Nature Newsblog
« The fish that crawled out of the water | Main | Arctic water flow speeding up »
Interim report on London case shows no evidence of contamination.
The drug-trial disaster that put six British patients in intensive care does not seem to have been due to contamination or a failure to follow protocol, says the agency investigating the incident. If the preliminary finding is confirmed, it would indicate that the drug itself caused the negative effects.
Read the story here.
TrackBack URL for this entry:
http://blogs.nature.com/cgi-bin/mt/mt-tb.cgi/477
Listed below are links to weblogs that reference Drug to blame for clinical-trial disaster?:
» Drug Rehab from Drug Rehab
Includes a tour of the premises, FAQs, staff information, and testimonials. Ron Hubbard. In Laguna Niquel, CA.Uses met... [Read More]
» Drugs from Drugs
Select a type of drug below to requestA searchable catalog of FDA approved drug products both prescription and over the counte... [Read More]
Comments
The publicity surrounding the negative effects of this trial have been blown out of all proportion. Adverse effects, and even deaths, happen with regularity in a variety of clinical trials. It appears that tegenero adhered to the study protocols. Let's not label antibodies as a 'potentially dangerous' class of drug, the have proven to be safe and effective for a wide range of diseases. The irony is with the CD28 story that the drug obviously has profound physiological effects, there will undoubtedly be some medical appplication for something with such activity.
Posted by: Dr. Stockwin | April 6, 2006 02:07 PM
An overhaul of our current drug testing regime is well overdue. Animal testing has no place in twenty-first century medical research. And using healthy human 'volunteers' is incompatible with the hippocratic oath ('first do no harm').
Rational drug testing should rely on human-based methodologies, and researchers should proceed with caution rather than leaps of faith.
Posted by: Andre Menache | April 7, 2006 04:36 PM
I find it amusing that the poster Andre is advocating updating testing methods, by adhering to the text of the Hippocratic Oath which is thousands of years old. This oath also compelled physicians not to remove any stones from a patient, but this is ethical and routine treatment today. And the use of quotes to describe volunteers is disingenuous. These volunteers are absolutely as defined by the literal meaning of the word, except that they also get paid.
Posted by: Dr. Mike Semoff | April 8, 2006 07:25 PM
The big question to me and many other immunologists is how this sequence of events could not have been foreseen by the MHRA. Were no immunologists consulted as I'm sure that the reaction seen in these patients would have been predicted as a possibility of administration? Presumably these facts may be revealed in an independent enquiry.
Regarding Andre's comment the argument is made for better and more realistic animal testing rather than its abolishment.
Posted by: Gareth Pryce | April 10, 2006 01:24 PM
It is now clear that for the first time, non-human primate safety studies completely failed to predict toxicities of an immunomodulatory drug. Although the Tegenero antibody's target epitope was identical in man and monkey, there are potential significant differences between man and old-world monkeys. Most mammalian cell surfaces display two major sialic acids, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Humans lack Neu5Gc due to a mutation in CMP-Neu5Ac hydroxylase, which occurred after evolutionary divergence from great apes. Indeed this accounts for the resistance of monkeys and chimpanzees to human malarial infections. SIGLEC receptors, which recognize these sialic acids serve to downregulate macrophage activation by via the FcR. Antibodies produced in CHO cells may have sialic residues not recognized by human Siglecs. While this area of cross-species comparative immunology is still early and speculative, the Tegenero trial results point out the importance of further research to human immuno-pharmacology and immunotoxicology.
Unfortunately, unless the MHRA and Tegenero share the antibody with qualified scientists to further research viable hypotheses regarding the failure of predictive toxicology in primates, this tragic study will not result in any advance in medicine or science. So far the full investigative resources of the scientific and drug development community are not being applied to the important issues raised by this study, and will not be until the data from the preclinical safety studies, data from the abortive human trial, and the antibody reagents are more freely available to outside scientists willing to perform unbiased investigations.
Posted by: Dr. Edward Bernton | April 10, 2006 02:54 PM
It has been said that multiple-organ failure in all six volunteers was an unexpected result of the clinical trial with a super agonistic CD28 antibody [1,2]. TGN1412 is a super agonistic antibody, since the antibody activates T lymphocytes without needing a second signal [2]. Multiple-organ failure is a disastrous effect of septic shock. This can be circumvented by using CD28-deficient mice [3] or by blocking of CD28 activation [4]. This would allow the prediction that activation of CD28 causes multiple-organ failure.
The monoclonal antibody has been designed to specifically activate human CD28, and may thus have a lower affinity for rabbit and monkey CD28. If TGN1412 does not (fully) activate rabbit and monkey CD28, it can be predicted that tests in rabbits and monkeys will lead to no adverse effects. This is in line with the observations made by TeGenero [1].
Twenty years ago not humanized antibodies, but human cytokines were the new immunotherapy against cancer. Overkill of immune stimulation by systemic interleukin 2 (IL-2) therapy resulted in vascular leakage [5]. This has severely hindered the development of cytokine therapy against human cancer. Only recently, a clinical trial with local IL-2 has been published with major clinical effects. After intratumoural administration of IL-2, the five-year disease free survival of stage III-IV nasopharyngeal carcinomas increased from 8% tot 63% [6]. In contrast to local administration, systemic administration had only side effects but no therapeutic effect against this tumour [7]. Increased therapeutic effects after local versus systemic IL-2 therapies have been observed in different tumours [8].
The side effect of IL-2, vascular leakage, is a major anti-tumour mechanism when IL-2 is injected at the site of the tumour, where it is associated with tumour cell death [9]. The analogy between immune overkill by IL-2 and TGN1412, suggests that it will be interesting to investigate intratumoural administration for TGN1412.
References
(1) Wadman M.. Nature 440, 388-389 (2006).
(2) Parson H. Nature 440, 388 (2006).
(3) Rajagopalan G., Smart M.K., Marietta E.V. & David C.S. (2002). Int. Immunol. 14, 801-812 (2002).
(4) Wang R. et al. J.Immunol. 158, 2856-2861(1997).
(5) Rosenstein M., Ettinghausen S.E. & Rosenberg S.A. J.Immunol. 137, 1735-1742 (1986).
(6) Jacobs J.J.L. et al. Cancer Immunol Immunother. 54, 792-798.
(7) Chi K.H. et al. Oncology 60, 110-115.
(8) Bernsen M. R. et al. Cancer Treat Rev. 25, 73-82 (1999).
(9) Jacobs J.J.L., Sparendam D. & Den Otter W. Cancer Immunol Immunother. 54, 647-54.
Posted by: John Jacobs | April 11, 2006 11:56 AM
I wonder whether there are no in vitro methods (cell sorting, immunofluorescence microscopy, cytokine measurements) to check beforehand which cell types get activated?
Posted by: Herman Schreuder | April 18, 2006 07:52 AM
A cursory reading of the Clinical Trial Application on the MHRA website [1] reveals that at the lowest dose of 0.1mg/kg one might predict to achieve plasma concentrations of approximately 16nM, compared with a binding affinity of 2nM. By starting at 8x the binding affinity of the "super" agonist one might expect 90% CD28 receptor binding after the first dose, with perhaps 3x lower binding in tissue.
Agonists typically have steeper response curves than antagonists, and maximal effect may be achieved with as little as 10% occupancy. For an antagonist (as are most clinical antibodies) such a starting dose might be viewed as appropriate. In fact TeGenero showed very high receptor occupancy in their 28-day cyno monkey experiments. Using GAFS analysis they were unable to identify unbound CD28 receptors even at the lowest dose. Assuming binding affinities similar to humans, the predicted occupancy would be in excess of 99%.
Guiding starting doses using only preclinical no effect limits (as is recommended in officical FDA guidance [2]) has in this instance proved very unwise. Starting doses should have been set using established pharmacological principles; First, binding affinity and secondly, where available, an in vitro assay of functional potency. A starting dose of 100x lower, coupled with smaller escalations (to accomodate steeper agonistic responses) would have provided a more conservative but pharmacologically based approach.
[1] http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2023515&ssTargetNodeId=389
[2] http://www.fda.gov/cder/guidance/5541fnl.htm
Posted by: Dr. Daren Austin | April 18, 2006 01:09 PM
When an antibody is humanised, it becomes part of the human immune system. This is fine if we do not mind destroying cells that the antibody binds to, but if we are trying to activate them with the antibody, what could the consequences be (Should one perhaps consider resurrecting the old liposomes?)?
Have we perhaps forgotten that, in testing, it is the closest equivalent model that needs to be tested, rather than just an identical molecule (of course, with normal chemical drugs, the closest equivalent model may well be the drug itself)? In the case of antibody therapy tested on a mouse or monkey the antibody ought, in general, to be raised against the animal in question, and then in addition murinised or simianised, respectively.
Posted by: John Rokos | April 19, 2006 07:54 PM
When raising equivalent antibodies for testing on animals it will be necessary to ensure a good statistical chance that at least one antibody is at least as effective as the human one it models. This must involve raising and evaluating more antibodies against the animal than were investigated for the human (the same number would give only a 50/50 chance that the most effective is at least as effective as the drug being modelled). If a kind statistician is reading this, could he/she please define for us the relationship between the two quantities involved (might the relevant distribution be Rank Poisson?)?
Posted by: John Rokos | April 25, 2006 05:27 PM
Nature is one of the most beautifull thing of this world and we need to try to do are best to take care of it when ever we can do it. Another thing that I will like to say is that I am 12 years old and when I grow up I will like to try to save many part of nature and the criatures (animals) that life in it. Mybe you could be thinking ´´what is a 12 year old girl is writing comments about nature in the Internet´´ well, you chould know that it´s better that I start thinking about how to save nature and try to save this world with my years than don´t doing enythingand leting this world extingt.
Posted by: Daniela Salerno | April 28, 2006 03:07 AM
Check out this introduction article on Multiple organ failure:
http://www.articleworld.org//Multiple_organ_failure
Content:
1.Causes
2.Hepatorenal syndrome
3.Cardiopulmonary Failure
4.Shock
Posted by: Multiple organ failure | June 7, 2006 10:20 PM
I am particpating in a clinical drug trial in Japan. Its very interesting and I am publishing an online diary at http://whitemice.wordpress.com/
Posted by: yy | June 26, 2006 11:28 AM
And now TeGenero have gone bankrupt, and the wonderfully corrupt Medicines and Healthcare Regulatory Agency (MHRA) whitewashed their role in the problem as usual.
Just great.
Posted by: Helena Davies | July 4, 2006 11:55 PM