Fosrenol(R) Demonstrates Effective Phosphate Control With as Few as Three Tablets a Day

Fosrenol(R) Demonstrates Effective Phosphate Control With as Few as Three Tablets a Day

July 19, 2006

New Data Show FOSRENOL Is an Effective Monotherapy -- Leading to Improved Phosphate Reduction in Dialysis Patients Previously Receiving Alternative Phosphate Binder Therapies

    BASINGSTOKE, England, July 19 /Xinhua-PRNewswire/ --
New data show calcium-free FOSRENOL (lanthanum carbonate)
further reduces phosphate levels in dialysis patients
previously receiving other monotherapies or combined
phosphate binders, including calcium carbonate and
sevelamer hydrochloride(1). The data, presented today at
the XLIII ERA-EDTA Congress in Glasgow, also showed that
FOSRENOL significantly increased the number of patients
achieving Kidney Disease Outcome Quality Initiative
(K/DOQI) targets compared to those who were previously
treated with other monotherapies.

    Dr Alastair Hutchison from the Manchester Institute of
Nephrology & Transplantation and one of the trial's
lead investigators said, "These study results add
further weight to the extensive data package which
demonstrates FOSRENOL is an effective phosphate binder.
FOSRENOL offers patients with hyperphosphataemia an
effective treatment option which could simplify their
management by reducing tablet burden to as little as one
tablet taken during each meal."

    A total of 359 dialysis patients were treated with
FOSRENOL as monotherapy and were available for analysis
from this multicentre, open label study, following a switch
from their previous binder therapy. Over 40% of patients
were previously on combination phosphate binder therapy (2
or more binders).  The study found that at 12 weeks of
FOSRENOL monotherapy, patients' mean serum phosphate levels
were 1.84 mmol/L compared with 1.99 mmol/L on other
previously received phosphate binding therapies*. In
addition, there was an increased percentage of patients who
reached KDOQI targets. The study also demonstrated that
FOSRENOL was well-tolerated throughout.

    (* For patients assessed at Week 12, the mean change
from screening to Week 12 was -0.13 (P < 0.05).)

    Further data presented at the ERA-EDTA Congress showed
that treatment with FOSRENOL was associated with a high
level of patient and physician satisfaction, based on a
number of assessments and linked to a reduction in tablet
burden(2). The majority of patients and physicians
expressed a preference for FOSRENOL over previous phosphate
binders.

    "Poor patient adherence is a problem often found
in patients with hyperphosphataemia," says Dr Rajnish
Mehrotra from the Harbor-UCLA Medical Center, California
and one of the lead investigators of the trial. "These
findings show that FOSRENOL may help to tackle this
problem."

    Other data presented at the meeting also extended
FOSRENOL's existing body of evidence. Data from 93
patients, 17 of whom were followed for up to 6 years in an
open-label extension study, showed that FOSRENOL
effectively maintained reductions in mean serum phosphate
levels whilst remaining tolerated(3).

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

    Dr Raymond Pratt, Vice President Shire Global Medical
Affairs, said, "Shire welcomes the presentation of
these data which further add to the robust evidence
supporting the effectiveness and tolerability of FOSRENOL
in patients with hyperphosphataemia, as well as showing a
high-level of patient and physician satisfaction. Shire is
very proud to be able to offer a calcium-free alternative
with proven efficacy and tolerability for patients in need
of an effective and well-tolerated phosphate binder, which
may also help to simplify the management of their
condition."

    FOSRENOL has been available in the US for 18 months
with over 44,000 patients receiving Fosrenol since launch
and will continue to be launched across Europe in the
remainder of 2006 and into 2007.

    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. 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.  Accumulating evidence shows that
hyperphosphataemia contributes to cardiovascular disease,
which accounts for almost half of all deaths among dialysis
patients.  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.(8) 

    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.  Although these agents can
be effective, some can cause potentially serious side
effects including hypercalcaemia, bone toxicity and
tolerability problems.  

    Lanthanum carbonate (FOSRENOL(R))

    FOSRENOL(R) works by binding to dietary phosphate in
the GI tract; once bound, the FOSRENOL(R)/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(R) involving over 5500
patients, some of whom have been treated for up to 6 years.
This programme has demonstrated that FOSRENOL(R) is an
effective phosphate binder with a tolerability profile for
long-term use.  FOSRENOL(R) 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(R) 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(R) 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.

    It is unknown whether lanthanum is excreted in human
breast milk.  The excretion of lanthanum in milk has not
been studied in animals.  Breast feeding is not recommended
when the mother is treated with Fosrenol.

    Tissue deposition of lanthanum has been shown with
Fosrenol in animal studies.  In 105 bone biopsies from
patients treated with Fosrenol for up to 4.5 years, rising
levels of lanthanum were noted over time.   No clinical
data are available on deposition of lanthanum in other
tissues.  Safety data exceeding 24 months are currently
limited.  The risk/benefit from longer-term administration
should be carefully considered.

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

    Approximately 24% of all ESRF patients who participated
in registration clinical studies, reported a drug related
adverse reaction, as determined by the investigator.  No
individual ADR was reported at a frequency greater than
10%.  The most commonly reported 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 . 

    1. Hutchison A et al. Efficacy of Lanthanum Carbonate
Monotherapy in 
       Dialysis Patients Previously Receiving Alternative
Phosphate Binder 
       Therapy. Presented at the XLIII ERA-EDTA Congress,
Glasgow, UK, 15-18 
       July, 2006.

    2. Mehrotra R et al. A New Formulation of Lanthanum
Carbonate is Preferred 
       by Patients and Physicians. Presented at the XLIII
ERA-EDTA Congress, 
       Glasgow, UK, 15-18 July, 2006.

    3. Hutchison A et al. Sustained Safety, Tolerability
and Efficacy of 
       Lanthanum Carbonate: Results from up to Six Years of
Treatment. 
       Presented at the XLIII ERA-EDTA Congress, Glasgow,
UK, 15-18 July, 
       2006.

    4. Block G et al. Mineral Metabolism, Mortality, and
Morbidity in 
       Maintenance Hemodialysis. Am Soc Nephrol 2004; 15:
2208-18. 

    5. Lederer E et al. Hyperphosphataemia. 
       http://www.emedicine.com/med/topic1097.html .
Accessed 23-Mar-06.

    6. Block G et al. 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

    7. United States Renal Data System. Medication Use
Among Dialysis Patients 
       in the DMMS. American Journal of Kidney Disease
1998; 32 (2) Suppl 1 
       (August): S60-68

    8. 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

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