Annex M
CONFIDENTIALITY AGREEMENT
This Confidentiality Agreement forms an integral
part of your Contract of Employment.
1.(a) The Employee shall fully and promptly
disclose to the Company all inventions, improvements, discoveries,
ideas, processes, designs or coprights (herein collectively called
"Inventions") whether patentable or not, that the Employee
may create or develop, alone or with others, during the Employee's
term of employment with the Company, and relating to his duties,
pertaining to products, potential products, machines, processes,
activities and business of the Company and of any and all of its
Affiliates, the said Affiliates being defined as all companies
at any time under the direct or indirect control of, or having
a direct controlling interest in, British Bio-technology Group
plc.
(b) Save as otherwise required by Law, all
Inventions shall be the sole and absolute property of the Company,
whether or not patent applications or registered design applications
are filed thereon.
(c) The Employee shall, at the request and
expense of the Company whether during or after the Employee's
period of employment with the Company, furnish all assistance
and execute any document, act or thing which may be required to
obtain patents or registered designs on said Inventions in the
United Kingdom and in foreign countries as necessary to vest title
therto in the Company or its nominee, and to protect or enforce
the Company's rights or those of its nominee under said patents
or registered designs or any other rights arising out of said
Inventions.
2.(a) The Employee shall not at any time
during or subsequent to the Employee's employment use or disclose
to others, without the consent of the Company, any Confidential
Information in the possession of the Company or of any of its
Affiliates (as defined above), as owner or otherwise, of which
the Employee becomes informed while employed by the Company. "Confidential
Information" is defined as matters of a technical nature,
such as know-how, formulae, secret processes or machines, inventions,
research projects, laboratory notebooks, management information
systems and computer programmes, and matters of a business nature
such as information about costs, profits, markets, sales, plans
for future development, lists of customers and any other information
of a similar nature. Confidential information shall not include
any information in the public domain other than through wrongful
disclosure by the Employee or any other person.
(b) The Employeee shall not release any of
the Company's or any of its affiliates' Confidential Information
or that of any third party given to the Employee in the course
of his employment. The Company will regard such unauthorised release
of Confidential Information as a serious breach of the Employee's
employment terms entitling the company to give summary notice
of dismissal to the Employee.
(c) The Employee shall return promptly, and
on request by the Company, any laboratory notebooks, published
papers, written records, books, products, equipment or other Company
property when requested to do so during employment. All Company
property, including laboratory notebooks, management information
systems and computer programmes, and matters of a business nature
such as information about costs, profits, markets, sales, plans
for future development, lists of customers and any other information
of a similar nature not in the public domain, must be returned
to the Company by the employee immediately on termination of employment.
3. Once an employee has left the Company
there will exist a Restriction Period of 18 months during which:
(a) The Employee will not solicit in competition
with the Company any customer or client who was a customer or
client of the Company during his/her employment.
(b) The Employee will not induce, nor attempt
to induce, any employee of the Company to leave and act for another
Employer in a similar capacity in relation to the same field of
work.
4. The restrictions herein are considered
by the Employee to be reasonable for the protection of the Company's
and its affiliates' legitimate intrerests.
Paul Littlewood, British
Biotech
Dear Paul,
I acknowledge receipt of various letters from you
and the cheque. I will address the points separately.
MINUTES OF
DISCIPLINARY MEETING
These are unacceptable because there are distortions
of what I said and omissions which are too numerous to list. I
stated at the start of the meeting, that it was my right to record
the meeting and a tape would be a fair way of doing this. Not
recording the meeting allows what was said to be obfuscated, which
is what has happened. The disciplinary meeting was therefore clearly
unfair and my dismissal was clearly unfair. Having said that,
the distortions and omissions are too numerous to list, there
is one omission to which I would draw your attention:
— I stated that in May last year it
came to my attention that Peter Lewis had been failing to pass
on appropriate warnings to the other executive directors and board
about some pessimistic aspects of the emerging clinical trial
data. I stated this to Keith. Keith told me these were serious
allegations I was making about Peter Lewis and asked if I would
be prepared to back them up in court. I said I would and put them
in writing to him on 15 May. He told me he would fire Peter Lewis
immediately. This never happened, but nor did the business plans
change. At the end of May I phoned Sir John Raisman with my concerns.
He told me that what Peter did was despicable, but that the company
could not afford the scandal of firing him. He told me that while
Keith was very optimistic he had great confidence in him. My concerns
about the business plans and the management of the clinical trials
continued from there on and increased.
This vital aspect of my justification of my
actions has clearly not been taken into account during the disciplinary
process which is therefore unfair. I am also suspicious that this
was not properly investigated by Cameron McKenna as I have not
been allowed to see the report. I therefore intend to go to an
industrial tribunal about this as is my right and I shall pursue
the company for compensation for unfair dismissal and unjustified
summary dismissal and stigma as far as I can. I shall also wish
to take into account my stock options in looking for compensation.
I shall start proceedings for an industrial tribunal on Friday
if I have not heard from you and I shall continue to take legal
advice on all aspects of the case as it develops.
CONFIDENTIALITY
I have spoken to various people at different
times on different matters including confidential information,
but not improperly disclosed confidential information to them.
My actions have been justified, because I have suspected the stock
market has been misled and my actions have been in the public
best interest as well as the company's best long term interest.
Furthermore my actions and events demonstrate that I never wanted
this in the media, but to be resolved behind closed doors. On
the occasions when I have spoken to the press, it has always been
in response to company press activity, including the original
derogatory statements at the time of my suspension, leaking of
the Cameron McKenna report and the misrepresentation of this as
a fair and independent investigation into my grievances and other
company statements. These people are Perpetual, Mercury Asset
Management, Kleinwort Benson, Jane Henderson, Paul Durman of the
Times, Nils Pratley of Sunday Business and Jonathan Guthrie of
the Financial Times. In addition, last night I contacted the SEC
and an FDA officer. I now undertake not to disclose any confidential
information as requested.
I request, that in order to save me buying a
new car to transport my children around, you allow me to continue
to use the Audi, until such time as these difficulties are resolved.
It remains my intention to return to work at British Biotech in
an organisation with rational business plans and people and I
still consider that this can be achieved. I remain the best qualified
person available to direct the programmes on marimastat and lexipafant.
Yours sincerely
Andrew Millar
25 April 1998
MEMORANDUM
| To: | Peter Lewis
| From: | Andy Millar |
| Paul Littlewood |
| |
| Peter Brown |
| |
| Peter McCann |
| |
| Greg Hockel |
| |
| Bob Blakie |
| |
| Neil Graham |
| |
| Russ Smith |
| |
| cc: | Keith McCullagh | Date:
| 13 October 1994 |
| James Noble |
| |
| Alan Drummond |
| |
| |
| |
RE: INTRA-PERITONEAL
ADVERSE EFFECTS
AND BATIMASTAT
It has been reported by Dr Mike Hawkins of Georgetown University
Hospital, Washington that patient No 005 in study D02/IVB/307
underwent laparotomy for small bowel obstruction on 9 October
1994.
This patient had advanced ovarian cancer without evidence
of widespread peritoneal disease apart from two nodules on the
stomach which were removed and no ascites at laparoscopy. It is
significant that during placement of the intra-peritoneal catheter
on 28 July 1994 prior to first administration of batimastat on8
March1994 that puncture of the gallbladder occurred "without
sequelae". Batimastat was administered at a dose of 1,200
mg/M2 at four weekly intervals. After the first dose, the patient
developed a pyrexia of 102F and had abdominal tenderness.
She had also developed abdominal distension and ascites was drained.
She went on to develop increasing abdominal distension and tenderness
after the third administration of batimastat which did not settle
with conservative resuscitation.
At laparotomy, the patient was found to have a large mass
of white "elephant skin" material 2-3 mm thick densely
adherent to multiple loops of small bowel in the right upper quadrant.
It was also adherent to the parietal peritoneum. The material
appeared to be some form of concretion of batimastat. Careful
dissection over 2-3 hours freed all the bowel which was found
to be "pristine", in particular it was free of any signs
of malignancy. There was one nodule in the transverse mesocolon
distal from the site of the concretion.
A sample of the material has been sent to British Biotech
for analysis for batimastat content, but the assumption is that
this represents a concretion of batimastat with inflammatory protein
or other substances. The placement of the intraperitoneal catheter
in the right upper quadrant and the finding of the white material
confined to the same area indicates that in this patient without
ascites batimastat was not distributed freely around the peritoneal
cavity and the vehicle and dextrose used to administer it presumably
was absorbed and left the batimastat to precipitate.
It is not possible to judge accurately the extent to which
the inadvertent gall bladder puncture contributed to the findings
in this patient. It is important to note that not only did this
patient not have ascites, but she has also received the largest
total amount of drug administered to a human to date.
The report from Dr Hawkins is pertinent to the report from
Professor Kerr in Birmingham where patient No 63 in study D02/IVB/309,
who had advanced ovarian adenocarcinoma with ascites was dosed
with batimastat on 18 August 1994 and was re-admitted with vomiting
on 26 August 1994. Small bowel obstruction failed to resolve with
conservative management and laparatomy was performed on 16 September
1994. At laparotomy the bowel was found to be stuck together with
a dense "super-glue"-like exudate (consultant surgeon's
description). Histopathology revealed that the exudate showed
typical features of adenocarcinoma.
In Professor Smyth's first study there were two cases of
sub-acute intestinal obstruction which settled with conservative
management. It is not known whether these represented the natural
history of the disease, a fibrous reaction or other "tumour
agglutinating reaction" caused by the pharmacological effect
of batimastat, a physical irritant effect of batimastat or any
other mechanism.
Examination of the current preliminary data of patients in
study D02/IVB/309 (30 patient II ascites study) reveals that a
high proportion have reported abdominal pain, vomiting or bowel
disturbance. The dose here was 1 g/m2. These effects could be
due to tumour, a physical irritant effect of batimastat or sub-acute
bowel obstruction. It is probably not possible to determine which
without a controlled comparative study.
At present, the data in the non-ascitic abdomen are very
preliminary; however the findings in patient 005 are clear. A
reasonable explanation is that the volume of vehicle is inadequate
to disperse the drug adequately throughout the peritoneal cavity
and as the vehicle is rapidly absorbed through the normal peritoneum
batimastat precipitates. It is then combining with exudative protein
to form an adhesive concretion which is impairing normal gut motility.
If this is the mechanism then this might well occur in other patients
with normal peritoneal cavities if similar doses and methods of
delivery are used.
It is noteworthy that the AUC for this patient No 005's blood
levels has been relatively low compared to those for the ascites
patients in general and one other "non-ascites" patient
from Georgetown. This would be consistent with the batimastat
going in to a non-bioavailable form such as this apparent concretion.
The data are scanty at this stage, but it is my impression that
the blood levels in the non-ascites patients are lower than the
ascites patients and that we are not seeing dose proportionality.
This may indicate that the dry peritoneum's ability to keep batimastat
in a biologically available state is being exceeded.
The current blood levels appear high compared to the IC50
although free drug levels are not known. Dose reduction is a possibility
for overcoming the problem of concretions and still maintaining
adequate blood levels. Increasing the volume of vehicle and using
physical movement to achieve wider dispersion also seems attractive.
Methods for increasing dwell time (high molecular weight dextran)
should also be reconsidered.
These findings have implications for the current clinical
research programme:
1. We do not now have adequate data or confidence to broaden
the programme in the non-ascitic abdomen using the current dose
in the protocol of 1,000 mg/m2. These studies, all in the US,
should be put on hold. We should inform the FDA and the clinical
investigators of this decision.
Action Greg Hockel and Peter McCann.
2. All patients in all clinical studies including the
ascites studies should be informed that there is a risk of gastrointestinal
obstruction as an element of informed consent.
Action self (write letter to investigators), Peter Brown
and UK/US CRAs).
3. We should consider ways of acting in the best interests
of patient 005. For example determining what benefit she m7ay
have received from administration of batimastat, eg discuss progression
and CA125 levels.
Action self (discuss with Mike Hawkins and James Barter).
Peter McCann and Paul Littlewood (consideration of legal situation).
4. Revise current protocol with Mike Hawkins to explore
lower doses and larger volumes of infusate.
Action self.
5. Discuss situation with UK investigators involved with
dry abdomen studies and take similar action to US.
Action self and Peter Brown.
Implications for ascites phase III programme
The situation with respect to ascites is less clear at present,
but based on the current data the risk to patients is less than
for non-ascites patients, on the other hand if the drug is effective
and renders the abdomen dry then repeated administration might
produce the same effect. It therefore seems that the repeated
dosing proposed in the European and Australian protocols should
be looked at again.
The situation should become clearer with a little more time
as patients progress through study 309 and data comes in house
over the few weeks (see below).
The dose of 1,000 mg/m2 produces adequate blood levels (with
the caveat that free levels and tissue distribution have not yet
been determined). It is therefore possible that dose reduction
would increase tolerability and maintain efficacy particularly
if the main effect is topical. We already have lower dose levels
(500 and 250 mg/m2) in the European and Australian protocols.
It may be worth reconsidering a lower dose level in the UK study
although this may be time consuming. Unless the 309 indicates
that the dose is definitely too high on the grounds of safety
there is no reason to change the dose of 1,000 mg/m2. If the dose
does appear too high then we might need a further pilot study
at a lower dose. However, based on John Smyth's first 24 patients
and current impressions this will not be the case.
It seems prudent to proceed cautiously in order not to risk
the malignant ascites project. The current situation will be reviewed
with John Smyth on 2 November. I predict that around that time
it will become clear that it is appropriate to proceed with the
UK ascites study without much change, if any to the current format.
On the other hand, it seems imprudent at this stage to widen recruitment
to 60 different hospitals throughout Europe and Australia. In
the initial stages we should restrict the UK study to 10 or 15
centres to keep the data under control and reviewable.
Implications for the pleural effusion study
There seems to be no adverse implications for the treatment
of pleural effusion. Particulate matter and pleurodesis are part
of standard therapy and there are no problems akin to bowel obstruction
in the pleural cavity. Furthermore the possible need for dose
reduction in ascites is in no way disadvantageous. We will proceed
to expand this programme.
Action: Peter Brown.
| Centre | Patient
| Start | 2 Month
| CRF in-house |
| 01 | 01 | 9 June
| 9 August | |
| Beattie | 02 | 7 July
| 7 September | |
| 03 | 14 July
| 14 September | |
| 04 | 15 July
| 15 September | |
| 05 | 18 August
| 18 Octember | |
| 06 | 18 August
| 18 Octember | |
| 07 | ? September
| ? November | |
| 08 | ? September
| ? November | |
| 02 | 20 | 6 May
| 6 July | YES* |
| Miles | 21 | 6 May
| 6 July | YES |
| 22 | 9 May
| 9 July | YES* |
| 23 | 10 May
| 10 July | YES* |
| 24 | 9 June
| 9 August | |
| 25 | 2 August
| 2 October | |
| 26 | 22 September
| 22 November | |
| 03 | 30 | 8 September
| 8 November | |
| Carmich | 31 | 9 September
| 9 November | |
| 32 | 23 September
| 23 November | |
| 04 | 40 | 4 July
| 4 September | YES* |
| Coleman | 41 | 12 July
| 12 September | |
| 42 | 28 July
| 28 September | |
| 43 | 1 August
| 1 October | YES* |
| 44 | 25 August
| 25 October | |
| 05 | 50 | 20 May
| 20 July | |
| Perren | 51 | 28 July
| 28 September | YES* |
| 52 | 3 August
| 3 October | |
| 53 | 28 September
| 28 November | |
| 06 | 61 | 15 June
| 15 August | YES* |
| Kerr | 62 | 8 July
| 8 September | YES* |
| 63 | 13 August
| 13 October | YES* |
| 64 | 16 September
| 16 November | YES* |
| 65 | 29 September
| 29 November | |
| 66 | 6 October
| 6 December | |
| 07 | 70 | 4 October
| 4 December | |
| Green | 71 | 6 October
| 6 December | |
| |
| | |
35 Patients entered.
11 CRFs In-House (10 of which are for patients who withdrew
before day 28).
10 Additional CRFs to be collected at sites now.
4 Further CRFs by end October.
British Biotech Plc
Cancer drug batimastat starts pivotal
Phase III trials and new oral cancer drug, BB-2516, starts human
clinical testing
HIGHLIGHTS
British Biotech announces the start of pivotal Phase III
efficacy trials with its new cancer drug, batimastat, and the
start of human clinical testing of its new oral anti-cancer drug,
BB-2516.
Batimastat
— Batimastat is the first of a new class of drug
for the treatment of cancer.
— Batimastat has satisfactorily completed a Phase
II study in 40 patients with late stage abdominal cancer.
— Phase III is the final stage of clinical testing
prior to applying for European marketing approval.
— British Biotech is aiming to file a European Marketing
Authorisation Application for batimastat by the end of the first
quarter of 1996.
— Batimastat is an injectable drug.
BB-2516
— BB-2516 is of the same class of drug as batimastat
and has similar anti-cancer activity, but is designed to be an
oral drug which can be taken by mouth.
— BB-2516 is being administered to 12 healthy volunteers.
— The Phase I trial will investigate the absorption
and tolerability of the drug.
— The first trials of BB-2516 in cancer patients
are scheduled to start in the second quarter of 1995.
British Biotech owns full commercial rights to both batimastat
and BB-2516 and the company intends to develop and market both
products itself in Europe and North America.
Commenting on today's news, Dr Keith McCullagh, Chief Executive
Officer of British Biotech, said "Both batimastat and BB-2516
are progressing through product development with exceptional speed.
The commencement of multi-centre Phase III trials of batimastat
announced today confirms that British Biotech is on schedule to
achieve its target of a European registration submission for batimastat
early in 1996. The start of human clinical trials with BB-2516
is also important because this new second generation MMP inhibitor
has the potential to become the company's most substantial product,
revolutionising the treatment and prospects of a wide range of
cancer patients at all stages of disease."
Batimastat Phase III study design
The European Phase III study programme currently comprises
two separate multi-centre clinical trials in patients with malignant
ascites, a serious complication of late stage ovarian and other
abdominal cancers. The first trial (the "UK study")
has now started and is being conducted at approximately 20 hospitals
in the UK. The second trial (the "Continental European study")
will commence early in the New Year and will be conducted at approximately
20 hospitals in Germany, France, Italy, the Netherlands, Belgium
and Switzerland.
The UK study
The UK study will enrol 150 patients and compare batimastat
treatment following abdominal fluid drainage with a control group
receiving drainage treatment alone. In this study, 100 patients
will receive a single 1000mg/m2 dose of batimastat with a second,
equal dose to be administered on the first reaccumulation of fluid
requiring drainage. The control group of 50 patients will receive
no treatment other than drainage and a diuretic. Both groups will
be followed in parallel for 84 days.
Continental European study
The Continental European study, due to start in the first
quarter of 1995, will also enrol 150 patients and will compare
batimastat treatment with a wider range of alternative treatments
for malignant ascites, including intraperitoneal chemotherapy.
In this study, patients will be randomised into three 50-patient
groups. Patients will receive either a single 1000mg/m2 or a 500mg/m2
dose of batimastat with a second, equal dose to be administered
on the first reaccumulation. The control group of 50 patients
will receive no treatment other than intraperitoneal chemotherapy
or a diuretic.
Clinical endpoints
Both batimastat studies will measure the frequency and quantity
of ascitic fluid drainage and will also assess cancer progression
via tumour size (by CT scan), quality of life and, for ovarian
cancer patients, plasma levels of CA125.
BB-2516
BB-2516 is British Biotech's second potential drug in the
MMPI field. In preclinical testing, BB-2516 has similar anti-tumour
activity to batimastat, but has the added advantage that it is
well absorbed when taken by mouth. The Phase I trial being announced
today is therefore of great significance to British Biotech, since,
if it confirms the good oral absorption and safety profile suggested
by pre-clinical studies, British Biotech will consider BB-2516
to be its leading product in terms of market potential, based
on the number of patients suitable for treatment and the likely
duration.
The Phase I trial of BB-2516 has started in the United Kingdom
and will enrol 12 healthy volunteers; it is designed to test the
absorption and tolerability of BB-2516. If the Phase I trial is
successful, the first trials in cancer patients are scheduled
to start in the second quarter of 1995 in both Europe and the
USA.
BB-2516 is the first orally active compound of its class
to commence human clinical trials for cancer. It is designed to
slow down and prevent the spread of a wide range of cancers. Based
on pre-clinical data, drugs of this class could be useful in treating
most solid tumours, including breast, lung, colorectal, prostate,
ovarian and gastric carcinomas. There are currently almost 5 million
patients with these tumours in Europe and North America alone.
Batimastat and BB-2516
Batimastat and BB-2516 are both drugs belonging to the class
of matrix metalloproteinase inhibitors (MMPIs). Batimastat was
the first MMPI to enter human clinical trials. The compounds,
however, differ in some important respects, as follows:
— Batimastat and BB-2516 are different chemical
compounds covered by different patent applications.
— Batimastat is administered by injection into the
peritoneal or pleural cavity.
— BB-2516 is formulated as a capsule to be taken
by mouth.
— Batimastat is designed as a treatment for late
stage cancers and is initially targeted at malignant ascites and
pleural effusion.
— BB-2516 is designed for potential use as a chronic
therapy, administered from the first detection of cancer. Most
existing anti-cancer therapies are too toxic for prolonged treatment.
— Batimastat is now in the final stage of clinical
testing (Phase III); BB-2516 has commenced initial clinical trials
(Phase I).
If trials with both drugs are successful, British Biotech
will allocate its resources in this field as follows:
— Clinical trials with batimastat will focus on
malignant ascites and pleural effusion, two indications where
an injectable product is preferred.
— Clinical trials with BB-2516 will focus on patients
with rapidly advancing but earlier stage cancers.
Background to MMPIs and cancer therapy
Batimastat and BB-2516 are inhibitors which block the action
of matrix metalloproteinases, enzymes that destroy connective
material between cells and allow cancers to spread and grow. British
Biotech believes that it is currently the only company with matrix
metalloproteinase inhibitors (MMPIs) undergoing human clinical
trials in cancer.
The potential advantages of MMPIs over existing cancer therapies
are:
— Unlike traditional cancer treatments, MMPIs are
not cytotoxic drugs and hence are not toxic to normal tissue.
— MMPIs act by blocking the biological mechanism
by which tumours spread and grow. This mechanism is common to
most solid cancers.
Background
British Biotech plc, founded in 1986, combines approaches
in molecular biology and synthetic chemistry to develop new therapeutic
agents for the treatment of cancer. In addition, the company is
pursuing research in inflammatory, vascular and viral diseases,
particularly AIDS. The company has recently established a new
subsidiary, Neures Limited, to investigate the role of metalloproteinase
inhibitors in neuro-inflammatory diseases. British Biotech, based
in Oxford, England, is listed on the London Stock Exchange and
quoted on NASDAQ under the symbol BBIOY. A US subsidiary, British
Biotech Inc., was established in Annapolis, Maryland, in December
1993.
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