Shire Announces Results of FOSRENOL(R) Study in Pre-Dialysis CKD Stage 3 & 4 Patients

Shire Announces Results of FOSRENOL(R) Study in Pre-Dialysis CKD Stage 3 & 4 Patients

November 07, 2007

    PHILADELPHIA and BASINGSTOKE, England, Nov. 6
/Xinhua-PRNewswire/ -- 

    Shire plc (LSE: SHP, Nasdaq: SHPGY, TSX: SHQ) today
announced the results of a Phase II study indicating that
FOSRENOL can effectively reduce serum phosphate levels in
chronic kidney disease (CKD) patients not on dialysis.(1)
FOSRENOL is a non-calcium phosphate binder, indicated to
treat hyperphosphatemia in end stage renal disease (ESRD),
also known as CKD Stage 5.(2)  

    While the results of this exploratory study did not
achieve its specified primary endpoint (control of serum
phosphate to within normal levels), more FOSRENOL treated
patients achieved this goal than did patients in the
placebo arm of this multi-center, double-blind,
placebo-controlled study of 90 
pre-dialysis patients with CKD Stage 3 and 4 and
hyperphosphatemia(1) (serum phosphate above the upper limit
of normal, which the body cannot excrete). (3), (1)  

    As a secondary endpoint, patients taking FOSRENOL were
found to have statistically significant reductions in serum
phosphate levels after eight weeks of treatment vs those
patients in the placebo arm.  

    The findings complement the conclusions of a recent
Shire initiated U.S. Food and Drug Administration (FDA)
Cardiovascular and Renal Drugs Advisory Committee,(4) which
voted by majority to recommend in favor of phosphate binders
extending their label to treat CKD Stage 4 patients with
hyperphosphatemia.  

    "This study provides valuable insights into the
evolution of kidney disease and the development of the
hyperphosphatemic state in patients with CKD," said
Raymond Pratt, vice president and scientific leader for the
Renal Business Unit of Shire Pharmaceuticals. "There is
a paucity of data in this population and this study marks an
important step toward learning more about the management of
this patient population -- and importantly, shows that a
little bit of kidney function still goes a long way to
maintain phosphate balance."  

    "The need for effective phosphate management
before patients reach dialysis is recommended by the KDOQI
guidelines and is a growing area of interest and debate. As
a company, Shire is committed to continued research in this
area and to understand how effective treatment may help
patients cope with some of the serious complications of
kidney disease."  

    This Phase II study involved the initial screening of
281 CKD Stage 3 & 4 patients with 90 randomized to
receive either FOSRENOL or placebo.(1) When investigators
looked at the change in phosphate levels from baseline,
they found statistically significant reductions in serum
phosphate at week 8 versus placebo.(5) Serum parathyroid
hormone (PTH) levels were significantly decreased in the
FOSRENOL-treated subjects compared with an increase in the
placebo group. The full results will be submitted for
publication and presentation at upcoming scientific
meetings.  

    Shire is working closely with the FDA to explore the
regulatory pathway forward for phosphate binding medicines
in pre-dialysis patients with CKD Stage 4.  

    As kidney disease progresses, the kidneys lose the
ability to effectively excrete phosphate and patients
ultimately develop hyperphosphatemia.(6) While the
condition is more common when patients have reached CKD
Stage 5, the problem of elevated serum phosphate can start
before patients require dialysis.(6) Phosphate control is
critical for these patients because, if not managed
successfully, hyperphosphatemia can lead to serious health
problems, including renal osteodystrophy (a bone disorder
resulting in painful, brittle bones that may fracture or
lead to deformities) and cardiovascular disease, which
accounts for almost half of all deaths in dialysis
patients.(6), (7)  

    Over 5,200 patients have been treated with FOSRENOL
during an extensive clinical development program,(5) with
some having been followed up for up to six years.(8) In the
United States, over 87,000 patients have been prescribed
FOSRENOL since it was launched in 2005.(5), (9) 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 phosphate reduction in a majority of patients, with
some patients being followed up over a six-year
duration.(8)  

    FOSRENOL is now available in 23 countries worldwide and
has been met with solid support from the clinical nephrology
community, because it provides a simplified and effective
monotherapy treatment option(2) for the 1.5 million people
on dialysis(7) globally who are at risk from the serious
consequences of hyperphosphatemia.  

    Managing Hyperphosphatemia  

    Phosphorus, an element found in nearly all foods, is
absorbed from the gastrointestinal tract into the
bloodstream.(3) When the kidneys fail, they no longer
effectively remove phosphorus.(3) While the normal adult
range for phosphorus is 2.5 to 4.5 mg/dL,(10) the blood
phosphorus levels of many patients on dialysis often exceed
6.5 mg/dL.(11) Such levels have been linked to a
significantly higher morbidity and mortality risk for
patients who have undergone at least one year of
dialysis.(12) Research has shown that for each mg/dL
increase in mean serum phosphorus, the relative risk of
death increases by six percent.(11)  

    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.(10) 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.(10), (11)  

    FOSRENOL  

    FOSRENOL is indicated to reduce serum phosphate in
patients with ESRD.(2)  

    FOSRENOL is an effective, non-calcium, phosphate binder
that reduces high phosphorus levels in ESRD patients.(2)
FOSRENOL is formulated as an easy-to-use, unflavored,
chewable tablet that can be taken without water,(2) 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.(2) 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.(2) Once bound, the FOSRENOL/phosphorus complex
cannot pass into the bloodstream and is eliminated from the
body, thereby decreasing mean serum phosphorus levels.  
    
    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 US 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.  

    "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 (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)(lisdexamfetamine dimesylate) (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).  SM Sprague, WF Finn, and P Qiu (2007)
Hyperphosphatemia in Chronic 
          Kidney Disease Stages 3 and 4: Findings from a
Randomized, Multi-
          Center Trial. Abstract for ASN Renal Week 2007,
Filename: 555494  
    (2).  FOSRENOL(R) U.S. PI.  
    (3).  Venes D and CL Thomas, eds. (2001) Cyclopedic
Medical Dictionary. 
          20th ed. Philadelphia, Pa: FA Davis Company.
1037, 1173, 1543.  
    (4).  U.S. Food and Drug Administration (FDA)
Cardiovascular and Renal 
          Drugs Advisory Committee. Federal Register / Vol.
72, No. 176 / 
          Wednesday, September 12, 2007 / Notices.  
    (5).  Data on file, Shire U.S., Inc.  
    (6).  National Kidney Foundation. K/DOQI clinical
practice guidelines for 
          bone metabolism and disease in chronic kidney
disease. Am J Kidney 
          Disease 2004; 42: 24-45, 55-63, 69-71.  
    (7).  Vanholder R, et al. (2005) Chronic kidney disease
as cause of 
          cardiovascular morbidity and mortality. Dial
Transplant; 20: 1048-
          1056.  
    (8).  Hutchison AJ and R Pratt. (2005) Evidence for the
long-term safety 
          and tolerability of lanthanum carbonate. Poster
presented at 38th 
          annual meeting of the American Society of
Nephrology, Philadelphia, 
          PA. November 8-13.  
    (9).  Verispan's Total Patient Tracker: January
2005-August 2007.  
    (10). Moe SM. Calcium, phosphorus and vitamin d
metabolism in renal 
          disease and chronic renal failure. In: Kopple JD
and SG Massry, 
          eds. Nutritional Management of Renal Disease.
Philadelphia, PA: 
          Lippincott Williams & Wilkins; 2004: 261.  
    (11). Block GA, Hulbert-Shearon TE, Levin NW and FK
Port. (1998) 
          Association of serum phosphorus and calcium x
phosphate product 
          with mortality risk in chronic hemodialysis
patients: A national 
          study. Am J Kidney Dis; 31: 607-617.  
    (12). Block GA. (2000) Prevalence and clinical
consequences of elevated 
          Ca x P product in haemodialysis patients. Clin
Nephrol; 54(4): 318-
          24. 


    For more information, please contact:

     Ann Blumenstock
     Resolute (ex-US.)
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     Email:  [e-mail]

     Carrie Fernandez of Porter Novelli (US)
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