Query: ETELCALCETIDE

title: Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis
abstract: Supplemental Digital Content is available in the text.  Left ventricular hypertrophy (LVH) is highly prevalent in patients with chronic kidney disease and increases their risk of cardiac events and mortality. FGF23 (fibroblast growth factor 23) and parathyroid hormone levels, which are associated with the development of LVH, rise progressively with declining renal function.  To determine whether FGF23 suppression by calcimimetic therapy may reduce LVH progression in comparison to FGF23 elevation under vitamin D analogs at equal parathyroid hormone suppression under either therapy as well as tight volume control.  We conducted a single blinded trial with 1:1 block randomization to investigate the effect of the intravenous treatment with etelcalcetide versus alfacalcidol on LVH progression in 62 maintenance hemodialysis patients with secondary hyperparathyroidism and LVH. In the intention to treat analysis of 59 patients, the mean difference in the change of left ventricular mass index determined by cardiac magnetic resonance imaging from baseline to 12 months of treatment was 6.9 g/m2 (95% CI, 12.6 to 1.2, P=0.022) in the etelcalcetide compared with the alfacalcidol group. The effect estimate was 8.2 g/m2 (95% CI, 14 to 2.4) in the per protocol analysis on 52 patients. The trajectories of parathyroid hormone, phosphate, and aKlotho were similar in both groups throughout follow up. FGF23 levels, which showed a strong positive association with left ventricular mass index, were decreasing under etelcalcetide and increasing under alfacalcidol at similar parathyroid hormone suppression. Mild hypocalcemia was the most common adverse event under etelcalcetide. Blood pressure and the distribution of antihypertensive medications were similar between groups.  In this trial, we were able to show that FGF23 suppression by etelcalcetide inhibited the progression of LVH compared with alfacalcidol in hemodialysis patients. A successful prevention of increasing hypertrophy may reduce the risk of sudden cardiac death in this population.

title: Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.
abstract: Vitamin D receptor activators and calcimimetics (calcium sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol.  A randomized, multicenter, open label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 ug thrice weekly (maxacalcitol group) The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community Based Integrated Care System from baseline to 12 months, respectively.  In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159) and 321 were included in the intention to treat analysis (median age, 66 years; 113 women [35% The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90 151) to 131 minutes (interquartile range, 102 176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98 174) to 166 minutes (interquartile range, 127 218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004) No significant between group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community Based Integrated Care System score.  Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs.

title: Etelcalcetide

title: Effect of switching from cinacalcet to etelcalcetide on secondary hyperparathyroidism in patients undergoing hemodialysis: an ESCORT trial
abstract: Etelcalcetide is the first intravenously administered calcimimetic agent used to manage secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. We evaluated the safety and efficacy of replacing cinacalcet with etelcalcetide in HD patients.  One hundred and thirty three patients HD on cinacalcet were screened, and 93 patients with serum intact parathyroid hormone (iPTH) level of 60 pg/mL and serum albumin corrected calcium (cCa) level of 8.4 mg/dL were enrolled. The patients were divided into three groups based on the dose of cinacalcet (i.e. 25, 50, and 75 mg) and switched to etelcalcetide. Etelcalcetide was administered three times per week for 24 weeks. The primary and secondary endpoints were etelcalcetide conversion dose and etelcalcetide effectiveness for iPTH levels (target range: 60 240 pg/mL) respectively.  Of the 68 patients whose iPTH level was within the management target at screening, 60 patients maintained the target level at the end of the study. Among patients whose iPTH level exceeded 240 pg/mL at screening, it decreased from 401 246 pg/mL to 220 209 pg/mL p 0.001) at the end of the study. Among 22 patients with the iPTH level of 240 pg/mL, 17 achieved the target level. The mean dose of cinacalcet was 41.4 22.2 mg/day and that of etelcalcetide at the end of the study was 6.4 3.7 mg/session in all patients. In 45 patients whose iPTH level was within the management target throughout the study and active vitamin D agent and calcium based phosphate binder doses were constant, the mean dose of cinacalcet was 45.0 22.4 mg/day and that of etelcalcetide at the end of the study was 6.1 3.1 mg/session. The spKt/V might affect the ratio of etelcalcetide per session to oral cinacalcet per day (45 patients, p 0.087; 90 patients, p 0.05) in the generalized linear model. Etelcalcetide induced severe adverse events were not observed.  This study reports the conversion dose of etelcalcetide and demonstrates its safety and efficacy in HD patients with SHPT previously treated with cinacalcet.

title: Etelcalcetide decreases the PTH calcium setpoint without changing maximum and minimum PTH secretion in mice with primary hyperparathyroidism
abstract: Etelcalcetide binds to the extracellular domain of the calcium sensing receptor (CaSR) while cinacalcet binds to the 7 transmembrane domain of the CaSR; however, it is unknown, whether etelcalcetide has similar effects to cinacalcet on parathyroid hormone (PTH) secretion. The PTH calcium setpoint and maximum and minimum PTH secretion were determined using an 'in vivo setpoint analyses. The PTH calcium setpoint was obtained in a mouse model of primary hyperparathyroidism (PC) and wild type (WT) mice, with PC mice divided into two groups. The setpoint was obtained after 7 days of etelcalcetide (3.0 mg/kg BW/day) or vehicle administration via anosmotic pump. After 7 days of crossover administration, the setpoint was obtained again. Parathyroid glands were obtained after crossover administration, and CaSR expression was analyzed by immunohistochemistry. Etelcalcetide administration significantly decreased the setpoint from 9.03 0.56 mg/dL to 6.80 0.28 mg/dL, which was restored to 8.81 0.38 mg/dL after vehicle administration. In the second group of mice, vehicle administration did not alter the setpoint (8.84 0.69 mg/dL to 8.98 0.63 mg/dL) but subsequent etelcalcetide administration significantly decreased it to 7.10 0.72 mg/dL. There was no significant change in maximum and minimum PTH secretion. Expression levels of parathyroid CaSR were lower in PC mice than in WT mice; however, no significant differences were observed between the two mouse groups. Etelcalcetide decreased the PTH calcium setpoint without changing maximum and minimum PTH secretion in PC mice, suggesting that like cinacalcet, etelcalcetide has calcimimetic potency.

title: Parsabiv (etelcalcetide) an allosteric modulator of the calcium sensing receptor in hemodialysis patients with SHPT
abstract: Patients suffering from ESRD (end stage renal disease) have a reduced renal function, which alters the metabolism of calcium, phosphorus and vitamin D. These changes often lead to SHPT (secondary hyperparathyroidism) which is characterized by elevated levels of PTH and is often associated with hyperplasia of the parathyroid glands Cunningham, et al.  This chronic and progressive disease develops early in the course of CKD, worsens with reduced renal function, and affects most patients with CKD at an advanced stage. Etelcalcetide is the only calcimimetic therapy for intravenous (i.v. administration. In addition, etelcalcetide is an allosteric activator of CaSR that binds directly to the extracellular medium. Etelcalcetide is a calcimimetic that can achieve clinically significant and sustained reductions in PTH, calcium and phosphorus levels. In addition to this i.v. method of administration of etelcalcetide also addressed some of the non clinical reasons why patients did not follow or discontinue other SHPT treatments. In this way, etelcalcetide can provide a treatment that addresses the unmet medical need of patients with CKD and CKD.

title: Effect of etelcalcetide on parathyroid hormone secretion by primary hyperparathyroidism patient derived primary parathyroid cells
abstract: Etelcalcetide (Parsabiv(r) AMG 416/ONO 5163) is a novel allosteric modulator for the calcium sensing receptor approved for hemodialysis patients with secondary hyperparathyroidism of uremia. Etelcalcetide reduced parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism of uremia in clinical studies. However, its direct effect on parathyroid hormone secretion in human parathyroid cells remains unknown. This study aimed to determine if etelcalcetide suppresses parathyroid hormone secretion by human parathyroid cells in vitro. We prepared primary cell cultures from human parathyroid tissue and determined calcium sensing receptor expression levels by immunohistochemistry. Pathyroid tumors were removed from fourteen patients with primary hyperparathyrodism. Parathyroid tissue was dispersed with collagenase, resuspended in culture medium, incubated for 2 h with etelcalcetide and Ca2+ and the medium was then collected. Final etelcalcetide concentrations in the medium were 0.005 50 umol/L. Levels of human parathyroid hormone in the medium were determined by enzyme linked immunosorbent assay. In eight of the fourteen parathyroid cell cultures, extracellular Ca2+ reduced parathyroid hormone levels. In four of the eight parathyroid cell cultures which responded extracellular Ca2+ etelcalcetide reduced hormone secretion with the 50% effective concentrations of 0.57, 20.8, 0.42, and 0.57 umol/L. Expression levels of the calcium sensing receptor were significantly lower in primary hyperparathyroidism patient derived parathyroid tissues compared with controls. This is the first report that etelcalcetide directly reduced parathyroid hormone secretion from the primary cultured human parathyroid cells from patients with primary hyperparathyroidism. To verify this conclusion, further studies are needed using secondary hyperparathyroidism patient derived parathyroid cells.

title: A Prospective, Randomized Clinical Trial of Etelcalcetide in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism (the DUET Trial)
abstract: The clinical trial on the Development of a treatment strategy for chronic kidney disease mineral and bone disorder by a mUltilateral mechanism of ETelcalcetide hydrochloride, or the DUET trial, was designed to determine the efficacy of etelcalcetide, an intravenous calcimimetic, for control of secondary hyperparathyroidism (SHPT) Methods Eligible SHPT maintenance hemodialysis patients (n 124) were randomized (1:1:1) for inclusion in the DUET trial, a 12 week, multicenter, open label, parallel group study (jRCTs041180108) and assigned to either an etelcalcetide active vitamin D group (group E+D) an etelcalcetide oral calcium preparation group (group E+Ca) or a control group (group C) The primary endpoint was number of patients with a 50% reduction from baseline of intact parathyroid hormone (iPTH) levels, and iPTH levels 240 pg/mL at 12 weeks after start of the trial.  The proportion of patients reaching the primary endpoint (95% confidence interval [CI] was 90.0% (76.3% 97.2% in group E+D, 56.8% (39.5% 72.9% in group E+Ca, and 19.5% (8.8% 34.9% in group C. Etelcalcetide treatment led to a significant increase in the number of patients achieving the endpoint (odds ratio, 13.4; 95% CI, 5.10 35.3) on logistic regression analysis, with iPTH, corrected serum calcium, and phosphate at baseline as covariates. Significantly more patients achieved the endpoint in group E+D compared with group E+Ca (odds ratio, 6.35; 95% CI, 1.79 22.48) There were fewer hypocalcemic visits in group E+D compared with group E+Ca (P 0.018) yet the former group was prone to hyperphosphatemia.  Etelcalcetide showed good control of iPTH for maintenance hemodialysis patients with SHPT. Active vitamin D was useful in correcting hypocalcemia, but the oral calcium preparation was superior for suppression of hyperphosphatemia.

title: Safety and efficacy of etelcalcetide, an intravenous calcimimetic, for up to 52 weeks in hemodialysis patients with secondary hyperparathyroidism: results of a post marketing surveillance in Japan
abstract: Etelcalcetide is a second generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan.  This PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs) and efficacy [serum intact parathyroid hormone (iPTH) corrected calcium (cCa) phosphorous (P) and alkaline phosphatase (ALP) were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician's discretion.  Of 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1% Metabolism and nutrition disorders (8.8% adverse laboratory test results (1.8% and gastrointestinal disorders (1.6% were the most frequent classes of ADRs. Hypocalcemia related ADRs occurred in 104 patients (8.7% The percentage of patients with iPTH levels within the target range (60 240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled.  This was the first real world, large scale, long term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels.

title: Etelcalcetide versus placebo for secondary hyperparathyroidism in patients receiving hemodialysis: A meta analysis of randomized controlled trials
abstract: The aim of the study was to evaluate the efficacy and safety of etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in patients receiving hemodialysis, and a meta analysis was performed using randomized controlled trials (RCTs)  We searched studies published on PubMed, Cochrane Central Register of Controlled Trials, and Embase to collect RCTs comparing etelcalcetide with placebo for the treatment of SHPT. Unpublished studies and information were also searched in ClinicalTrials.  Five RCTs involving 1,268 participants were eligible for inclusion in this meta analysis. Compared with placebo, etelcalcetide contributed to more participants who achieved 30% reduction in parathyroid hormone (PTH) (relative risk (RR) 8.64; 95% CI, 6.66 to 11.19; p 0.00001) and a PTH level of 300 pg/mL (RR 11.80; 95% CI, 8.15 to 17.08; p 0.00001) as well as an increase in the incidence of hypocalcemia (RR 18.76; 95% CI, 4.55 to 77.26, p 0.0001) nausea (RR 1.79; 95% CI, 1.19 to 2.70; p 0.006) or vomiting (RR 1.82; 95% CI, 1.17 to 2.85; p 0.008) Etelcalcetide reduced serum phosphate (mean difference (MD) 7.28; 95% CI, 8.82 to 5.74; p 0.00001) calcium phosphorus product (MD 14.48; 95% CI, 15.07 to 13.88; p 0.00001) and bone specific alkaline phosphatase (MD 24.80; 95% CI, 28.91 to 20.68) levels compared with the placebo.  Etelcalcetide can effectively control serum PTH and disorder of mineral metabolism but with more side effects than placebo. Further studies comparing etelcalcetide with other medication treatments for SHPT will be needed to evaluate if etelcalcetide might be a valuable choice with less pill burden for patients with SHPT receiving hemodialysis.