Healthcare Industry News: SPD476
News Release - November 17, 2006
FOSRENOL(R) Data Show Evidence of Trends Towards Improved Bone Formation in CKD Stage 5 Patients, New Data Presented at ASN MeetingAdditional Study Shows Majority of Patients Achieve Phosphorus Control With Reformulated FOSRENOL(R) As Monotherapy
SAN DIEGO, Nov. 17 (HSMN NewsFeed) -- Treatment with the phosphate binder FOSRENOL® (lanthanum carbonate) was associated with slight improvements in bone formation in chronic kidney disease (CKD) Stage 5 patients with hyperphosphatemia (high phosphorus levels in the blood), according to long- term (two-year) data presented at the American Society of Nephrology (ASN) meeting. Additional studies presented at ASN document the efficacy and safety of the reformulated and higher-dose FOSRENOL® tablets.
Of the approximately 20 million Americans who have some form of kidney disease, more than 530,000 have developed CKD Stage 5. Even with dialysis and a low-phosphorus diet, most CKD Stage 5 patients in the United States will develop hyperphosphatemia. Without effective treatment, hyperphosphatemia may lead to renal osteodystrophy, a collection of bone diseases characterized by bone pain, brittle bones, skeletal deformities and fractures.
"Renal osteodystrophy develops early during chronic kidney disease, so by the time many patients reach dialysis, they may have painful and debilitating bone conditions. Treating hyperphosphatemia through diet and an effective phosphate binder can help patients maintain bone health while on dialysis," explained Hartmut H. Malluche, M.D., study author and chief of Nephrology, Bone and Mineral Metabolism in the Department of Internal Medicine at the University of Kentucky College of Medicine. "Our study showed that FOSRENOL® treatment was associated with increased bone formation in participants and that there were no signs of bone abnormalities, such as progressive evolution of mineralization defects or decreases in bone turnover."
This planned sub-study of a large Phase III clinical trial evaluated potential differences between standard therapy and lanthanum carbonate on the evolution of abnormalities of bone turnover, bone balance and mineralization in patients with CKD Stage 5. Investigators used bone biopsies to assess participants' bone health at baseline and at one and two years of treatment with FOSRENOL® (n=32 and 32, respectively) or standard phosphate binder therapy (n=34 and 24, respectively). The study results showed that FOSRENOL® effectively reduced serum phosphorus levels. In addition, FOSRENOL® treatment was associated with lower serum calcium, higher serum parathyroid hormone (PTH) and increased biochemical parameters indicative of bone formation. Individual patients showed improvements in their bone turnover and formation after two years of FOSRENOL® treatment, compared to standard treatment (n=12 and 3, respectively).
During year two, a greater proportion of patients in the standard therapy group showed movement of bone volume away from the normal range compared with the FOSRENOL® group (50 percent versus 31 percent). Similarly, improvements toward normal bone formation rates were seen in 38 percent of patients receiving FOSRENOL® at both one and two years. Patients in the standard therapy group showed improvements of only 24 and 12 percent at one and two years, and bone formation worsened in 63 percent of the patients in the two-year group. The results were not measured for statistical significance.
"The lower calcium and higher PTH levels in patients treated with FOSRENOL® may allow health care professionals a greater window for use of vitamin D analogs to improve bone health in patients on dialysis," added Dr. Malluche.
Additional Data Demonstrate FOSRENOL® as Monotherapy Is Effective in Patients With CKD Stage 5
In a separate 12-week, open-label Phase IIIb study in CKD Stage 5 patients most participants treated with only FOSRENOL® experienced reduced serum phosphorus and enhanced achievement of Kidney Disease Outcomes Quality Initiative (K/DOQI) targets, including those previously receiving combination phosphate binder therapy.
"FOSRENOL® is an effective, well-tolerated phosphate binder that may simplify treatment for CKD Stage 5 patients," said Alastair J. Hutchison, M.D., Renal Unit, Manchester Royal Infirmary. "Changing patients to FOSRENOL® monotherapy, not only reduces serum phosphorus levels, but also reduces phosphate binder pill burden."
The majority of participants who reached the K/DOQI target required approximately 3 grams (g) of FOSRENOL® daily, demonstrating that most patients can be controlled with a single 1 g tablet per meal. (Dosing based on three meals per day. Number of meals per day may vary. To achieve certain doses, additional tablets may be required.)
Of the 367 patients enrolled, 274 (75 percent) completed the study. Mean serum phosphorus levels at enrollment for the patients taking only one alternative phosphate binder was 6.14 mg/dL, with just 36 percent achieving the K/DOQI target, but after converting to FOSRENOL® and completing 12 weeks of monotherapy, 52 percent reached the target (P < 0.05). Similarly, mean levels of patients receiving two binders were 6.11 mg/dL at screening, with only 35 percent reaching the K/DOQI target, but the proportion increased to 44 percent after completing 12 weeks of FOSRENOL® monotherapy.
Majority of CKD Stage 5 Patients Achieved Phosphorus Control on Reformulated and Higher Dose FOSRENOL® Tablets
According to another study evaluating the efficacy and safety of reformulated FOSRENOL®, higher daily doses, 3,750 or 4,500 milligrams (mg), of FOSRENOL® may provide serum phosphorus control for those CKD Stage 5 patients who do not respond to doses of 3 g per day, without a dose-related increase in adverse events.
"This study demonstrates that higher doses of FOSRENOL® may help patients with difficult to control serum phosphorus levels reach K/DOQI targets," said Rajnish Mehrotra, M.D., Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. "The reduction in phosphate binder tablet burden that higher doses of FOSRENOL® provides may help improve patient adherence to their medication regimen and, thus, their phosphorus control."
Of note, participants previously receiving monotherapy with sevelamer HCl, with a highest total daily dose of 14,400 mg (18 tablets), required a markedly smaller daily dose of FOSRENOL® in the study. The total average FOSRENOL® daily doses at weeks four, eight and 24 did not exceed 3,500 mg, 4,200 mg and 3,400 mg, respectively, resulting in patients needing a maximum of five FOSRENOL® tablets to maintain phosphorus control.
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. There are no controlled clinical trials with FOSRENOL® demonstrating a reduction in morbidity or mortality.
Hyperphosphatemia is managed with a combination of dialysis, diet restriction and phosphorus-binding agents, since 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.
Despite the availability of phosphorus-binding agents, it remains a challenge for some CKD Stage 5 patients to maintain target ranges. According to the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease, Guideline 3, Evaluation of Serum Phosphorus Levels, fewer than 30 percent of dialysis patients are able to maintain serum phosphorus levels in the target range.
FOSRENOL® is indicated to reduce serum phosphate in patients with end stage renal disease (ESRD).
FOSRENOL® (lanthanum carbonate) 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-only 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, including the reformulated strengths of 500 mg, 750 mg and 1 g, as well as the original 250 mg. With the reformulated doses, patients can achieve serum phosphorus target levels with as few as three tablets per day. (Dosing based on as few as three tablets per day. Number of meals per day may vary. To achieve certain doses, additional tablets may be required.)
FOSRENOL® 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 serum phosphorus levels.
FOSRENOL® has been clinically tested in more than 5,500 patients. Nearly 1,000 of these patients have been treated with lanthanum carbonate for more than one year. Over 53,000 patients have been treated with FOSRENOL®. The long-term safety profile of FOSRENOL® shows no evidence of toxicity at clinical doses. Trials involving patients treated with FOSRENOL® showed sustained serum phosphorus reduction in a majority of patients.
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 www.fosrenol.com.
Shire's strategic goal is to become the leading specialty pharmaceutical 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 believes that a carefully selected portfolio of products with a strategically aligned and relatively small-scale sales force will deliver strong results. Shire's focused strategy is to develop and market products for specialty physicians. 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.
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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, manufacturing and commercialization; the impact of competitive products, including, but not limited to the impact of those on Shire's Attention Deficit and Hyperactivity Disorder (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 dates of SPD503 (guanfacine extended release) (ADHD), SPD465 (extended release of mixed amphetamine salts) (ADHD), MESAVANCETM (mesalamine) with MMX technology (SPD476) (ulcerative colitis), ELAPRASE(TM) (idursulfase) (Hunter Syndrome) and NRP104 (lisdexamfetamine dimesylate) (ADHD), including its scheduling classification by the Drug Enforcement Administration in the United States; Shire's ability to secure new products for commercialization and/or development; and other risks and uncertainties detailed from time to time in Shire's and its predecessor registrant Shire Pharmaceuticals Group 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, 2005.
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