FDA Advisory Committee Votes in Favor of Earlier Use of Phosphate Binders in Stage 4 Kidney Disease Patients With Hyperphosphatemia

FDA Advisory Committee Votes in Favor of Earlier Use of Phosphate Binders in Stage 4 Kidney Disease Patients With Hyperphosphatemia

October 17, 2007

    PHILADELPHIA, Oct. 17 /Xinhua-PRNewswire/ -- At the
U.S. Food and Drug Administration's (FDA's) Cardiovascular
and Renal Drugs Advisory Committee meeting today, the
majority of members voted to recommend the use of phosphate
binders, including Shire Pharmaceuticals' non-calcium
FOSRENOL(R) (lanthanum carbonate), to treat
hyperphosphatemia (elevated levels of phosphorus in the
blood) in chronic kidney disease (CKD) Stage 4 patients. 
Currently, FOSRENOL is indicated to reduce serum phosphate
in patients with end stage renal disease (ESRD). 

    The Committee did not reach consensus on which
additional studies may be required, and Shire will work
closely with the FDA to agree upon the pathway forward. 
The FDA Advisory Committee's recommendation is not binding
on the FDA, and no time has been set by which the FDA will
decide whether to follow this recommendation. 

    CKD is divided into five stages based on the level of
kidney function, with higher stages of disease representing
lower kidney filtration rates.  In the United States,
approximately 20 million adults have some form of CKD, of
whom 500,000 have developed ESRD (or CKD Stage 5).  An
additional 400,000 individuals have significant loss of
kidney function and are classified as having CKD Stage 4. 
Worldwide, almost 1.5 million people with CKD are on
dialysis.  

    "As the Committee heard today, CKD patients are at
an increased risk of death.  In fact, a 30-year-old dialysis
patient has the same risk of death as that of a 90-year-old
with normal kidney function," said Keith Hruska, M.D.,
Professor of Pediatrics, Medicine and Cell Biology,
Director, Division of Pediatric Nephrology, Washington
University School of Medicine.  "These patients that
progress to dialysis represent the 'survivors.'  That's why
it's important to help kidney patients stay as healthy as
possible from the early stages of their disease." 

    As a result of ongoing dialogue with the FDA, Shire had
requested that an Advisory Committee Meeting be convened to
provide guidance on the studies needed to expand the use of
phosphate binders.  Following these discussions, the FDA
formally invited all three sponsors who presented at
today's meeting to collaborate on demonstrating their case
for treating CKD Stage 4 and 5 patients who have
hyperphosphatemia with phosphate binders. 

    "Shire is committed to offering its effective
phosphate binder, FOSRENOL, to kidney patients who need
protection from the complications of elevated serum
phosphorus," said Joseph Schlitz, vice president, U.S.
Renal Business, Shire Pharmaceuticals.  "The high
affinity of FOSRENOL for phosphate provides effective
monotherapy in a simple dosing regimen, which is one tablet
per meal for most patients.  Along with its well-established
safety profile, FOSRENOL offers an attractive solution for
both patients and their healthcare providers.  Shire is
therefore confident that FOSRENOL is well suited to be a
first-line, non-calcium treatment of choice for CKD Stage 4
patients."

    While the normal adult range for serum phosphorus is
2.5 to 4.5 milligrams per deciliter (mg/dL), the serum
phosphorus levels of many patients on dialysis often exceed
6.5 mg/dL.  The National Kidney Foundation's Kidney Disease
Outcomes Quality Initiative (K/DOQI) guidelines recommend
that monitoring for hyperphosphatemia should begin in
patients with CKD Stage 3, and that serum phosphorus should
be maintained within the target range of 2.7 to 4.6 mg/dL in
patients with CKD Stages 3 and 4, or 3.5 to 5.5 mg/dL for
CKD Stage 5.

    "Based on data in dialysis patients, it is
reasonable to expect that treating pre-dialysis patients
for secondary conditions, such as hyperphosphatemia, may
slow the progression of their bone and cardiovascular
disease," said Hartmut H. Malluche, M.D., chief,
Nephrology, Bone and Mineral Metabolism, Department of
Internal Medicine, University of Kentucky College of
Medicine.  "Studies have shown that FOSRENOL also is
associated with a trend toward positive bone health -- a
treatment attribute that also may be of benefit to CKD
Stage 4 patients." 

    Most CKD Stage 4 and 5 patients will develop chronic
kidney disease-mineral and bone disorder (CKD-MBD) -- a
systemic disorder of mineral and bone metabolism due to
CKD.  CKD-MBD often manifests as hyperphosphatemia, which
causes bone disease characterized by bone pain, brittle
bones, skeletal deformities and fractures, and vascular or
other soft tissue calcification.  Evidence also shows that
hyperphosphatemia contributes to cardiovascular disease,
which accounts for almost half of all deaths among dialysis
patients.

    "Shire recently completed a multicenter,
placebo-controlled study in patients with CKD Stages 3 and
4 with hyperphosphatemia.  The results showed that
FOSRENOL-treated patients had statistically significant
reductions in serum phosphate levels compared to placebo
after eight weeks of treatment.  This study provided
valuable insights into controlling hyperphosphatemia in CKD
Stages 3 and 4 patients," said Ray Pratt, M.D., vice
president, scientific leader, Renal Business Unit, Research
and Development, Shire Pharmaceuticals.  "We are
committed to offering all patients the most effective
phosphate binder therapy and will continue to invest in a
clinical program that includes the development of
additional FOSRENOL formulation options aimed at further
simplifying treatment for all CKD patients." 

    Managing Hyperphosphatemia

    Phosphorus, an element found in nearly all foods, is
absorbed from the gastrointestinal tract into the
bloodstream.  When the kidneys fail, they no longer
effectively remove phosphorus.  While the normal adult
range for phosphorus is 2.5 to 4.5 mg/dL, the blood
phosphorus levels of many patients on dialysis often exceed
6.5 mg/dL.  Such levels have been linked to a significantly
higher morbidity and mortality risk for patients who have
undergone at least one year of dialysis.  Research has
shown that for each mg/dL increase in mean serum
phosphorus, the relative risk of death increases by six
percent.

    Hyperphosphatemia is managed with a combination of
dialysis, diet restriction, and phosphorus-binding agents,
because diet and dialysis alone generally cannot adequately
control phosphorus levels.  Such binders "soak up"
phosphorus in the gastrointestinal tract, before it can be
absorbed into the blood, and aid patients in maintaining
acceptable levels of mean serum phosphorus. 

    FOSRENOL

    FOSRENOL is indicated to reduce serum phosphate in
patients with ESRD.

    FOSRENOL is an effective, non-calcium, phosphate binder
that reduces high phosphorus levels in ESRD patients. 
FOSRENOL is formulated as an easy-to-use, unflavored,
chewable tablet that can be taken without water, an
important consideration for ESRD patients who must restrict
their fluid intake.

    FOSRENOL is available in a broad range of dosage
strengths comprised of 500-milligram (mg), 750-mg, and 1-g
tablets.  Patients taking FOSRENOL can achieve serum
phosphorus target levels with as few as three tablets per
day.  (Dosing based on three meals per day.  Number of
meals per day may vary.  To achieve certain doses,
additional tablets may be required.)   

    FOSRENOL has a high affinity for phosphate and works by
binding to dietary phosphorus in the gastrointestinal tract.
 Once bound, the FOSRENOL/phosphorus complex cannot pass
into the bloodstream and is eliminated from the body,
thereby decreasing mean serum phosphorus levels.  

    To date, FOSRENOL has been clinically tested in more
than 5,200 patients globally, with nearly 1,000 of these
patients having been followed for more than one year.  In
addition, more than 87,000 patients have been prescribed
FOSRENOL in the U.S. alone.  FOSRENOL has the most
extensive long-term safety data package of any phosphate
binder and is generally well tolerated.  Trials involving
patients treated with FOSRENOL showed sustained serum
phosphorus reduction in a majority of patients, with some
patients being followed over a six-year duration.

    FOSRENOL is now available in 23 countries, including
Canada, France, Germany, Italy, and the UK, and continues
to be launched in new markets around the world.

    Important Safety Information

    The most common adverse events were gastrointestinal,
such as nausea and vomiting, and generally abated over time
with continued dosing.  The most common side effects leading
to discontinuation in clinical trials were gastrointestinal
events (nausea, vomiting, and diarrhea).  Other side
effects reported in trials included dialysis graft
complications, headache, abdominal pain, and hypotension. 
Although studies were not designed to detect differences in
risk of fracture and mortality, there were no differences
demonstrated in patients treated with FOSRENOL compared to
alternative therapy for up to three years.  The duration of
treatment exposure and time of observation in the clinical
program were too short to conclude that FOSRENOL does not
affect the risk of fracture or mortality beyond three
years.  While lanthanum has been shown to accumulate in the
GI tract, liver, and bone in animals, the clinical
significance in humans is unknown.  Patients with acute
peptic ulcer, ulcerative colitis, Crohn's disease, or bowel
obstruction were not included in FOSRENOL clinical studies. 
Caution should be used in patients with these conditions. 
FOSRENOL should not be taken by patients who are nursing or
pregnant.  FOSRENOL should not be taken by patients who are
under 18 years of age.  

    For Full Prescribing Information on FOSRENOL, please
visit http://www.fosrenol.com .

    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. 

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

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