1. Jason Dowd on March 17, 2006 11:31 PM writes...

Interestingly, I read an article yesterday that said since this episode, a web site where people could sign up for trials had received a RECORD NUMBER of applications!

So the early indication is that it might actually be a boon.

2. Paul Dietz on March 18, 2006 8:37 AM writes...

So, is TGN1412 going to be the latest biowar agent? Just how much of this antibody was administered?

3. Abel PharmBoy on March 18, 2006 8:44 PM writes...

I'll also be curious to see where this antibody accumulated and whether any protein array work was done to assess the promiscuity of TGN1412 vs other human targets. I am reminded of the unexpected cardiotoxicity of Herceptin with taxanes or anthracyclines due to unanticipated HER-4 binding in myocardium. This case is far more disturbing, however, since it was a single agent.

My thoughts are with the volunteers and their families.

4. S Silverstein on March 18, 2006 9:38 PM writes...

As we move from relatively simple molecules to complex organic molecules such as monoclonal antibodies, one wonders if the same paradigms used to test the former are appropriate for the latter.

Animal testing of such molecules may not predict the response in humans, and it seems this company hit the bullseye in terms of finding just the right chemical structure that would do little in dogs and rats - yet act as human insecticide.

One just hopes in this case that some MBA lacking biomedical training did not override the objections of scientific personnel.

-- SS

5. tango on March 19, 2006 7:41 AM writes...

Thankfully, the four patients on the lower dose are showing signs of recovery. All four are fully conscious - two of the volunteers have been taken off organ support while another two are receiving less organ support, according to the hospital.

6. Mike on March 19, 2006 4:58 PM writes...

Yet another reminder of the issues with biological therapies. The Tysabri experience was chilling..and this is not going to help. If man is the experimental animal now, we need to be very clear about the risks of testing such agents in healthy volunteers.

7. Still Scared of Dinosaurs on March 20, 2006 12:38 PM writes...

I'm not sure how the Tysabri experience relates, unless it's in a very general "you can never really be sure" kind of way. On one hand, three cases of PML over 10K people at therapeutic doses in a patient pool that was quite likely exposed to all sorts of prior therapies. On the other, catastrophic reactions in every (?) healthy volunteer at doses intended to approximate the no-effect level.
As far as SS's question (#4), I know of one test from the small molecule paradigm that fails to deliver in biologics, and that is PK equivalence. Genetech lost time in its development of Raptiva because a manufacturing change required a bioequivalence study that failed.
Comparing blood concentrations of large proteins that may have structural differences (different cell lines can mean different genes) and are almost guaranteed to have different patterns of goo stuck to them just don't tell you that much.
Well, if the PK is spot on and the PD (or safety or efficacy) differ then you can say it's a result of something other than PK, which, ummmm, is nice to know, but...can you bring something else to the table?
And this is particularly true when the desired effect is to "send a signal" at a receptor site, where small hits are intended to produce large effects.

8. Steven Jens on March 20, 2006 5:29 PM writes...

If I could put my ignorance on display, I'm curious -- are the dosages used in phase I trials generally comparable to the dosages expected to be appropriate if the drug makes it to market? Or do they (you) use very low dosages at first, and only try higher dosages in phase II and III?

9. Derek Lowe on March 20, 2006 7:48 PM writes...

Steven, at first it's the latter. Phase I is mainly to get a look at blood levels and tolerability. So you start at a lower-than-needed dose just to see if the blood levels you've estimated are in the right ballpark, and adjust later (higher) doses in light of that data.

10. Servumpecus on March 21, 2006 2:38 AM writes...

Hello,

how can we still accept stupid and unnecessary animal experiments in the year 2006, in order to "test" chemical compounds or antibodies, as it is the case here for the TGN1412 ?!?

The results ? Six guinea pigs in the hospital. Fortunately, not 20 or 100 !!!

In their website: http://www.tegenero.com/news/statement_re_tgn1412/index.php, the charming Chief Scientific Officer (not chief scientific officer, please) of TeGenero said that the TeGenero Company was, I am citing:

"We are shocked about the symptoms we have seen in the volunteers. Extensive pre-clinical tests showed no sign of any risk. We observed strict standards for this clinical test and we obtained all required approvals both in Germany and Great Britain. The drug was tested extensively in laboratories and has been tested on rabbits and monkeys. We saw no drug related adverse events and there were no drug related deaths."

We are also deeply shocked...

Perform more and more animal testings, it will be better and better ! Congratulations for this kinf of a-scientific research ! Are we not clever than rabbits or monkeys ?!?

Servumpecus

11. Derek Lowe on March 21, 2006 7:50 AM writes...

I'm not sure what you're getting at - are you suggesting that it's a bad thing that these compounds are tested on so many animals before they went into humans?

Believe me, it's extraordinarily uncommon for a compound to show clean animal results and then do something like this in people. I think you'd be amazed at the number of compounds that get stopped at just the rat stage of things.

Would some of those go on to be clean in people, anyway? No doubt a small group of them would. But we're not going to find out.

12. Jeff W. on March 28, 2006 12:55 PM writes...

The Chief Scientific Officer of TeGenero states:
"We observed strict standards for this clinical test ..."

TeGenero continues to deny the mistake of testing on 6 people at once. Therefore they will continue to follow what they consider strict standards, and continue to hurt and kill additional people unnecessarily. They need to admit fault and re-evaluate these strict standards.

13. Sandy Wilson on April 12, 2006 2:32 PM writes...

Derek, according to the IB and IMPD published on the MHRA website the animal studies were NOT clean. Immunological effects (but not wholesale cytokine release) were unambiguously identified and were predicted to be present at the doses administered to the volunteers. TeGenera, Paraexel and MHRA disregarded the immunological effects when considering the initial dose. Their reasoning does not bear scrutiny.

14. Dr.U.K.Sharma on April 13, 2006 12:07 AM writes...

If the IB knew about the animal studies being "not clean" and that immunological effects were going to possibly be widespread and unpredicatble why was the study approved at IRB or IEC level? This is the last point of no-return in Phase I.
What was the chief investigator doing? Why did he/she not read up more, a similar drug had resulted in a Phase I problem some time ago.
I think EVERYONE failed to do their prime job of protecting subject well-being.The emphasis on paper work seems to have replaced good-old clinical common sense.
This failure is now being seen as justified because the subjects were paid lucrative incentives, and their well being somehow slipped off everyone's radar screens, because they were "paid" volunteers; paid, so lump it all.

15. bhumika jadeja on April 13, 2006 9:25 AM writes...

it is indeed truly going to be difficult to recruit patients in p-1 trials.but the big question here is ...why are always the members of the minority, the poor, and the disadvantaged the usual guinea pigs? why are they put on the line in the name of "scientific medicine"!

16. Sandy Wilson on April 15, 2006 3:00 PM writes...

Yes, I agree Dr Sharma, simple incompetence! Someone (possibly the author of the primate tox study) started it off by saying the immunological effects were not adverse. Whether an effect is adverse depends on its context eg what is OK (not viewed as adverse)in a patient might not be acceptable in an "innocent" bystander. Then all the others followed like sheep and calculated the first dose whilst disregarding the immunological effects. The Chief Investigator would rely on other experts opinions. He/she would not necessarily appreciate the lack of evidence regarding prediction of cytokine release syndrome through animal studies. Whoever did the safety review merits a good dose of TGN1412!