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25.05.2009 – 12:05

Amgen Inc.

New Findings Provide Additional Insights into the Management of Anaemia and Secondary Hyperparathyroidism in Chronic Kidney Disease Patients

Milan (ots/PRNewswire)

Data presented from large-scale observational studies provide new insights into the day-to-day management of two major complications of CKD: anaemia and secondary hyperparathyroidism (SHPT).(1), (2), (3), (4)

    - CKD anaemia: Aranesp(R) (darbepoetin alfa) flexible dosing intervals
      help maintain haemoglobin (Hb) levels within the target range for
      dialysis and pre-dialysis patients, while offering the convenience of
      extended dosing(1), (2), (3)
    - SHPT: New European data show the importance of early initiation of
      Mimpara(R) (cinacalcet) to achieve therapeutic targets in SHPT(4) 

A nephrology pioneer for more than 20 years, Amgen presented at the World Congress of Nephrology 2009 (WCN) additional results from observational studies with Aranesp and Mimpara demonstrating its commitment to nephrology research and innovation.

An interim analysis of the EXTEND study,(1) conducted among 1,957 pre-dialysis patients in Europe, showed that subcutaneous Aranesp, given either Q2W* or QM*, corrected and maintained target Hb levels in both ESA-prior (n=917) and ESA-naive (n=1040) patients. No dose increase was associated with switching to an extended dosing regimen and target Hb levels were maintained or improved. Aranesp Q2W or QM also brought ESA-naive patients to target Hb levels within three months.

Analyses from the ALTERNATE study(2), (3) showed that the majority of haemodialysis (n=2,849) and peritoneal dialysis (n=428) patients successfully converted to and maintained Q2W Aranesp dosing over 12 months. Before the switch, most patients received ESA dosing intervals ranging from TIW/BIW* to QW*.

Overall ESA dose was maintained after conversion to Aranesp Q2W, and extending the dosing interval did not change the proportion of patients maintained within the defined target Hb range.(2), (3) This was initially set at 11-13g/dL, but was revised in European countries to 10-12g/dL in line with new guidance issued during the course of the study.(5)

Speaking at WCN, Professor Bernard Canaud, Hopital Lapeyronie, Montpellier, France commented: "Data from two large observational studies - EXTEND(1) and ALTERNATE(2), (3) - show that the majority of CKD anaemia patients can switch to extended dosing regimens with darbepoetin alfa, offering further insights into its efficacy and safety."

Treating CKD anaemia is difficult due to the complexity involved with maintaining Hb targets in the presence of intercurrent events, such as inflammation, and patient comorbidities, including diabetes and cardiovascular disease. Evidence of the frequency of events that can interfere with erythropoiesis and induce Hb excursions can be found in a study carried out in France. The investigators found an average of 7.7 events per patient each month. Based on these observations, the investigators recommended close monitoring of clinical events and Hb levels, and adapting ESA treatment to specific patients' needs.(6) An ESA that offers flexible dosing intervals, such as Aranesp is considered by many nephrology experts to better address these underlying patient conditions and adapt to changing patient circumstances.

"We cannot currently predict which patients will need to switch back to more frequent dosing, either on a temporary or permanent basis," remarked Professor Canaud. "Best practice in ESA treatment offers a flexible dosing regimen - QW/Q2W/QM - to enable physicians to manage natural haemoglobin fluctuations in a timely and convenient manner."

The need for flexible dosing interval is clearly demonstrated in the ALTERNATE analysis of haemodialysis patients.(2) After conversion to the extended Q2W regimen, 23.5% (669 of 2,849) of patients were switched back to QW dosing at some point during the study. For many, this switch was temporary and at month twelve, 80% of patients were receiving Aranesp Q2W. In most cases, the switch was to manage either low or high Hb levels.(2)

New European data show the importance of early initiation of Mimpara (cinacalcet) to achieve therapeutic targets in SHPT(4)

The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI(TM)) provides evidence-based clinical practice guidelines that have transformed the care of patients with kidney disease.(7)

Data from the previously presented observational COSMOS study, established to survey bone mineral disturbances among haemodialysis patients across Europe, have shown the difficulty of meeting these targets in current clinical practice. The percentage of patients achieving K/DOQI targets was only 29.1% for parathyroid hormone (PTH) and only half of patients were achieving the targets for Calcium (Ca) and Phosphorus (P) - 50.5% and 51.5% respectively.(8)

The new data presented at WCN from the ECHO European observational study, established to characterise practice patterns with Mimpara, show important differences among countries regarding PTH levels at Mimpara initiation. Although the study shows that PTH, Ca and P levels were reduced consistently across all countries after initiation of Mimpara, a higher proportion of patients achieved the K/DOQI target range for PTH at month 12 in countries where Mimpara was initiated at lower baseline PTH levels (36% in Austria with a mean baseline PTH of 605 pg/mL as opposed to 14% in UK/Ireland with a mean baseline PTH of 954 pg/mL). The target achievement for Ca and P also increased 12 months after the initiation of Mimpara across all countries as compared to baseline, 51% versus 40% for Ca and 48% versus 39% for P.(4)

When not fully controlled, SHPT is a serious life-threatening condition and guidelines show that effective treatment should address all key biochemical parameters. The data from the ECHO study clearly show the efficacy of cinacalcet across all of these parameters, and provide evidence that more aggressive treatment by earlier intervention with cinacalcet provides more comprehensive control with more patients achieving these targets.(4)

Notes to Editors:

* Key to ESA dosing schedules: TIW Three times a week BIW Twice a week QW Once a week Q2W Once every two weeks QM Once a month

About the Studies:

EXTEND is a multicenter, international, observational, longitudinal, non-interventional study of non-selected adult patients with CKD not undergoing dialysis to assess the efficacy and safety of switching to an extended sub-cutaneous dosing regimen (Q2W/QM) of Aranesp(R). Approximately 300 centres and 3,500-4,000 patients in Europe and Australia are expected to participate.

ALTERNATE (A Long-term Non-interventional Trial to Evaluate the Effectiveness of Aranesp(R) in Dialysis Patients When Administered Once Every Two Weeks) is a non-interventional study among >6,000 patients greater than or equal to 18 years of age, with CKD and receiving dialysis treatment, who started treatment for renal anaemia with Aranesp(R) Q2W on or after August 1, 2004, with or without prior ESA treatment. Patients enrolled in the study from selected dialysis centers in participating countries were treated according to the usual clinical practice in the respective centre; clinical management was not altered for this non-interventional study.

COSMOS (Current management Of Secondary hyperparathyroidism - a Multicentre Observational Study) is a 3-year, multicentre, open-label, prospective study surveying bone mineral disturbances in haemodialysis patients. It includes data from 4,500 dialysis patients at 227 centres in 20 European countries.

ECHO is the first pan-European, multicentre, observational study to explore Mimpara(R) use in daily "real-world" clinical practice. 1,865 patients were enrolled between July 2005 and October 2007 from 187 sites in 12 countries. This was a part retrospective and part prospective study of patients receiving dialysis who received Mimpara(R) for the treatment of SHPT. Data for eligible patients were collected through chart review. The study collected relevant retrospective data for the 6 months before the start of Mimpara(R) therapy and retrospective/prospective data for the 12 months after commencement of therapy.

About CKD Anaemia

Anaemia is one of the most common symptoms of CKD. It occurs when failing kidneys no longer produce sufficient erythropoietin, a hormone that stimulates the production of oxygen-carrying red blood cells (RBCs) that contain haemoglobin, an iron-rich protein that carries oxygen from the lungs to the body's tissues.

Anaemia can be a serious disease that is often under-diagnosed and under-treated.(9) When anaemia occurs, the body gets less oxygen and therefore has less energy than it needs to function properly. The major symptoms of anaemia include fatigue, weakness, shortness of breath, difficulty concentrating or confusion, dizziness or fainting, pale skin, rapid heartbeat and feeling unusually cold.

About SHPT

Secondary hyperparathyroidism (SHPT) is a metabolic disorder that develops in chronic kidney disease (CKD) patients on dialysis and results in increased secretion of parathyroid hormone (PTH), which may lead to bone disease, bone pain and fractures, cardiovascular and soft tissue calcification and parathyroid hyperplasia.

SHPT develops as the parathyroid gland secretes increased PTH to normalise blood levels of calcium, which are low in patients with CKD. While SHPT initially helps to normalise serum calcium, over time, continuous PTH secretion leads to excessive growth of the parathyroid gland, high levels of PTH, calcium and phosphorus in the blood, and complications including bone disease and soft tissue and vascular calcification, which increases the risk for cardiovascular events.

K/DOQI sets out targets for the key parameters implicated in SHPT: parathyroid hormone (PTH; target 150-300 pg/mL), calcium (Ca; target 8.4-9.6 mg/dL) and phosphorus (P; target 3.5-5.5 mg/dL).

The majority of an estimated 324,000 CKD patients on dialysis in Europe suffer from some degree of SHPT.

About Aranesp(R)

Aranesp(R) is a therapy for the treatment of anaemia in chronic kidney disease (CKD). It is a novel recombinant erythropoiesis stimulating agent (ESA) that maintains haemoglobin levels in the blood by stimulating red blood cell (RBC) production.(6)

Aranesp(R) was granted marketing authorisation by the European Commission in 2001 for the weekly (QW) treatment of anaemia associated with chronic renal failure in adults and children of 11 years of age or older. In 2004, approval was granted for an extended dosing schedule for Aranesp in the nephrology setting, meaning that for the first time, CKD patients not on dialysis could receive Aranesp(R) on a once monthly basis (QM). In 2006, the Aranesp(R) SmPC was updated to allow CKD patients on dialysis to switch from a rHuEPO dosing schedule of two to three times a week to once every two weeks (Q2W) with Aranesp. In 2007, the European Commission approved Aranesp(R) for the treatment of CKD anaemia in paediatric patients on/not on dialysis.

Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times weekly may be converted to Aranesp(R) with Q2W dosing. The initial Q2W dose of Aranesp(R) (micrograms/every other week) is determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200.(5)

About Mimpara

Mimpara(R) (also known as Sensipar(R) in the United States, Australia, New Zealand and Canada) is a calcimimetic agent that is approved for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease receiving dialysis.(10)

Mimpara is a first-in-class calcimimetic that modulates the activity of the calcium-sensing receptor. It is a small molecule that acts as an allosteric modulator of the calcium-sensing receptor (CaR) on the parathyroid cell surface. The primary role of the CaR is control of parathyroid hormone (PTH) secretion in response to extracellular calcium concentration. Cinacalcet acts to reduce circulating PTH concentration through activation of the CaR by increasing its sensitivity to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium.

About Amgen

Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realise the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

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REFERENCES

(1) Claes K et al. Efficacy of darbepoetin alfa in a population of patients with chronic kidney disease not undergoing dialysis: EXTENDed dosing intervals (Q2W or QM) in patients on previous erythropoiesis-stimulating agents (ESA) and patients with no previous ESA treatment. World Congress of Nephrology, Milan, May 2009. Abstract # M299

(2) McMahon L et al. Conversion to darbepoetin alfa administered once every two weeks in haemodialysis patients: results of the ALTERNATE study. World Congress of Nephrology, Milan, May 2009. Abstract # M581

(3) Feriani M et al. Efficacy of darbepoetin alfa administered once every two weeks for twelve months in peritoneal dialysis patients. World Congress of Nephrology, Milan, May 2009. Abstract # M485

(4) Bencova V et al. "Real-world" use of cinacalcet in the management of SHPT among European countries. World Congress of Nephrology, Milan, May 2009. Abstract # Su577

(5) Araensp SmPC. http://www.emea.europa.eu/humandocs/PDFs/EPAR/aranesp/H-332-PI-en.pdf (last accessed 14th May 2009)

(6) Rottembourg JB et al. Stable haemoglobin (Hb) in hemodialysis (HD) patients: forest for the trees - A 12-week pilot observational study. ERA-EDTA, Barcelona, 2007

(7) Eknoyan G, Levin A, Levin NW. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Disease 2003; 42 (Suppl 3):S1-S202

(8) Covic A et al. Treatment of secondary hyperparathyroidism and K-DOQI guidelines

Achievement. COSMOS, a European observational study. American Society of Nephrology Renal Week 2008

(9) de Jong PE, van der Velde M., Gansevoort, RT, Zoccali C. Screening for chronic kidney disease: where does Europe go? Clin J Am Soc Nephrol 2008 3:616-623.

(10) Mimpara SmPC. http://www.emea.europa.eu/humandocs/PDFs/EPAR/mimpara/H-570-PI-en.pdf (last accessed 14th May 2009)

Contact:

Media, Toby Viering, +41-(0)78-7507-326 ; or Investors, Arvind Sood,
+1-805-447-1060, both of Amgen

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