New Non-Clinical Data Links DYNEPO(R) (Epoetin Delta) to Reduced Angiogenic Potential

New Non-Clinical Data Links DYNEPO(R) (Epoetin Delta) to Reduced Angiogenic Potential

November 05, 2007

    BASINGSTOKE, England, Nov. 5 /Xinhua-PRNewswire/ -- New
data presented today at the 40th annual American Society of
Nephrology (ASN) meeting and scientific exposition in San
Francisco, CA, USA, show that epoetin delta -- the only
erythropoiesis-stimulating agent (ESA) produced in a human
cell line -- has less pronounced angiogenic properties than
darbepoetin alfa in vitro at similar pharmacokinetic
concentrations.(1)

    Angiogenesis, the formation of new blood vessels from
pre-existing vessels, plays an important role in tumour
growth, malignancy and diabetic retinopathy. The study
evaluated the angiogenic potential of human cell-derived
epoetin delta and darbepoetin alfa at broad concentration
ranges using a novel in vitro model that incorporates key
aspects of the complex angiogenesis process.(1)

    "Although this research is at a very early stage,
this data is the first step towards evaluating whether
different EPO analogues produce different angiogenic
effects," said primary investigator Professor Alan
Stitt, Centre for Vision Science, Queen's University,
Belfast, Northern Ireland, UK. "In the clinical
setting, there are situations where reduced angiogenic
potential is beneficial, for example, in patients with
malignancies or proliferative retinopathy. Additional
studies, in both the non-clinical and clinical setting, are
needed to further examine the angiogenic potential and
related molecular mechanisms of epoetin delta."

    The authors of the study concluded that the observed
pharmacological effects of epoetin delta and darbepoetin
alfa on the angiogenic response may be associated with
their different glycosylation patterns at clinically
relevant doses.(1) Glycosylation (the process of adding
carbohydrate structures to a protein) is dependent on
various factors including species and cell type.(2) As
epoetin delta is produced in human cells by activating the
erythropoietin gene -- and all other commercially available
ESAs are presently made in Chinese Hamster Ovary (CHO) cells
-- epoetin delta has a different glycosylation pattern to
other currently marketed ESAs.(3)

    Neuropathy also commonly develops in people with
diabetes who also suffer from CKD. Additional non-clinical
data accepted for publication at ASN show that in rats,
epoetin delta corrects the reduced nerve conduction
velocity (a parameter of nerve function) associated with
neuropathy. This occurred even at doses below those
promoting haematopoiesis.(4)

    "This data is particularly interesting," said
primary investigator Professor Norman E Cameron, School of
Medical Sciences, University of Aberdeen, Scotland.
"We know that ESAs are effective in correcting
anaemia, but this data suggests that, at least in the
non-clinical setting, epoetin delta may have pleiotropic,
non-hematopoietic effects. Further research is needed to
investigate whether structural differences across ESA
analogues influence diabetic co-morbidities, such as
diabetic neuropathy, differently."

    To further understand the implications of epoetin delta
being manufactured in a human cell line, Shire is sponsoring
a non-clinical research programme to investigate how epoetin
delta affects tissues and processes outside of the
haematopoietic system. Of particular interest is whether
epoetin delta's human cell derivation may influence
co-morbidities of the renal anaemia patient, such as
diabetic complications and vascular disease, in a way that
is different to ESA's derived from animal cells. The
research presented today marks the publication of the first
data from the programme.

    About DYNEPO

    DYNEPO is the first commercially available ESA produced
in a human cell line.(5) This is accomplished by activating
the endogenous human erythropoietin gene in a human cell
line using specialised gene-activating DNA sequences.(6)
All other commercially available ESAs are produced in CHO
cells. Anaemic patients with CKD require treatment with an
ESA such as DYNEPO in order to increase red blood cell
production.

    DYNEPO is indicated for the treatment of anaemia in
patients with chronic renal failure (CRF) and may be used
in patients on dialysis and in patients not on
dialysis.(7)

    DYNEPO is a registered trademark of Hoescht GmbH.

    (i) While common terminology is now chronic kidney
disease (CKD), some regulatory agencies have not adopted
this terminology, instead they refer to chronic renal
failure (CRF); these terms are essentially
interchangeable.

    Notes to editors

    Shire plc

    Shire's strategic goal is to become the leading
specialty biopharmaceutical company that focuses on meeting
the needs of the specialist physician. Shire focuses its
business on attention deficit and hyperactivity disorder
(ADHD), human genetic therapies (HGT), gastrointestinal
(GI) and renal diseases. The structure is sufficiently
flexible to allow Shire to target new therapeutic areas to
the extent opportunities arise through acquisitions.
Shire's in-licensing, merger and acquisition efforts are
focused on products in niche markets with strong
intellectual property protection either in the US or
Europe. Shire believes that a carefully selected portfolio
of products with strategically aligned and relatively
small-scale sales forces will deliver strong results.

    The "Safe Harbor" Statement Under the Private
Securities Litigation Reform Act of 1995

    Statements included herein that are not historical
facts are forward-looking statements. Such forward-looking
statements involve a number of risks and uncertainties and
are subject to change at any time. In the event such risks
or uncertainties materialize, Shire's results could be
materially affected. The risks and uncertainties include,
but are not limited to, risks associated with: the inherent
uncertainty of pharmaceutical research; product development
including, but not limited to, the successful development
of JUVISTA(R) (Human TGF beta 3) and GA GCB (velaglucerase
alfa); manufacturing and commercialization including, but
not limited to, the launch and establishment in the market
of VYVANSE(TM) (Attention Deficit and Hyperactivity
Disorder ("ADHD"); the impact of competitive
products including, but not limited to, the impact of those
on Shire's ADHD franchise; patents including, but not
limited to, legal challenges relating to Shire's ADHD
franchise; government regulation and approval including,
but not limited to, the expected product approval date of
INTUNIV(TM) (guanfacine extended release) (ADHD); Shire's
ability to secure new products for commercialization and/or
development; and other risks and uncertainties detailed from
time to time in Shire plc's filings with the Securities and
Exchange Commission, particularly Shire plc's Annual Report
on Form 10-K for the year ended December 31, 2006.

    References

    (1) McVicar C, Gardiner T, Stitt A. Human-cell-derived
epoetin delta is less angiogenic than darbepoetin alfa in
vitro. Poster presented at American Society of Nephrology
Renal Week, San Francisco, CA, USA. 2-5 November 2007.

    (2) Skibeli V, Nissen-Lie G, Torjesen P. Sugar
profiling proves that human erythropoietin differs from
recombinant human erythropoietin. Blood 2001; 98(13):
3626-3634.

    (3) Shahrokh Z, Flatman S, Davies M, et al.
Erythropoietin produced by a human cell line has only trace
levels of potentially immunogenic N-glycolylneuraminic acid
residues. Presented at the European Haematology Association
11th Annual Congress, Amsterdam, The Netherlands. 15-18 June
2006.

    (4) Cameron N and Cotter M. Potential benefits of
epoetin delta in diabetic rats: focus on neuropathy.
Abstract accepted at American Society of Nephrology Renal
Week, San Francisco, CA, USA. 2-5 November 2007.

    (5) Pratt, R. Epoetin delta for the treatment of anemia
in patients with CKD not requiring hemodialysis. Poster
presented at American Society of Nephrology Renal Week, San
Diego, CA, USA; 14-19 November 2006

    (6) Deicher R and Horl W. Differentiating factors
between erythropoiesis-stimulating agents. Drugs 2004;
64(5): 499-509.

    (7) DYNEPO Summary of Product Characteristics. Shire
Pharmaceuticals. April 2007.

    For further information on Shire, please visit the
Company's website: http://www.shire.com.


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