Healthcare Industry News:  dialysis 

Biopharmaceuticals

 News Release - October 7, 2009

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, October 7 (Healthcare Sales & Marketing Network) --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® (lanthanum carbonate) and sevelamer hydrochloride (Genzyme's Renagel®) 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.

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® (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

Issuer of this News Release is solely responsible for its content.
Please address inquiries directly to the issuing company.



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