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)

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