14th Nov 2005 07:00
NEW SIX-YEAR DATA SUPPORTS FOSRENOL‚® AS A TREATMENT CHOICE FOREND-STAGE RENAL DISEASE PATIENTSDATA SHOWS FOSRENOL‚® WORKS LONG TERM TO LOWER PHOSPHATE LEVELS EFFECTIVELY, ANDFURTHER REINFORCES ITS SAFETY AND TOLERABILITY PROFILEBasingstoke, UK - November 12, 2005 - According to data presented on Saturdayat the annual meeting of the American Society of Nephrology (ASN), non-calciumFOSRENOL‚® (lanthanum carbonate) effectively maintains reductions in mean serumphosphorus levels while demonstrating safety and tolerability in end-stagerenal disease (ESRD) patients for up to six years.1"These study results provide strong evidence of the safety and efficacy ofFOSRENOL‚®," said Dr. Alastair Hutchison, one of the trial's lead investigatorsfrom the Manchester Institute of Nephrology & Transplantation, Manchester,United Kingdom. "With a robust long-term safety profile, ESRD patients andphysicians can rely on FOSRENOL‚® to help manage hyperphosphatemia and meet K/DOQI (Kidney Disease Outcomes Quality Initiative) guidelines."The open-label extension study enrolled 93 patients, of which 32 were treatedwith FOSRENOL‚® for up to six years. The study revealed that as patientscontinued on FOSRENOL‚® therapy, the number of drug-related adverse events didnot increase in frequency as drug exposure increased. The most commontreatment-related adverse events were gastrointestinal (GI) in nature and nonew or unexpected adverse events occurred during long-term treatment withFOSRENOL‚®.Importantly, FOSRENOL‚®-treated patients in the study also maintained reducedserum phosphorus and calcium-phosphorus product (Ca x P) levels, demonstratingthe long-term effectiveness of FOSRENOL‚®.2 The patients successfully controlledtheir serum phosphorus and Ca x P levels to within the K/DOQI guidelineseffective at the time the study was conducted.Phosphate-Binding Affinity of FOSRENOL in VitroFurther data presented at the ASN meeting showed that the phosphate-bindingaffinity of FOSRENOL‚® was more than 200 times higher compared to sevelamerhydrochloride (HCl) at pH 3.3 When assessed at pH 5 to 7, the affinity ofFOSRENOL‚® was four-fold higher compared to sevelamer HCl, demonstrating the pHbinding affinity and independence of FOSRENOL‚® in vitro.4 In addition, thepresence of bile acids did not affect the stability of the FOSRENOL‚®-phosphatecomplex, whereas bile acids led to a more than 13-fold reduction inphosphate-binding affinity of sevelamer HCl with the consequent release of itsphosphate.5 The clinical relevance of the effect of pH on in vivo phosphatebinding of FOSRENOL‚®has not been established.6Dr. Raymond Pratt, Vice President Shire Global Clinical Medicine, said, "Shireis very pleased with the presentation at ASN of these in-vitro and clinicaldata. The company is committed to bringing effective treatment options such asFOSRENOL to the worldwide market to benefit ESRD patients. FOSRENOL iscurrently available in the US and will be launched across Europe over thecoming months. Shire is very proud to be able to provide a calcium-freealternative to patients in need of an effective and well-tolerated phosphatebinder."Managing HyperphosphatemiaEven with a low-phosphorus diet, most ESRD patients will develophyperphosphatemia (high phosphorus levels in the blood).7,8 Without effectivetreatment, hyperphosphatemia may lead to renal osteodystrophy, a collection ofbone diseases characterized by bone pain, brittle bones, skeletal deformitiesand fractures.9 Evidence also shows that hyperphosphatemia may contribute tocardiovascular disease, which accounts for almost half of all deaths amongdialysis patients.10,11Phosphorus, an element found in nearly all foods, is absorbed from thegastrointestinal tract into the bloodstream.12 When the kidneys fail, they nolonger effectively remove phosphorus, even with the help of blood-cleansingdialysis machines. While the normal adult range for phosphorus is 2.5 to 4.5 mg/dL,13 the blood phosphorus levels of many patients on dialysis often exceed6.5 mg/dL.14 Such levels have been linked to a significantly higher illness anddeath risk for patients who have undergone at least one year of dialysis. 15As many as 80% of dialysis patients develop hyperphosphataemia. Additionally,there are currently almost a million people on dialysis worldwide, and thenumbers are increasing due to the rise in cardiovascular disease, diabetes andan aging population.16Hyperphosphatemia is managed with a combination of diet restriction andphosphorus-binding agents, since diet alone generally cannot adequately controlphosphorus levels. Such binders "soak up" phosphorus in the gastrointestinaltract, before it can be absorbed into the blood.17,18,19 Because dietaryphosphorus absorption begins as soon as phosphorus enters the stomach, it isimportant for phosphate binders to work at the variety of pH levels foundthroughout the gastrointestinal tract.Despite the availability of phosphorus-binding agents, it remains a challengefor some ESRD patients to maintain target ranges. According to the K/DOQIClinical Practice Guidelines for Bone Metabolism and Disease, Guideline 3,Evaluation of Serum Phosphorus Levels, fewer than 30 percent of dialysispatients are able to maintain serum phosphorus levels in the target range.20.The K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease alsonote in Guideline 5, Use of Phosphate Binders in Chronic Kidney Disease (CKD), thatnon-calcium and non-aluminum phosphate binders are a first-line treatmentoption in lowering serum phosphorus levels.21Lanthanum carbonate (FOSRENOL‚®)FOSRENOL‚® works by binding to dietary phosphate in the GI tract; once bound,the FOSRENOL‚®/phosphate complex cannot pass through the intestinal lining intothe blood stream and is eliminated from the body. As a consequence, overallphosphate absorption from the diet is decreased. Shire has conducted anextensive clinical research programme for FOSRENOL‚® involving over 3000patients, some of whom have been treated for up to 6 years. This programme hasdemonstrated that FOSRENOL‚® is an effective phosphate binder with a provensafety profile for long-term use. FOSRENOL‚® was approved by the FDA in October2004 and is now available for prescription in the US. In March 2005 regulatoryauthorities in the EU granted marketing authorization for FOSRENOL‚® in sixteenmember states. This completes the first step in securing marketing approvalthroughout Europe. The company has out-licensed the rights to develop, marketand sell FOSRENOL‚® in Japan to Bayer Yakuhin Ltd.The most common adverse events were gastrointestinal, such as nausea andvomiting, and generally abated over time with continued dosing. The most commonside effects leading to discontinuation in clinical trials weregastrointestinal events (nausea, vomiting, and diarrhea). Other side effectsreported in trials included dialysis graft complications, headache, abdominalpain and hypotension. Although studies were not designed to detect differencesin risk of fracture and mortality, there were no differences demonstrated inpatients treated with FOSRENOL‚® compared to alternative therapy for up to threeyears. The duration of treatment exposure and time of observation in theclinical program are too short to conclude that FOSRENOL‚® does not affect therisk of fracture or mortality beyond three years. While lanthanum has beenshown to accumulate in the GI tract, liver and bone in animals, the clinicalsignificance in humans is unknown. Patients with acute peptic ulcer, ulcerativecolitis, 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.Shire Pharmaceuticals Group plcShire's strategic goal is to become the leading specialty pharmaceuticalcompany that focuses on meeting the needs of the specialist physician. Shirefocuses its business on central nervous system (CNS), gastrointestinal (GI),general products (GP) and human genetic therapies (HGT) - all being areas inwhich Shire has a commercial presence. The structure is sufficiently flexibleto allow Shire to target new therapeutic areas to the extent opportunitiesarise through acquisitions. Shire believes that a carefully selected portfolioof products with a strategically aligned and relatively small-scale sales forcewill deliver strong results.Shire's focused strategy is to develop and market products for specialtyphysicians. This approach aims to deliver increased returns and lower risks.Shire's in-licensing and merger and acquisition efforts are focused on productsin niche markets with strong intellectual property protection either in the USor Europe.For further information on Shire, please visit the Company's website:www.shire.com."SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF1995Statements included herein that are not historical facts are forward-lookingstatements. Such forward-looking statements involve a number of risks anduncertainties and are subject to change at any time. In the event such risks oruncertainties materialize, Shire's results could be materially affected. Therisks and uncertainties include, but are not limited to, risks associated with:the inherent uncertainty of pharmaceutical research, product development,manufacturing and commercialization; the impact of competitive products,including, but not limited to, the impact of those on Shire's Attention Deficitand Hyperactivity Disorder (ADHD) franchise; patents, including, but notlimited to, legal challenges relating to Shire's ADHD franchise; governmentregulation and approval, including, but not limited to, the expected productapproval dates of DAYTRANA (MTS/METHYPATCH) (ADHD), SPD503 (ADHD), SPD465(ADHD), MESAVANCE (SPD476) (ulcerative colitis), I2S (iduronate-2-sulfatase)(Hunter syndrome), and NRP104 (ADHD), including its scheduling classificationby the Drug Enforcement Administration in the United States; Shire's ability tobenefit from its acquisition of Transkaryotic Therapies, Inc.; Shire's abilityto secure new products for commercialization and/or development; and otherrisks and uncertainties detailed from time to time in Shire's filings with theSecurities and Exchange Commission, including its Annual Report on Form 10-Kfor the year to December 31, 2004. ### For further information, please contact:SHIREInvestor Relations Clƒ©a Rosenfeld +44 1256 894 160Media Jessica Mann +44 1256 894 280Global (outside US & Canada)Tara Breen - Resolute Communications +44 20 7357 8187Eleanor Heightman - Resolute Communications +44 20 7357 81871 Ray Pratt, et al. ASN poster, "Evidence For The Long-Term Safety AndTolerability Of Lanthanum Carbonate."2 Ray Pratt, et al. ASN poster, "Evidence For The Long-Term Safety AndTolerability Of Lanthanum Carbonate."3 Steve Damment, et al. ASN poster, "Influence Of Bile Acids On ThePhosphate-Binding Efficacy Of Lanthanum Carbonate And Sevelamer Hydrochloride."4 Steve Damment, et al. ASN poster, "Influence Of Bile Acids On ThePhosphate-Binding Efficacy Of Lanthanum Carbonate And Sevelamer Hydrochloride."5 Steve Damment, et al. ASN poster, "Influence Of Bile Acids On ThePhosphate-Binding Efficacy Of Lanthanum Carbonate And Sevelamer Hydrochloride."6 Steve Damment, et al. ASN poster, "Influence Of Bile Acids On ThePhosphate-Binding Efficacy Of Lanthanum Carbonate And Sevelamer Hydrochloride."7 http://www.kidney.org/professionals/kdoqi/guidelines_bone/guide3/htm. K/DOQIClinical Practice Guidelines for Bone Metabolism and Disease in Chronic KidneyDisease. National Kidney Foundation. Accessed June 17, 2004.8 http://www.emedicine.com/emerg/topic266.htm. "Hyperphosphatemia," by Leigh APatterson, MD, Staff Physician, Department of Emergency Medicine, CharityHospital, Louisiana State University, December 11, 2001.9 http://www.kidney.org/professionals/kdoqi/guidelines_bone/background.htm. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in ChronicKidney Disease. National Kidney Foundation. Accessed June 22, 2004.10 Molowa DT. First annual nephrology survey. JP Morgan Securities Inc., EquityResearch, February 13, 2002.11 USRDS 2004 Annual Data Report: Atlas of End Stage Renal Disease in theUnited States. U.S. Renal Data System, National Institutes of Health, NationalInstitute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, 2003, page75.12 http://www.emedicine.com/emerg/topic266.htm. "Hyperphosphatemia," by Leigh APatterson, MD, Staff Physician, Department of Emergency Medicine, CharityHospital, Louisiana State University, December 11, 2001.13 http://www.emedicine.com/emerg/topic266.htm. "Hyperphosphatemia," by Leigh APatterson, MD, Staff Physician, Department of Emergency Medicine, CharityHospital, Louisiana State University, December 11, 2001.14 Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serumphosphorus and calcium x phosphate product with mortality risk in chronichemodialysis patients: A national study. Am J. Kidney Dis 1998; 31:607-617.15 Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serumphosphorus and calcium x phosphate product with mortality risk in chronichemodialysis patients: A national study. Am J. Kidney Dis 1998; 31:607-617.16 Market Research, Insight International, Dec 01/Jan 02 HyperphosphataemiaExploratory Research J152417 http://www.emedicine.com/emerg/topic266.htm. "Hyperphosphatemia," by Leigh APatterson, MD, Staff Physician, Department of Emergency Medicine, CharityHospital, Louisiana State University, December 11, 2001.18 Molowa DT. First annual nephrology survey. JP Morgan Securities Inc., EquityResearch, February 13, 2002.19 FOSRENOL‚® U.S. PI.20 http://www.kidney.org/professionals/kdoqi/guidelines_bone/guide3/htm. K/DOQIClinical Practice Guidelines for Bone Metabolism and Disease in Chronic KidneyDisease. National Kidney Foundation. Accessed June 17, 2004.21 http://www.kidney.org/professionals/kdoqi/guidelines_bone/guide5.htm. K/DOQIClinical Practice Guidelines for Bone Metabolism and Disease in Chronic KidneyDisease. National Kidney Foundation. Accessed June 17, 2004.Hampshire International Business Park Chineham Basingstoke Hampshire RG24 8EP United Kingdom Tel +44 (0)1256 894000 Fax +44 (0)1256 894708 www.shire.com Press Release Registered in England 2883758 Registered Office as aboveENDShire Pharmaceuticals Group PLCRelated Shares:
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