Agency criticises drug trialBMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7553.1290-a (Published 01 June 2006) Cite this as: BMJ 2006;332:1290
All rapid responses
Day comments on the Drug Trial that went wrong (1) and point to the
study which left six previously healthy volunteers critically ill after
the first dose to man of a new monoclonal antibody , TGN1412. Your news
item points to the way in which the Medicines and Health Care Products
Regulatory Agency (MHRA), has put out a report saying that the events
which “occurred were not a result of any errors etc “ , leaving the way
open to the view that no one is responsible and we cannot predict or
prevent such catastrophic events. The Academy of Medical Sciences report
is more sceptical.(2).
In fact , at least two major preventable errors were made, and were
evident before the event.
First, as has been pointed out by C Chan,(3) one does not give the first
dose of a new class of compound to six people at one time.
Secondly, for a “first time in man” study one starts with a dose that is
well below the dose that is calculated to have pharmacological or toxic
effects. For TGN 1412 one can calculate the likely pharmacological effects
and dose , from the data in the Investigators Brochure (published by MHRA
TGN 1412 is a humanised monoclonal antibody which binds onto a specific
portion of the CD28 receptor protein found on the surface of all T
lymphocytes. The bound antibody activates the whole population of T
lymphocytes to release cytokines, become resistant to cell death, and
start multiplying. The activation is unusual in that it bypasses the
normal control which requires cooperation of several molecules to activate
just one clone of T lymphocytes. It might well be useful to have a drug
that activates many T lymphocytes, for a number of disease states but we
have a warning from clinical use of the very different immunosuppressant
anti-lymphocyte antibodies like OKT3 that an excessive cytokine release
storm can have most serious adverse effects.
Rodent CD28 does not bind 1412 ,so studies in rats were not very useful.
However ‘in vitro’ binding studies with human CD28 ,give a binding
constant Kd of 2.10^-9 molar, which is about 0.3mg/liter. The starting
dose of 1412 was 0.1mg/kg , and pharmacokinetic evidence tells us that
this will result in plasma levels of about 0.5mg/liter,that is, in the
middle of the expected active dose for binding of antibody to lymphocytes,
and so far higher than the normal starting dose.
Moreover, the 5mg dose given will provide about 10,000 molecules of
1412 antibody for each of the 10^12 lymphocytes in the human body. (5)
.From studies of OKT3 and other antibodies we know that this is probably
quite enough to start the activation process.
Monkey CD28 does bind 1412, but the effect is mild , and in a control
system like the one on the surface of lymphocytes, one cannot predict
detailed responses from one species or tissue to another. Cynomolgus
monkeys tolerated 50mg/kg doses of 1412, and the company claimed that
0.1mg/kg would give a 500fold margin of safety. This is quite incorrect.
The result of pressing a trigger does not depend on the pressure exerted !
It looks as if what went wrong was that the toxicology, pharmacokinetics
and pharmacology results were not put together to make a coherent whole,
taking into account the way in which the same receptor can have different
functions in different cell types or species, and previous experience with
different but related antibodies, and the general rules for new compounds.
1. Day M, Agency criticises drug trial. BMJ 2006;332:1290.(3 June.)
2 :Position Paper. Academy of Medical Sciences , at
3. Chan CC. Textbook of Pharmaceutical Medicine Warns of Trial Risks.
BMJ 2006 ; 332: 870.
4. TeGenero ,Investigators Brochure and Protocol ,at
5. Trepel F (1974) Number and distribution of lymphocytes in man. A
critical analysis. Klin Wochenschr 52: 511-515
Competing interests: No competing interests