Examination of Witnesses (Questions 60
- 79)
WEDNESDAY 1 JULY 1998
DR KEITH
MCCULLAGH
AND DR
PEDER JENSEN
Dr Turner
60. In the light of what you have just told
us, Dr McCullagh, is it not rather remarkable that on 10 January
1995 you are discussing this with clinicians involved in the trial
and concluding there is not a problem identified with abdominal
events, yet on 24 January 1995, ie fourteen days later, you halt
the trial? This seems to defy explanation. Can you offer us an
explanation?
(Dr McCullagh) We halted the trial because further
events in patients came to light which we thought were sufficiently
related in time terms to the administration of drug that we had
to answer as to whether or not what I said before was now correct.
We thought we should stop the trial and just make sure that in
fact this drug was not responsible for these serious adverse events.
That is the reason we suspended the trial. We did not halt the
trial, we suspended it temporarily while we looked into the matter.
I believe that was an important and responsible thing to do.
61. Did you restart the trial?
(Dr McCullagh) We recommenced clinical testing of
batimastat some months later following a reformulation of the
product because we had concerns that in the scale-up of the drug
in the manufacture of phase three we had produced a formulation
which was more irritant in some way.
Dr Gibson
62. What does reformulation mean? Re-synthesis?
(Dr McCullagh) The chemical mechanism, the chemical
root of synthesis and the way in which the product was produced.
batimastat was administered as a suspension not a true solution
and it was a very fine micro-amorphous suspension.
63. Was it a different compound you tested?
(Dr McCullagh) It was not a different compound; it
was the same compound.
64. Delivered differently is what you are saying?
(Dr McCullagh) We had changed the formulation for
the mechanism of manufacture between phase two and phase three.
65. Why did you do that?
(Dr McCullagh) In a minor manner in order to achieve
a scalable route.
Dr Turner
66. Can you explain that?
(Dr McCullagh) When you start off clinical testing
you are making the drug in small quantities and one uses methods
to synthesise the drug at a kilo scale. One puts it into a small
number of phials and suspension. If you are going into phase three
one scales that process up to ten or twenty kilos manufacturing
scale and makes several thousand ampoules of drug rather than
just a few. The process in order to produce those larger quantities
had minor changes. For example the powder was dried from an alcoholic
suspension rather than an acetone suspension. They were relatively
minor changes but they might have introduced a slight difference
in the crystalline structure in the final particulate nature of
the drug. We wanted to make sure that if that was the case that
we put it back to the previous small-scale method and we duplicated
that precisely at the larger scale. Having satisfied ourselves
that we had done that we then recommenced trials.
67. Having done that and having restarted trials
two years ago, you should by this stage have expected to have
come to a successful completion of that series of trials and received
licensing of the drug. Have you?
(Dr McCullagh) No. The product was overtaken by the
follow-on compound marimastat which was an oral drug taken twice
a day which was being tested and showing encouraging results in
the same patient group and we felt it was better to switch the
patients to receive marimastat and participate in those trials
since that was a more effective and long-term route of adminstration.
So in fact the trial was overtaken by a second programme.
68. Are the two compounds acting by the same
mechanism?
(Dr McCullagh) Correct.
69. The other thing which I think slightly puzzles
me, going back to the earlier stages of trials, is that you must
have had some pretty positive looking results from those to justify
embarking on a phase three trial.
(Dr McCullagh) Very much so.
70. So is it not faintly surprising that the
results should be so different between the two trials?
(Dr McCullagh) I am sorry, I do not believe that they
were different in regard to efficacy.
71. Did you demonstrate efficacy when you resumed
the trial?
(Dr McCullagh) We did not continue the phase three
trial. As I said, we transferred the patients from that project.
We stopped the use of batimastat in patients with intra-abdominal
cancer in favour of giving those same patients marimastat as part
of the phase two marimastat programme that led to some very encouraging
results from marimastat in those same patients. Going back to
the whole history of making metalloproteinaise inhibitors in the
treatment of cancer, batimastat was the prototype compound, the
first compound of its class to be brought to development and into
the clinic. We have 20 different pre-clinical models of different
types of human cancers that have shown substantial improvement
following treatment with batimastat. In the first phase one trials
we had repeated that with some good clinical data. The same applies
to marimastat. We had very good pre-clinical pharmacology and
also a very large number of patients in the phase two programme
who have shown benefit and by assessments of the activities of
their cancers we have been able to show marimastat has had a biological
effect on those patients.
Chairman
72. Can I say we did start quarter of an hour
late and we have had a ten minute interruption. It would be this
Committee's desire to continue to half past five if you two would
co-operate with us. We still have quite a bit of business to get
through so we will try and speed up a little bit. Is that agreeable
to you?
(Dr McCullagh) That is fine.
73. Before I turn to Mrs Lait, could I put one
point to you, Dr McCullagh. In my hand now is an affidavit from
Dr Millar signed by him and initialled on every page. He says
on page 5, paragraph 17: "Throughout October and November
1994 we received further reports of intra-abdominal problems suggestive
of peritonitis in batimastat phase two studies. At that time I
was not particularly interested in the company's press releases
as this was not my responsibility." I wonder if you would
care to comment on that because it does seem strange if this statement
is to be taken at face value that the person in charge of the
phase two trials was not being involved in any way in the contents
of press releases.
(Dr McCullagh) I do not believe that to be the case.
Our press releases as they relate to clinical trials and clinical
trials results have always been approved by the head of clinical
research.
Chairman: Thank you very much. Mrs Lait?
Mrs Lait
74. Between the ending of the phase two trial
and the beginning of the phase three trial I understand the Stock
Exchange got in touch with you. Would you care to give us any
indication of what that was about?
(Dr McCullagh) I think the Stock Exchange initial
investigation came about as a result of the reduction in our share
price when we halted the phase three trial of batimastat in February
1995. Subsequent to that the Stock Exchange wrote to the Company
Secretary Mr Weir asking for information about the circumstances
in which that was done.
75. And has there been any follow-up?
(Dr McCullagh) The Stock Exchange received a considerable
amount of information from us and after approximately two months
wrote to us and said they were satisfied with the information
we had provided and would take the matter no further.
76. Has anything subsequently re-emerged on
that issue at all?
(Dr McCullagh) No, until Dr Millar's allegations,
and I have to ask the Committee to consider why they are being
brought up more than three years after the event. There is no
suggestion, and I take it as a very serious allegation that there
was any impropriety. There simply was not. There was a very valid
set of circumstances supported and recommended by Dr Millar as
to why we stopped the trial. We took his recommendation to halt
the trial early in 1995 and it was on his recommendations, when
we restarted, that we started with a pilot study to make sure
the drug was safe. So I do not think there was any difference
of view between Dr Millar and myself about the manner in which
we should suspend the trial or the manner in which we restarted.
As I said, it is a surprise to me that these allegations have
been brought at this time. They are sufficiently serious, however,
for the non-executive directors, when they heard about them, to
ask a third party, an independent law firm, Cameron McKenna, to
conduct further due diligence into them. As you know, Cameron
McKenna produced a report and in their conclusions they said very
clearly at the time the dealings were concerned, as far as the
share transactions were concerned, and at the time of the transactions
themselves, there was no basis on which the directors of the company
could have predicted that an announcement of the suspension of
the trial could be likely. On that basis, we are fully exonerated
and have acted within the Model Code. That is the end of the matter
as far as I am concerned. There was no impropriety and I think
it is a very serious allegation to suggest that there was.
Dr Williams
77. I have three or four short questions on
marimastat. As I understand it, this is your most promising project
and about 80 per cent of your company's value is based on the
potential success or otherwise of this treatment. What is your
latest assessment of the prospects of success?
(Dr McCullagh) As we have said earlier, it is very
difficult to predict the likelihood of success. I happen to be
a firm believer in MMP inhibitors as a new mechanism for drug
action in cancer. I think such drugs will have a major impact
on the treatment of cancer to the benefit of patients. We are
trying to define that in our pivotal clinical trials, but it might
be helpful if Dr Jensen quickly runs through what those trials
are.
(Dr Jensen) There is a very extensive phase three
programme on marimastat in cancer. We have eleven studies going
on in six different cancer indications. These studies are going
to read out within the next three year period. That is not to
say that all studies will read out at the same time, some of them
will read out as early as next year, about a third of the studies
will read out in the year 2000, and the last of the studies will
read out in 2001. It is reflecting the fact that there is no precedent;
there is no other company which has developed these compounds.
It is not very normal to have six different cancer indications
at the same time in phase three, but it is reflecting the fact
that the pre-clinical data is not really able to predict in which
kind of tumour these classes of compound will work.
78. My next question is a bit before Dr Jensen's
time. Back in 1995 and 1996 there was a succession of very up-beat
press releases about marimastat, and I can remember at the time
following the journals and being very excited about this new approach
and the potential for this wonder cancer drug. I understand that
by today, however, the US Securities and Exchange Commission is
investigating the background to those very up-beat press releases.
Is that so?
(Dr McCullagh) Yes, it is true. Let me tell you the
details of what we said at that time. Those press announcements
were the results of our phase two trials which had shown remarkable
activity against the markers of cancer which are cancer antigens
in blood, and they often are interpreted as being a reflection
of the underlying growth of the tumour. We had dramatic reductions
in the cancer antigen levels within the patients being treated
by marimastat and everybody was excited by that. We reported the
factually correct results of those trials, we made no comment
on the ability to get the drug registered at that point, we said,
"These are encouraging data but they will require confirmation
in definitive phase three studies which the company is about to
start." The market, however, interpreted those statements
very positively and, yes, our share price went up dramatically.
79. Five fold.
(Dr McCullagh) That is the market's response to factual
statements which we verified and know are absolutely correct,
and the data has now been published in the medical journals.
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