New Analyses Demonstrate Positive Effect on Bone With FOSRENOL(R) Treatment Compared With Standard Therapy

New Analyses Demonstrate Positive Effect on Bone With FOSRENOL(R) Treatment Compared With Standard Therapy

November 20, 2006

Further Data Support the Contribution of FOSRENOL(R) (lanthanum carbonate) to the Overall Renal Health of the ESRD Patient While Reducing Mean Phosphate Levels to Within Guideline Targets

    BASINGSTOKE, England and SAN DIEGO, Nov. 20
/Xinhua-PRNewswire/ -- New data presented on Friday 17th
November at the American Society of Nephrology (ASN) Annual
Meeting, show FOSRENOL is an effective phosphate binder with
a similar efficacy profile to standard therapy(1). The 2
year data demonstrate that patients treated with FOSRENOL
showed similar phosphate control and lower serum calcium
levels than standard therapy. Treatment with FOSRENOL for 2
years had no adverse effects on bone histology and was not
associated with an increased incidence of osteomalacia
(bone softening). More patients treated with FOSRENOL also
demonstrated increases in bone formation rate than patients
receiving standard therapy(1). 

    Professor Hartmut Malluche, lead investigator of the
study, said "Patients with end-stage renal disease are
seriously ill and the burden of their illness is often
compounded by co-existing conditions. They can experience
significant bone problems as a result of
hyperphosphataemia, which can sometimes be exacerbated by
their treatment for the condition. These data show that
FOSRENOL not only effectively controls hyperphosphataemia,
but also demonstrates some positive effects on bone status
compared with standard therapy over the 2 year study
period."

    During year two, a greater proportion of patients in
the standard therapy group showed movement of bone volume
away from the normal range compared with the FOSRENOL group
(50 percent versus 31 percent).  Similarly, improvements
toward normal bone formations rates were seen in 38 percent
of patients receiving FOSRENOL at both one and two years. 
Patients in the standard therapy group showed improvements
of only 24 and 12 percent at one and two years, and bone
formation worsened in 63 percent of the patients in the
two-year group(1).  The results were not measured for
statistical significance. 

    FOSRENOL's therapeutic profile is further reinforced by
the publication of new cognitive function data in Kidney
International this month(2). This data assessed the
comparative cognitive decline in dialysis patients taking
FOSRENOL and standard therapy to control phosphate levels.
Cognitive decline is a significant problem in this
population and it is important that any treatment does not
affect this further. These long term two year data show
that FOSRENOL does not adversely affect the decline of
cognitive function compared to standard therapy(2). There
is a paucity of evidence looking at cognitive function in
this patient population and this study provides important
additional insight into the overall decline in cognitive
function in these patients.

    Dr Raymond Pratt, Vice President Shire Pharmaceutical
Development, said: "These results further add to the
robust body of evidence on FOSRENOL, with studies
successfully conducted in more than 5,500 patients, and
with a small number followed for up to 6 years now. Shire
is proud of this comprehensive data which support the
benefits FOSRENOL can bring to patients with CKD on
dialysis." 

    These studies are promising news for the estimated 1.4
million people on dialysis worldwide(3) who are at risk
from the serious consequences of hyperphosphataemia, shown
to be associated with long-term morbidity and mortality(4).
The majority of CKD patients will eventually develop
hyperphosphataemia(5) which, if not managed successfully,
may cause serious long-term health risks including renal
osteodystrophy (resulting in bone pain, brittle bones and
skeletal deformities)(6), and potentially contribute to
cardiovascular disease, which accounts for almost half of
all deaths among dialysis patients(7,8).  As a result,
patients on dialysis are often already taking as many as
eight or nine different medications(9). As FOSRENOL is
associated with a lower tablet burden than existing
phosphate binders (as few as one pill per meal), it may
offer simplified dosing for these patients(10).

    FOSRENOL has been available in the US for 22 months
with over 53,000 patients receiving Fosrenol since launch.
The first European launches took place at the end of 2005
and Shire continues to bring Fosrenol to market around the
world across this year and into 2007, subject to national
licensing, pricing and reimbursement negotiations. 

    References

    (1)  Malluche HH, Pratt RD. Renal osteodystrophy:
Comparison of
         evolution over 1 and 2 years during treatment with
lanthanum
         carbonate or standard phosphate binders. Presented
at ASN Renal
         Week, San Diego, November 14-19 2006.
    (2)  Altman P, Barnett ME, Finn WF. Cognitive function
in stage 5 CKD 
         patients on hemodialysis: no adverse effects of
lanthanum
         carbonate compared with standard phosphate-binder
therapy.
         Kidney Int advance online publication, October 11,
2006
    (3)  Grassman A, Gioberge S, Moeller S, Brown G. ESRD
patients in
         2004: global overview of patient numbers,
treatment modalities
         and associated trends. Nephrol Dial Transplant
2005; 20:
         2587-2593.
    (4)  Block G, Klassen PS, Lazarus MJ,  Ofsthun N,
Lowrie EG, Chertow
         GM. Mineral metabolism, mortality, and morbidity
in maintenance 
         hemodialysis. J Am Soc Nephrol 2004; 15:2208-18. 
    (5)  Lederer E, Ouseph R, Erbeck K. Hyperphosphataemia.

         http://www.emedicine.com/med/topic1097.html .
Accessed
         23-Mar-06.
    (6)  Martin K, Gonzalez A. Strategies to minimize bone
disease in
         renal failure. Am J Kidney Dis 2001; 38: 1430-36
    (7)  Salusky IB, Goodman WG. Cardiovascular
calcification in
         end-stage renal disease. Nephrol Dial Transplant
2002; 17:
         336-339.
    (8)  Block G, Port FK. Re-evaluation of risks
associated with 
         hyperphosphataemia and hyperparathyroidism in
dialysis patients: 
         recommendations for a change in management. Am J
Kidney Dis
         2000; 35 (6): 1226-1237. 
    (9)  United States Renal Data System. Medication use
among dialysis 
         patients in DMMS. Am J Kidney Dis 1998; 32 (2)
Suppl 1 (August):
         S60-68.
    (10) Mehrotra R. Efficacy and safety of reformulated
higher dosage 
         lanthanum carbonate. Presented at ASN Renal Week,
San Diego, 
         November 14-19 2006.

    Notes to editors:

    Managing Hyperphosphataemia
 
    Phosphorus, an element found in nearly all foods, is
absorbed from the gastrointestinal tract into the blood
stream.  When the kidneys fail, they no longer effectively
filter out phosphates, even with the help of
blood-cleansing dialysis machines.  While the normal adult
range for phosphorus is 2.5 (0.8mmol/L) to 4.5 mg/dL
(1.4mmol/L), the blood phosphorus levels of many patients
on dialysis exceed 6.5 mg/dL (2.1mmol/L). Such levels have
been linked to a significantly higher illness and death
risk for patients who have undergone at least one year of
dialysis(i). Most dialysis patients develop
hyperphosphataemia.

    Hyperphosphataemia disrupts the delicate interplay
between the body's levels of calcium, parathyroid hormone
(PTH) and vitamin D.  Over time, hyperphosphataemia can
ultimately lead to calcification of the heart, lung and
some arteries(ii).  Accumulating evidence shows that
hyperphosphataemia contributes to cardiovascular disease,
which accounts for almost half of all deaths among dialysis
patients(iii).  In fact, studies have shown that
cardiovascular mortality in dialysis patients aged 25-34
years is more than 5 times greater than that in people aged
65-74 in the general population(iv).

    Since dialysis and diet restrictions alone generally
cannot control phosphate levels, patients traditionally
manage hyperphosphataemia by taking phosphate binding
agents with every meal and snack.  Such binders "soak
up" phosphate in the gastrointestinal tract, before it
can be absorbed into the blood.  

    FOSRENOL(R) (lanthanum carbonate)

    FOSRENOL(R) works by binding to dietary phosphate in
the GI tract; once bound, the lanthanum/phosphate complex
cannot pass through the intestinal lining into the blood
stream and is eliminated from the body.  As a consequence,
overall phosphate absorption from the diet is decreased
significantly. Shire has conducted an extensive clinical
research programme for FOSRENOL involving over 5500
patients, with a small number followed for up to 6 years
now. This programme has demonstrated that FOSRENOL is an
effective phosphate binder with a good tolerability profile
for long-term use.  FOSRENOL was approved by the FDA in
October 2004 and is now available for prescription in the
US. In March 2005 regulatory authorities in the EU granted
marketing authorization for FOSRENOL in sixteen member
states, thus completing the first step in securing
marketing approval throughout Europe.  FOSRENOL has since
been launched in Ireland, Sweden, Finland, Denmark and
Austria.  The final step in the European process was
recently completed resulting in recommendation for approval
in the remaining 11 member states. Further roll-outs are
underway across the rest of Europe and other countries
around the world. The company has out-licensed the rights
to develop, market and sell FOSRENOL in Japan to Bayer
Yakuhin Ltd. 
   
    Patients with renal insufficiency may develop
hypocalcaemia.  Serum calcium levels should therefore be
monitored at regular time intervals for this patient
population and appropriate supplements given.

    No data are available in patients with severe hepatic
impairment.  Caution should, therefore, be exercised in
these patients, as elimination of absorbed lanthanum may be
reduced.

    FOSRENOL should not be used during pregnancy.

    Patients with acute peptic ulcer, ulcerative colitis,
Crohn's disease or bowel obstruction were not included in
clinical studies with Fosrenol.

    The most commonly reported Adverse Drug Reactions
(ADRs) (>1/100, 1/10) are gastrointestinal reactions
such as abdominal pain, constipation, diarrhoea, dyspepsia,
flatulence, nausea and vomiting.  These are minimized by
taking FOSRENOL with food and generally abated with time
with continued dosing.  Hypocalcaemia was the only other
commonly reported adverse reaction.

    Shire 

    Shire is a global specialty pharmaceutical company with
a strategic focus on meeting the needs of the specialist
physician and currently focuses on developing and marketing
products in the areas of attention deficit and hyperactivity
disorder (ADHD), gastrointestinal (GI), renal diseases and
human genetic therapies.  Shire has operations in the
world's key pharmaceutical markets (US, Canada, UK, France,
Italy, Spain and Germany) as well as a specialist drug
delivery unit in the US.

    For further information on Shire, please visit the
Company's website: http://www.shire.com .
 
    (i)   Block GA et al. Association of serum phosphorus
and calcium x 
          phosphate product with mortality risk in chronic
hemodialysis 
          patients: A national study. American Journal of
Kidney Diseases 
          1998; 31: 607-617
    (ii)  Norris KC. Toward a new treatment paradigm for
          hyperphosphataemia in chronic renal disease.
Dialysis &
          Transplantation 1998; 27 (12):  767-773
    (iii) Block G, Port FK. Re-evaluation of risks
associated with 
          hyperphosphataemia and hyperparathyroidism in
dialysis
          patients: recommendations for a change in
management. Am J
          Kidney Dis 2000; 35 (6): 1226-1237
    (iv)  Foley R et al. Clinical epidemiology of
cardiovascular disease
          in chronic renal disease. American Journal of
Kidney Disease
          1998; 32 (5) Suppl 3:112-119

    For more information, please contact:

    Media:
     Jessica Mann, Shire
     Tel:  [phone]

    Investor Relations:
     Clea Rosenfeld, Shire
     Tel:  [phone]

     Glen Halliwell
     Resolute Communications
     Tel:  [phone]

     Julia Kirby
     Resolute Communications
     Tel:  [phone] (on site)

SOURCE  Shire PLC