Data From a Head-to-Head Crossover Study Evaluating FOSRENOL(R) and Sevelamer
Published Today

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

DUBLIN, Oct. 7 /CNW/ - 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.
    

SOURCE Shire PLC

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