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Medeva PLC (MDV)


Monday 17 January, 2000

Medeva PLC

Results from Immunotherapy Trial in Asian Patients

Medeva PLC
17 January 2000



Results From Immunotherapy Trial In Asian Patients

Medeva PLC today announced the latest results from its clinical development
programme for Hepagene (R), the Company's triple antigen hepatitis B
immunogen, in the treatment of chronic hepatitis B infection.  These data
from a study in 103 patients, with an initial placebo-controlled 4-dose
treatment phase, which was reported in December 1998, followed by an open 8-
dose phase, provide further clinical support for Hepagene's (R) safety and
potential efficacy as an immunotherapeutic agent.  This study was carried out
in the Pacific Rim, where the level of chronic hepatitis B infection is far
higher than in the US and Europe and where patients are infected earlier in
life and do not respond well to currently available immunotherapy (alpha

The key findings were as follows:

*  After 4 doses at monthly intervals, one in five patients (19.6%)
   were free of replicating virus (placebo response rate: 7.7%), and
   in those with raised baseline aminotransferase activity ('raised
   ALT') the response was twice as high (38.1%) (placebo response
   rate: 18.2%).  This trend to efficacy was not statistically
   significant as the study was not sufficiently powered to show
*  After a second, open, treatment course (8 doses at monthly
   intervals following a nine month gap), 38.9% of patients (7 out of
   18) with raised ALT were free of replicating hepatitis B virus.
*  In those patients who received Hepagene (R) for the first time in
   the second phase of the study, the evidence of efficacy, as
   measured by loss of viral DNA, was not clearly shown when compared
   with the historical placebo control group although individual
   patients showed responses as measured by loss of viral DNA or HBe
*  Unlike antiviral therapy, when treatment stopped the effects of
   Hepagene (R) in clearing the virus were maintained during 3 to 9
   months of follow-up.
*  Hepagene (R) was well tolerated, with a good safety profile over
   the period of the study.

Results from this exploratory phase study are expected to be reported at the
21st Joint Conference of the US/Japan Hepatitis Panel to be held in San
Antonio, January 17th and 18th 2000 and the 10th International Symposium on
Viral Hepatitis and Liver Disease to be held in Atlanta, April 11th to 14th

Commenting on today's announcement, Medeva's Chief Scientific Officer, Dr.
Michael Young said: 'Hepatitis B affects 300 to 400 million people worldwide
and is a major cause of cancer and death.  The treatment of chronic Hepatitis
B is an important clinical objective and these results provide a further
indication of the safety and potential efficacy of Hepagene (R).

Further details of the study are summarised below:

The study was conducted in Asian patients, since previously it has been shown
that this patient group does not respond well to currently approved
immunotherapy (i.e. alpha interferon).  This is generally considered to be
related to differences in the natural history of hepatitis B viral infection
between Asian and Western patients.  It has previously been reported that the
response to alpha interferon is not more than 40% even in optimal Western
patients (i.e. those with raised aminotransferase levels and moderate levels
of viral DNA).

A total of 108 patients were recruited, to assess the efficacy and safety of
4, 8 or 12 doses of Hepagene (R), over a period of one or two years.  Prior
to entering the trial, patients were tested to show that they had stable
chronic infection with hepatitis B and were stratified into either those with
normal or near normal aminotransferase activity (i.e. ALT within normal range
or less than 1.5 times the upper limit of normal) or those with raised
aminotransferase activity (i.e. ALT at least 1.5 times the upper limit of
normal).  Both groups were then randomised to receive either 4 doses of
Hepagene (R) (20ug) or of placebo at monthly intervals.  The patients were
followed for 9 months after treatment, and then received a second course of
treatment which consisted of 8 doses of Hepagene (R)  at monthly intervals.
This second phase was conducted as an open study, since further placebo
treatment was considered to be unethical.  Follow up evaluations were made
three and/or six months after completing the second treatment course.

Five of the 108 patients were excluded from the efficacy analysis because
they had shown viral DNA levels falling almost below the level of
quantification before their first injection and so were not considered to
have stable chronic hepatitis B infection prior to treatment.  Of the
remaining 103 patients, 43 had raised ALT at entry into the study. Four
patients dropped out and since they did not enter the second open phase of
the study they were not included in the analyses of that phase. Therefore a
total of 99 patients entered the second phase (41 with raised ALT levels).
Subjects who spontaneously resolved on placebo were not included in the
efficacy analyses of the second phase and, together with those patients who
were lost to follow-up, this resulted in a final evaluable study population
of 87 patients (33 with raised ALT levels).

With specific immunotherapy such as Hepagene (R), the first question is 'does
the patient's immune system see an antigen which is so similar to the virus
itself and respond to it?'.  This can be evaluated by their production of
anti-HBs antibodies during treatment.  These data are shown in Table 1 below.

Table 1  -  Production of Hepatitis B Surface Antibodies During the Study

                          4 Dose Course    8 Dose Course       2 Courses
                         --------------   --------------  --------------
All patients      19.2%           47.1%            60.7%           74.5%

Some three quarters of the patients treated with Hepagene (R) developed anti-
HBs antibodies at some point during the study.  This happened in
significantly more patients who were treated with Hepagene (R) than in
patients given placebo (p<0.05).  Indeed, the more doses of Hepagene (R)
given, the more patients showed the immune response.

A primary efficacy parameter is loss of measurable viral DNA.  Results
measured at the last point after each treatment course (3, 6 or 9 months post
treatment) are shown in the Table 2 below:

Table 2  -  Elimination of Hepatitis B Viral DNA with Immunotherapy

STUDY             FIRST PHASE                     SECOND PHASE
          -------------------------------  -----------------------------
PATIENTS    N       Placebo       4 Doses    N       8 Doses     2 Courses
All        103   7.7% (4/52)  19.6% (10/51)  87   4.8% (2/42)  15.6% (7/45)
Raised     43  18.2% (4/22)   38.1% (8/21)  33  13.3% (2/15)  38.9% (7/18)

In this study, the rate of spontaneous recovery from hepatitis B was
comparable with rates given by others for these types of patients.  Of the 52
patients who received placebo only four (7.7%) lost viral DNA within one year
of evaluation.

Fifty-one (51) patients received a first course of active treatment (4 doses
of Hepagene (R)) and ten (19.6%) were free of quantifiable replicating
hepatitis B virus nine months after finishing this treatment.  The response
was twice as high (38.1%) in patients with a raised aminotransferase level
prior to beginning immunotherapy.

With an immunotherapeutic such as Hepagene (R), one of the first effects as
the immune system responds to this stimulant would be expected to be a loss
of HBe antigen.  Collectively these two parameters of efficacy in
immunotherapy provide a broad view of patients' immunological reponses; the
results are shown in Table 3 below.

Table 3  -  Loss of Either HBe Antigen or Viral DNA After Hepagene (R)

                           4 Dose Course   8 Dose Course       2 Courses
------------   ---------   -------------   -------------   -------------
All patients         9.6%           19.6%          11.9%           20.0%
------------    ---------   -------------  -------------   -------------
Raised ALTs         22.7%           38.1%          33.3%           38.9%
------------    ---------   -------------  -------------   -------------

Generally the patients who lost HBe antigen during treatment also showed a
prolonged loss of HBV DNA.

The treatment was well tolerated with no adverse events of clinical concern
even in those given up to twelve doses of Hepagene (R).  No patients withdrew
because of treatment related adverse events.  This study was conducted
jointly with Janssen Research Foundation.

Hepagene (R)  Development Strategy

Hepagene (R) has already been developed as a superior third generation
vaccine for protection against infection by the hepatitis B virus.  A
European Marketing Authorisation Application for this use has been filed.
The response is expected in the first quarter of this year and Medeva is
optimistic about the outcome.

The clinical development programme for Hepagene (R) as a treatment is well
underway and a large, European, double-blind, placebo-controlled, pivotal
study is fully enrolled. It is expected that the initial results from this
phase of the Hepagene (R) development programme will be reported in mid-2000.
A similar pivotal study is enrolling in Canada. No studies are on-going in
the US pending the resolution of certain outstanding issues with the Food and
Drug Administration.

Hepagene (R) is a triple antigen which is complex and expensive to
manufacture.  Consequently it has been developed as a prophylactic vaccine
for patient groups inadequately addressed by current vaccines and will be
sold at a premium price.  The treatment market is potentially larger and the
price of Hepagene (R) will be competitive in this setting.

Medeva PLC                                      Tel: +44 (0) 1372 364000
Bill Bogie, Chief Executive
Peter Cozens, Director of Business Development
and Intellectual Property

Brunswick                                      Tel: +44 (0) 171 404 5959
James Bradley


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