MUNICH, June 26, 2010 /PRNewswire/ -- Results from the ADVANCE study presented in a late breaking clinical trial session at the ERA-EDTA 2010 Congress provide new insights into the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients. ADVANCE (A randomiseD VAscular calcificatioN study to evaluate the effects of CinacalcEt) is a randomised, controlled open label study to evaluate the effects of treatment with Mimpara(R) (cinacalcet) plus low-dose vitamin D, compared to flexible doses of vitamin D alone, on the progression of vascular and valvular calcification in dialysis patients with SHPT. A trend was observed towards slower progression of vascular calcification at all sites evaluated among patients randomised to the cinacalcet arm, though the primary endpoint did not reach statistical significance.

The primary endpoint for the study was percentage change in the Agatston CAC score from baseline to week 52. Agatston CAC scores [median, (Q1, Q3)] increased by 24 percent (-1 percent, 63 percent) from baseline in the cinacalcet group and by 31 percent (8 percent, 81 percent) in the flexible vitamin D group (p=0.073). Additional analyses were also performed using volumetric scoring of CAC, an alternative method for measuring CAC, and showed cinacalcet plus low-dose vitamin D significantly slowed the progression of calcification compared with flexible doses of vitamin D alone. Volume CAC scores increased by 22 percent (2 percent, 52 percent) from baseline in the cinacalcet group and by 30 percent (10 percent, 78 percent) in the flexible vitamin D group (p=0.009).

Coronary artery calcification is common in dialysis patients and has been linked to an elevated risk of cardiovascular events and mortality in patients on dialysis, said Paolo Raggi, M.D., Professor of Medicine, Emory University School of Medicine, Atlanta, USA. Although the results for the primary endpoint were not statistically significant, the findings from ADVANCE further support the hypothesis that treatment with cinacalcet plus low doses of vitamin D may slow the progression of this marker of risk in patients on dialysis with SHPT.

ADVANCE also showed that cinacalcet plus low-dose vitamin D, compared to flexible doses of vitamin D alone, provided better biochemical control of SHPT as judged by the blood levels of parathyroid hormone (PTH), calcium, and phosphorus from baseline to the end of the study as demonstrated in previous studies.(1,2) Median (interquartile range) plasma PTH levels decreased by 132 pg/mL (-276,-24) from baseline to study end in the cinacalcet group and by 65 pg/mL (-184, 62) in the flexible vitamin D group (p=0.018). Mean (95 percent CI) serum calcium decreased by 0.51 mg/dL (-0.65, -0.37) in the cinacalcet group but increased by 0.17 mg/dL (0.06, 0.28) in the flexible vitamin D group (p0.001). Serum phosphorus decreased by 0.92 mg/dL (-1.28, -0.55) in the cinacalcet group and by 0.24 mg/dL (-0.55, 0.07) in the flexible vitamin D group (p=0.025). The incidence of adverse events was similar between the two treatment groups.

The results from ADVANCE, coupled with recently published data, including an observational study showing that cinacalcet significantly improved all-cause and cardiovascular survival in dialysis patients(3), underscore the importance of completing the ongoing EVOLVE (EValuation Of Cinacalcet Therapy to Lower CardioVascular Events(TM)) trial, a global, randomised, placebo-controlled, double-blind study evaluating the impact of cinacalcet on mortality and cardiovascular events in dialysis patients, said Chris Mix, Executive Medical Director of Global Development at Amgen. We look forward to sharing those results with the nephrology community when they become available.

Additional analyses presented at the ERA-EDTA 2010 Congress provide further support for the hypothesis that treatment with cinacalcet plus low doses of vitamin D may favourably affect the progression of calcification of cardiac valves compared to vitamin D alone(4) (Abstract Number: Sa116); highlight predictors of cardiovascular calcification in patients on dialysis(5) (Abstract Number: OSu039) and compare cardiovascular calcium scoring methods in the ADVANCE study(6) (Abstract Number: OM016).

ADVANCE Study Design

ADVANCE is a randomised, controlled trial to compare two treatment strategies for SHPT and their effects on the progression of CAC among patients on dialysis. ADVANCE studied 360 patients with SHPT and detectable CAC who were randomised to open label treatment with cinacalcet (30-180 mg/day) plus low-dose vitamin D (less than or equal to 2 ug IV paricalcitol equivalent/dialysis session) or to flexible vitamin D therapy. In both groups, calcium-based phosphate binders were used exclusively, and the therapeutic target for PTH was 150-300 pg/mL.

The primary endpoint for ADVANCE evaluated the percentage change in Agatston CAC score from baseline to week 52. Secondary endpoints for ADVANCE included:

-- Absolute change from baseline in CAC score at week 52 -- Absolute and percentage change from baseline in aortic calcification score at week 52 -- Absolute and percentage change from baseline in aortic and mitral valve calcification score at week 52 -- Proportion of patients achieving 15% progression of CAC at week 52 -- Absolute and percentage changes in laboratory parameters (PTH, calcium, phosphorus) -- Safety and tolerability of cinacalcet

About SHPT

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.(7)

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

About CAC and SHPT

Cardiovascular disease and CAC are common in dialysis patients and may be aggravated by elevated PTH levels and disturbances in calcium and phosphorus metabolism that characterise secondary HPT. Elevated PTH was found to be a predictor of the extent of CAC among ADVANCE patients at baseline.(8)

Additionally, CAC progresses more rapidly in patients on dialysis than individuals with normal kidney function. Previous studies have shown that the degree of CAC and cardiac calcification is 2.5 to 5 times greater in dialysis patients than in non-dialysis patients with diagnosed coronary artery disease.(9) Available methods for evaluating CAC in clinical trials are not compliant with Good Clinical Practice. Vascular calcification is not a validated surrogate endpoint for mortality or cardiovascular events in this patient population.

About Mimpara(R) (cinacalcet)

Cinacalcet is a calcimimetic agent that is approved for the treatment SHPT in patients with chronic kidney disease on dialysis and for the reduction of hypercalcaemia in patients with parathyroid carcinoma and with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines).

Cinacalcet is a first-in-class calcimimetic that modulates the activity of the calcium-sensing receptor (CaR). It is a small molecule that acts as an allosteric modulator of the CaR on the parathyroid cell surface. The primary role of the CaR is control of 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

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References 1. Messa P, Macario F, Yaqoob M, et al. The OPTIMA Study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol 2008;3:36-45 2. Moe SM, Reslerova M, Ketteler M. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney International 2005;67:2295-2304 3. Block GA, Zaun D, Smits G, et al. Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodyalisis patients. Kidney International Advance Online Publication, June 16, 2010. doi:10.1038/ki.2010.167 4. Urena P, Raggi P, Chertow G, et al. The effects of cinacalcet plus low-dose vitamin D on cardiac valve calcification in hemodialysis patients with secondary hyperparathyroidism. Data presented at ERA- EDTA, 25-28 June Munich 2010. 5. Floege J, Chertow G, Block G, et al. Predictors of progression of cardiovascular calcification in patients on hemodialysis. Data presented at ERA-EDTA, 25-28 June, Munich 2010. 6. Raggi P, Chertow G, Block G et al. Comparison of cardiovascular calcium scoring methods in the ADVANCE study. Data presented at ERA- EDTA, 25-28 June, Munich 2010 7. Williams ME. Chronic kidney disease/bone and mineral metabolism: the imperfect storm. Semin Nephrol 2009;29(2):97-104 8. Floege J, Raggi P, Block GA, et al. Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients. Nephrol Dial Transplant. 2010 Nephrol. Dial. Transplant;25:1916-1923 9. Braun J, Oldendorf M, Moshage W, et al. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients. Am J Kidney Dis. 1996;27:394-401


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