title: The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease.
abstract: Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27710, USA. Quar1001@mc.duke.edu
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Sherrard
authors.forename: Stephen
authors.initials: S
authors.lastname: Adler
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Rosansky
authors.forename: Laura C
authors.initials: LC
authors.lastname: McCary
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Turner
authors.forename: David A
authors.initials: DA
authors.lastname: Bushinsky
mesh_terms: D000328:Adult; D002118:Calcium / Q000097:blood; D000069449:Cinacalcet; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage* / Q000009:adverse effects; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000378:metabolism; D006435:Renal Dialysis; D014807:Vitamin D / Q000008:administration & dosage
chemical_list: D009281:Naphthalenes; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D014807:Vitamin D; D010758:Phosphorus; D002118:Calcium; D000069449:Cinacalcet