SYS-CON MEDIA Authors: Roberto Medrano, Dmitriy Stepanov, Gilad Parann-Nissany, Srinivasan Sundara Rajan, Sean Houghton

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Results From Study of Vascular Calcification in Dialysis Patients Presented in Late-Breaking Clinical Trial Session at ERA-EDTA 2010 Congress

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 (p<0.001). 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

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 has 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.

Forward-Looking Statements

This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission (SEC) reports filed by Amgen, including Amgen's most recent annual report on Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K. Please refer to Amgen's most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. Unless otherwise noted, Amgen is providing this information as of June 26, 2010 and expressly disclaims any duty to update information contained in this news release.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modelled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and products liability claims. We depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.

In addition, sales of our products are affected by the reimbursement policies imposed by third-party payors, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment as well as U.S. legislation affecting pharmaceutical pricing and reimbursement. Government and others' regulations and reimbursement policies may affect the development, usage and pricing of our products. In addition, we compete with other companies with respect to some of our marketed products as well as for the discovery and development of new products. We believe that some of our newer products, product candidates or new indications for existing products, may face competition when and as they are approved and marketed. Our products may compete against products that have lower prices, established reimbursement, superior performance, are easier to administer, or that are otherwise competitive with our products. In addition, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors and there can be no guarantee of our ability to obtain or maintain patent protection for our products or product candidates. We cannot guarantee that we will be able to produce commercially successful products or maintain the commercial success of our existing products. Our stock price may be affected by actual or perceived market opportunity, competitive position, and success or failure of our products or product candidates. Further, the discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations.

The scientific information discussed in this news release related to our product candidates is preliminary and investigative. Such product candidates are not approved by the U.S. Food and Drug Administration (FDA), and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidates. Only the FDA can determine whether the product candidates are safe and effective for the use(s) being investigated. Further, the scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labelling approved by the U.S. Food and Drug Administration (FDA) for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses. Only the FDA can determine whether the products are safe and effective for these uses. Healthcare professionals should refer to and rely upon the FDA-approved labelling for the products, and not the information discussed in this news release.

    
    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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