is limited. I put this down to incompetence or naivety for the MRA and wishful thinking re TeGenera. As a toxicologist I have reviewed dozens of drug dossiers prior to first administration and what happened here beggars belief.

And why on earth did they (TeGenera and Paraxel) administer TGN1412 to 6 people so close together and why did MHRA allow that?

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22. Mike S. on July 30, 2006 1:48 PM writes...

I'm not an immunologist, but the design of this experiment seemed moronic from the first news story (see Talk:TGN1412 on Wikipedia for more). Now I'm reading that TeGenero was designed to fold up and blow away at the first sign of trouble, with insurance that doesn't pay if the victims sue for any money. It is getting to the point where I'm starting to consider conspiracy theories. People have known that bacterial superantigens are potent biological warfare weapons for decades, and TGN1412 is something like a superantigen aimed at T cells. By hurrying to shoot up six people with an overdose, this company has very clearly proven that TGN1412 produces horrible, lifelong effects. TGN1412 cannot be weaponized - it has to be injected - but is there a less public company somewhere out there hawking a modified peptide or aptamer that will enter the body more easily? What a clever way to neutralize political opponents - with lupus, multiple sclerosis, arthritis, any random autoimmune condition that might pop up after a dose or two of something special. And now there are six poster boys to help it sell.

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23. MIranda Cros on November 27, 2006 7:35 AM writes...

I will say what comes to my mind in a very controversial (and most probably ignored) comment:
Medical Science knows obviously very little about biotechnology. How do you otherwise explain what has happened?
TeGenero shook me with it's original comments: they did not expect anything like that!
That's so unacceptable!
My conclusion as a physicist is: if you had no idea then you know nothing about your business.

It is not acceptable that knowing so little you go and endanger a human life.
I know the problem with the biotech business, how can it learn without humans? That's too bad for biotech.
My suggestion is to reconsider the entire idea of biotech....Yeah! that's controversial, sorry but somebody has to say it...
How can we go-on curing humans? Well, there are so many fields out there making outstanding new discoveries...it is maybe time to shift our focus from man-made molecules into man-using-nature to heal themselves....
I know the problem, I know: who gets rich with nature? Science can not patent nature....
But it is up-to-us!

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If this guy is able to get an ethics board or Institutional Review Board to let TGN1412 within a thousand miles of another human being's bloodstream, then he's going to be able to make a lot of money without having to sell one drop of the stuff. He'd ... [Read More]

Tracked on March 27, 2006 11:17 AM

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