R-568 reduces ectopic calcification in a rat model of chronic kidney disease-mineral bone disorder (CKD-MBD)

Moe, Sharon M.; Seifert, Mark F.; Chen, Neal X.; Sinders, Rachel M.; Chen, Xianming; Duan, Dana; Henley, Charles M.; Martin, Dave; Gattone, Vincent H.

doi:10.1093/ndt/gfp078

Cited by 37 publications

(46 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMG 416 (Velcalcetide) Activates the Calcium Sensing Receptor previously demonstrated that calcimimetics (such cinacalcet or homologs thereof) can delay or slow calcification in uremic rats (Lopez et al, 2006;Moe et al, 2009). In line with these observations, treatment of uremic rats with AMG 416 decreased renal mineralization compared with vehicle-treated uremic rats.…”

Section: Downloaded Frommentioning

confidence: 81%

Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients

Walter

Baruch

Dong

et al. 2013

J Pharmacol Exp Ther

View full text Add to dashboard Cite

A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicletreated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.

show abstract

Section: Downloaded Frommentioning

confidence: 81%

Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients

Walter

Baruch

Dong

et al. 2013

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…In rodent models, treatment with a calcimimetic lowered heart calcium content compared with control animals, whereas calcimimetic plus calcium did not. 28 Other studies showed that calcimimetics reduced arterial calcification compared with calcitriol and paricalcitol. 29,30 In a randomized trial of patients receiving hemodialysis, treatment with cinacalcet and lowdose vitamin D compared with flexible doses of vitamin D alone slowed the progression of coronary artery calcification on electron-beam computed tomography, with nominally significant changes as assessed with the volumetric method of The reduction of FGF23 with cinacalcet occurred within the first 20 weeks and was maintained throughout the study.…”

Section: Discussionmentioning

confidence: 99%

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

et al. 2015

View full text Add to dashboard Cite

Background-Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. Methods and Results-This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). Conclusions-Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23are associated with lower rates of cardiovascular death and major cardiovascular events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

show abstract

“…16 The animals utilized for the present study represent a subset of animals in a separate publication in which the effect of R-568 on extraskeletal calcification and bone were examined. 17 We performed immunohistochemistry on paraffin sections of kidney using a primary antibody to the CaR and a secondary antibody with a peroxidase chromagen product. We deparaffinized tissue sections (kidney and human parathyroid) in xylene and rehydrated them in descending alcohol concentrations.…”

Section: Concise Methodsmentioning

confidence: 99%

Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD

Gattone

Chen

Sinders

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/ϩ) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P Ͻ 0.001) and by 19% in the Ca group (P Ͻ 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.

show abstract

R-568 reduces ectopic calcification in a rat model of chronic kidney disease-mineral bone disorder (CKD-MBD)

Cited by 37 publications

References 24 publications

Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients

Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD

Contact Info

Product

Resources

About