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Data From a Head-to-Head Crossover Study Evaluating FOSRENOL(R) and Sevelamer Published Today
Date:10/7/2009

DUBLIN, October 7 /PRNewswire-FirstCall/ --

- For Medical and Healthcare Media Only -

- Direct Comparison of the Two non-Calcium Phosphate Binders Gives new Insights Into Relative Efficacy

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today announces the publication in Clinical Nephrology of findings from a head-to-head clinical study comparing the efficacy of two non-calcium based phosphate binders, FOSRENOL(R) (lanthanum carbonate) and sevelamer hydrochloride (Genzyme's Renagel(R)) in chronic kidney disease (CKD) patients on haemodialysis.

In this 12-week crossover study, patients (n=182) were randomized to receive either FOSRENOL or sevelamer for four weeks, and then switched to the alternative phosphate binder for the same period. Product doses were pre-defined to allow a direct efficacy comparison. Doses were based on those used in previous clinical trials[1,2] and established clinical practice.[3]

The study's primary endpoint, change in serum phosphorus from baseline to end of treatment, was evaluated using several statistical analyses; the primary analysis used last observation carried forward (LOCF) for the intention to treat (ITT) population (n=174), meaning that if a patient dropped out of the study during treatment, their last post baseline serum phosphorus measurement was used as the end of treatment value. The pre-determined key secondary analysis assessed the completer population; defined as those patients who had completed four weeks' treatment with both phosphate binders and had a serum phosphorus value at the end of treatment.[4]

The analysis of LOCF for the ITT population showed a numerically greater reduction in serum phosphorus with FOSRENOL (1.7mg/dL) versus sevelamer (1.4mg/dL), although this did not reach statistical significance (p=0.113). In the completer population (n=119), considered to be the most clinically relevant population, FOSRENOL reduced serum phosphorus by 1.8mg/dL, compared with 1.3mg/dL for sevelamer, a statistically significant difference (p=0.007). A statistically significant difference was also observed between the treatments at week 1 (p=0.024).[4]

Study investigators concluded that the statistically larger reduction within the completer group suggested that FOSRENOL may offer greater serum phosphorus reduction in CKD patients on haemodialysis.[4]

"This study is important, because up until now, there was no data comparing the relative efficacies of lanthanum carbonate and sevelamer," said lead investigator Professor Stuart Sprague of Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

"The findings suggest that over four weeks of treatment, FOSRENOL may be a more effective binder of phosphate. Further research is now required to evaluate whether the trends observed in this crossover study are continued in the long term," he added.

"The company's investment in this study underscores Shire's commitment to characterizing the differences of FOSRENOL and better understand its clinical potential," said Arnaud Partiot, Senior Vice President, Clinical Research and Development, Shire.

Current clinical guidelines recommend targets for phosphorus and other biochemical values including calcium and parathyroid hormone (PTH) in patients with CKD undergoing dialysis.[5] Sustained control within these ranges is associated with improved survival in patients starting dialysis.[6] The level of achievement of the targets in clinical practice has been assessed in large studies such as DOPPS (Dialysis Outcomes and Practice Patterns Study). Overall, they are modest with less than 50% of patients in the target range for phosphorus, calcium and PTH.[7] Therefore, there is a need for more effective treatment strategies.

    Notes to Editors

    About the Study

    - The Shire SPD405-319 study is a 12 week randomized,
      open-label crossover study conducted at multiple sites in the USA,
      Puerto Rico, Germany and the UK.

    - CKD patients aged over 18 years, undergoing haemodialysis 2-3
      times per week for at least two months before screening, and not
      receiving treatment with FOSRENOL or sevelamer were included.

    - Following screening, patients (most receiving
      calcium-containing phosphate binders) entered a washout period of 2-3
      weeks before assessment of biochemical parameters. Patients with serum
      phosphorus equal to or above 6.0 mg/dL and serum calcium equal to or
      above 8.4mg/dL were randomized (1:1 ratio) to receive FOSRENOL or
      sevelamer hydrochloride. Following 4 weeks' treatment with FOSRENOL or
      sevelamer, patients underwent a second washout period and were switched
      to the alternative phosphate binder for a further 4 weeks.

    - Treatment was initiated at 2250mg/day for FOSRENOL and
      4800mg/day for sevelamer. After week 1, doses were increased to 3000
      mg/day for FOSRENOL and 6400mg/day for sevelamer.

    - In statistical analysis, the safety population was defined as
      all patients who took at least one dose of FOSRENOL or sevelamer. The
      ITT population included all patients who had received at least one dose
      of either study drug and had at least one valid post-dose serum
      phosphorus measurement. The completer population was defined as all
      patients who completed 4 weeks of treatment on both study drugs and had
      a valid serum phosphorus measurement at week 4 of each treatment
      period.

    Shire expresses its thanks to the study authors (Stuart
    Sprague, Edward Ross, Subrata Nath, Pinggao Zhang, Raymond Pratt and
    Rolfdieter Krause) for their participation in the SPD405-319 study.

    About FOSRENOL(R) (lanthanum carbonate)

    - FOSRENOL is indicated:

    - In the EU as a phosphate binding agent for use in the control of
      hyperphosphataemia in chronic renal failure patients on haemodialysis
      or continuous ambulatory peritoneal dialysis.[8]

    - In the US to reduce serum phosphorus in patients with end stage renal
      disease.[9]

    - FOSRENOL is not available in all countries and prescribing information
      may differ between countries. Please consult your local prescribing
      information.

    - FOSRENOL 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.[8] As a consequence, overall phosphate absorption from the diet
      is decreased significantly.

    - FOSRENOL is available in a broad range of dosage strengths including
      500mg, 750mg, and 1000mg tablets[8] which facilitates an effective
      dosing regimen of one tablet per meal for the majority of patients.

    - FOSRENOL was first approved in Sweden in March 2004, and by the US FDA
      in October 2004. FOSRENOL was subsequently approved in all EU markets
      by the European Mutual Recognition Procedure and is now launched in 37
      markets worldwide. It continues to be approved and made available in
      new markets around the world.

    Important Safety Information

    - 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 are gastrointestinal
      reactions, such as abdominal pain, constipation, diarrhoea, dyspepsia,
      flatulence, nausea and vomiting. These are minimized by taking FOSRENOL
      with food and generally abate with time with continued dosing.
      Hypocalcaemia was the only other commonly reported adverse reaction.
      Full prescribing information is available on request.

    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
      hyperactivity disorder, human genetic therapies and gastrointestinal
      diseases as well as opportunities in other therapeutic areas to the
      extent they arise through acquisitions. Shire's in-licensing, merger
      and acquisition efforts are focused on products in specialist markets
      with strong intellectual property protection and global rights. Shire
      believes that a carefully selected and balanced 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.

    References

    1. Hutchison AJ, Barnett EM, Krause R, et al. Long-term efficacy and
       safety profile of lanthanum carbonate: results for up to 6 years of
       treatment. Nephron Clin Pract. 2008. 110(1): p. c15-23.

    2. Chertow GM, Burke SK, and Raggi P. Sevelamer attenuates the
       progression of coronary and aortic calcification in hemodialysis
       patients. Kidney Int. 2002. 62(1): p. 245-252.

    3. Dacon Report. Intercontinental Medical Statistic.; March 2006.

    4. Sprague SM, Ross EA, Krause R, et al. Lanthanum carbonate vs sevelamer
       hydrochloride for the reduction of serum phosphorus in hemodialysis
       patients: a crossover study. Clin Nephrol. 2009; 72(4): 252-258.

    5. Moe SM, Block GA, Cannata-Andia JB, et al. Kidney Disease: Improving
       Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice
       Guideline for the diagnosis, evaluation, prevention, and treatment of
       Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int
       Suppl. 2009 Aug;(113):S1-130.

    6. Danese MD, Belozeroff V, Smirnakis K and Rothman KJ. Consistent
       control of mineral and bone disorder in incident hemodialysis. Clin J
       Am Soc Nephrol 2008; 3(5): 1423-1429.

    7. Kim J, Pisoni RL, Danese MD, et al. Achievement of proposed NKF-K/DOQI
       Bone Metabolism and Disease Guidelines: Results from the Dialysis
       Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol 14:
       269A, 2003.

    8. Shire plc. FOSRENOL EU SmPC. Last revised July 2008.

    9. Shire plc. FOSRENOL US PIL. Last revised April 2008.



    For further information please contact:

    Matthew Cabrey (US)                              +1-484-595-8248
    Caren Weintraub, Resolute Communications (US)    +1-212-213-8181
    Con Franklin, Resolute Communications (UK)       +44(0)207-015-1354


SOURCE Shire Plc


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SOURCE Shire Plc
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