Treatment of secondary hyperparathyroidism in patients on hemodialysis using a novel synthetic peptide calcimimetic,etelcalcetide: a short-term clinical study

Abstract

Objective

Secondary hyperparathyroidism (SHPT) is a major complication in patients with chronic kidney disease (CKD). SHPT is related to chronic kidney disease-mineral bone disorder, leading to increased morbidity and mortality. Etelcalcetide is intravenously administered at the end of hemodialysis (HD). Etelcalcetide differs from the oral calcimimetic cinacalcet because it reduces gastrointestinal adverse events, thereby improving therapeutic effects. Etelcalcetide has only been approved by the U.S. Food and Drug Administration for several months. Therefore, there have only been a few reports regarding treatment of SHPT using etelcalcetide. This study aimed to evaluate the efficacy of etelcalcetide in patients on HD with SHPT.

Methods

Nine patients on HD (four men and five women, aged 58 ± 10 years) were enrolled in this study. All of the patients received etelcalcetide (5–10 mg, three times a week after HD). The observation period was 4.4 ± 1.0 months.

Results

All of the patients showed a significant reduction in serum parathyroid hormone levels during the observation period (−59% ± 20%). No significant adverse effects were observed.

Conclusions

Although this study had an uncontrolled small group and a short observation period, our results suggest that etelcalcetide could be a promising agent for SHPT treatment.

Keywords

Secondary hyperparathyroidism chronic kidney disease-mineral bone disorder etelcalcetide hemodialysis calcium calcimimetic agent

Introduction

Chronic kidney disease (CKD) induces several complications.^1–3 Secondary hyperparathyroidism (SHPT) is one of the most important complications of CKD, leading to vascular calcification and cardiovascular diseases.^4,5 The main mechanism underlying SHPT involves an increase in parathyroid hormone (PTH) levels, which may exacerbate an imbalance in calcium and phosphorus metabolism.^6,7 Furthermore, abnormalities in these parameters are associated with hospitalization.⁸ The estimated healthcare costs are more than three times higher for patients with CKD and SHPT than for those without SHPT. Therefore, treatment of SHPT may reduce the economic burden of SHPT in patients with CKD.^9–11 The updated Kidney Disease Improving Global Outcomes guidelines suggest that conventional treatment of SHPT in patients with CKD is limited to administration of the vitamin D analog, calcitriol, or dietary phosphate binders to reset the levels of serum calcium, phosphorus, and PTH.¹² However, administration of a vitamin D analog increases serum calcium and phosphorus levels.¹³ Therefore, effective therapies for SHPT that can control PTH levels without inducing hypercalcemia are needed.

Etelcalcetide, a novel calcimimetic agent, is a synthetic peptide agonist of the calcium-sensing receptor and differs from cinacalcet because it shows mild gastrointestinal symptoms, nausea, and vomiting. Furthermore, etelcalcetide may be administered via a hemodialysis (HD) venous line, thereby decreasing the oral medication load. Additionally, etelcalcetide and its metabolite are not absorbed in the fiber of polysulfone dialyzers.¹⁴

There have been few reports on the use of etelcalcetide for SHPT because etelcalcetide has only been recently approved by the U.S. Food and Drug Administration.^15–17 In this study, we investigated the efficacy and safety of etelcalcetide in Japanese patients on HD.

Methods

Patients and study protocol

Nine HD patients with CKD were enrolled in the study. They underwent outpatient HD three times a week at the Department of Nephrology, Kindai University Nara Hospital, Kindai University Faculty of Medicine (Nara, Japan) or Seiwadai Clinic (Nara, Japan). All of these patients were Japanese and older than 20 years. Patients on precipitated calcium carbonate or phosphate binders and active vitamin D analogs, and those with serum intact PTH (iPTH) levels >180 pg/mL and serum calcium levels ≥8.4 mg/dL were eligible for this study. The major exclusion criteria were a history of parathyroidectomy or parathyroid intervention before the study, congestive heart failure, acute coronary syndrome, poorly-controlled hypertension, and diabetes mellitus. Eligible patients received a bolus injection of etelcalcetide (5–10 mg) three times a week for 2 to 5 months (Table 1). The safety or tolerability of etelcalcetide was evaluated using vital signs, laboratory findings, 12-lead electrocardiograms (ECGs), and adverse events, such as gastrointestinal side effects, nausea, and vomiting. The dose was increased by 5 mg if iPTH levels were not decreased intermediately during the observation period and no adverse events were reported. Administration of etelcalcetide was stopped when serum calcium levels were less than 8.4 mg/dL or symptomatic hypocalcemia was recognized. Blood samples were collected at the start of HD and at the beginning of the week. Serum levels of iPTH, calcium, phosphorus, and alkaline phosphatase were measured before and at the end of the observation period of the study.

Table 1.

Clinical characteristics.

Patient number	Sex	Age (years)	Observation period (months)	Dosage of etelcalcetide (mg; 3 times a week after HD)	Dosage of calcium carbonate		Dosage of vitamin D analogs
Patient number	Sex	Age (years)	Observation period (months)	Dosage of etelcalcetide (mg; 3 times a week after HD)	Before therapy (mg/day)	On therapy (g/day)	Before therapy (µg/week)	On therapy (µg/week)
1	M	51	5	5	0	1.5	30 (maxacalcitol)	30 (maxacalcitol)
2	M	63	4	5	0	3	4.5 (calcitriol)	4.5 (calcitriol)
3	F	51	5	5	0	0	1.5 (calcitriol)	2 (calcitriol)
4	M	47	5	5	0	3	2 (calcitriol)	3 (calcitriol)
5	F	61	5	5	0	0	3 (calcitriol)	3 (calcitriol)
6	F	69	5	10	0	1	0	1 (calcitriol)
7	F	53	4	5	0	4.5	15 (maxacalcitol)	30 (maxacalcitol)
8	M	77	2	10	0	0	10 (maxacalcitol)	15 (maxacalcitol)
9	F	54	5	5	0	4.5	1 (calcitriol)	3 (calcitriol)

M: male; F: female.

These patients were treated as per the protocol and a retrospective waiver of consent was obtained from the Clinical Study Ethics Review Board of Kindai University Nara Hospital (approval number: 17-9).

Ethical approval

All of the procedures performed in this study involving human participants were in accordance with the ethical standards of Kindai University Nara Hospital Research Committee, as well as the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Data analysis

Statistical significance for differences was determined by the interquartile range and Mann–Whitney U test. All analyses were performed using StatView (SAS Institute, Cary, NC, USA). Statistical significance was defined as P < 0.05.

Results

Four male and five female patients were enrolled in the study. The mean (SD) age of the patients at onset of SHPT was 58 ± 10 years, while the observation period was 4.4 ± 1.0 months. The mean etelcalcetide dose at the end of the study was 6.1 ± 2.2 mg. The initial doses of vitamin D and phosphate binder were continued during the observation period, except when calcium levels reached below 8.4 mg/dL. Serum iPTH levels were significantly decreased during therapy compared with baseline levels (626 ± 326 versus 258 ± 207 pg/mL, P = 0.01, Figure 1). However, no changes were observed in the levels of serum calcium, phosphorus, and alkaline phosphatase during the observation period (calcium, 9.2 ± 0.8 and 9.1 ± 1.1 mg/dL; phosphorus, 5.6 ± 1.2 and 5.0 ± 1.1 mg/dL; and alkaline phosphatase, 257 ± 122 and 244 ± 120 IU/L before and during therapy, respectively) (Figure 2a–c). Except for one patient, the dosage of calcium carbonate or vitamin D analogs was increased when etelcalcetide treatment was started (Table 1). No adverse events, such as nausea, vomiting, hypotension, headache, muscle spasms, anemia, or abnormal 12-lead ECGs, were reported during the observation period.

Figure 1.

Box plot showing serum iPTH levels. Etelcalcetide significantly decreased serum iPTH levels at the end of the observation period compared with baseline levels. iPTH: intact parathyroid hormone.

Figure 2.

Box plots showing levels of serum calcium, phosphorus, and alkaline phosphatase. No changes in the levels of serum calcium, phosphorus, and alkaline phosphatase were observed during the observation period. (a) serum calcium, (b) serum phosphorus, and (c) serum alkaline phosphatase levels.

Discussion

In this study, we evaluated the efficacy and safety of etelcalcetide in Japanese patients on HD with SHPT. The iPTH-lowering effect in our study was strong, but different from that previously reported.^15,18,19 No significant differences in other bone metabolic markers were observed. There were no adverse events during the observation period.

Previous reports showed reduced serum calcium levels in patients on etelcalcetide compared with those on cinacalcet.¹⁵ However, no significant decrease in serum calcium levels was observed in our study. This observation may be attributed to several reasons. First, the doses of carbonate or active vitamin D analogs were freely increased in our protocol when serum calcium levels were decreased below 8.4 mg/dL. Second, calcium concentrations of the dialysate in our institute are relatively high (2.75 mEq/L).

The level of iPTH was decreased in our study by almost 60%, which is similar to that previously reported.^15,18,19 Serum levels of intact fibroblast growth factor 23 (FGF23), bone alkaline phosphatase, and tartrate-resistant acid phosphatase-5b are suppressed after treatment with etelcalcetide.^15,18,19 Therefore, etelcalcetide may modulate the balance between osteoblasts and osteoclasts, thereby improving bone density and quality. Our study clearly showed that administration of etelcalcetide improved levels of the bone metabolic marker iPTH. Therefore, further investigations are required to study the effect of etelcalcetide on FGF23, bone alkaline phosphatase, and tartrate-resistant acid phosphatase-5b.

Our previous studies showed that CKD is characterized by an increase in oxidative stress and inflammation and protein kinase C β-dependent glomerular endothelial dysfunction.²⁰ Interestingly, cinacalcet treatment decreases oxidative stress and improves endothelial function.²¹ Further prospective studies are needed, but treatment with calcimimetic peptides, including etelcalcetide, may exert possible beneficial effects on cardiovascular diseases in patients on HD.^22–25

The conventional therapy of SHPT mainly includes vitamin D analogs, phosphate binders, or calcimimetics. Vitamin D analogs may not only decrease PTH in SHPT, but also affect absorption of calcium and phosphate from the intestine, leading to hypercalcemia, hyperphosphatemia, and elevated serum FGF23 levels. These conditions induce vascular and ectopic calcification. The oral calcimimetic drug cinacalcet is widely used in treating SHPT. A previous meta-analysis showed that cinacalcet could achieve the efficacy endpoints in control of SHPT.²⁶ Increases in FGF23 levels may be associated with adverse effects, including coronary artery calcification, left ventricle hypertrophy, and mortality.^27–32 The Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) study clearly showed that administration of cinacalcet decreased FGF23 levels, leading to a significant reduction in heart failure, sudden death, and cardiovascular mortality.³³ Etelcalcetide, a novel, second generation calcimimetic, appears to be superior to cinacalcet. A greater than 50% reduction from baseline in mean serum PTH levels during the efficacy assessment phase was shown to be 52% in etelcalcetide and 40% in cinacalcet.³⁴ Moreover, a previous study showed a 30% decrease in FGF23 levels in the etelcalcetide treatment group, and this was a more distinct reduction than cinacalcet.³³ Gastrointestinal symptoms, nausea, and vomiting are major adverse events of oral SHPT treatment, resulting in poor adherence to treatment. A recent report showed that gastrointestinal side effects in the cinacalcet group were higher than those in the etelcalcetide treated group (46.7% vs. 37.8%, respectively). However, etelcalcetide leads to more frequent adverse effects of asymptomatic and symptomatic hypocalcemia that can be more distinct at the beginning of administration.³⁴ Therefore, administration of intravenous etelcalcetide may improve treatment efficacy and reduce the medication burden.

The unit costs of etelcalcetide from several European countries can be 15% or 30% higher than cinacalcet.³⁵ However, according to an analysis performed in the United Kingdom, the incremental cost effectiveness ratio for etelcalcetide is GBP 14,778 per-quality adjusted life year, which is lower than the National Institute for Health and Care Excellence threshold (GBP 20,000–30,000).³⁶

In summary, our study suggests that etelcalcetide is useful for improving the prognosis of patients with SHPT. However, a large number of case–control studies will be needed in the future to be able to evaluate this treatment.

Footnotes

Acknowledgements

Parts of this manuscript were presented at the 11th international congress of ISHD. We wish to thank Kazumasa Tanaka, Ryoichi Hirakawa, Yasuhiro Akai, and Yasuhiro Horii for consultation on the work-up of the patients and this study.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

A.M. has received research grants from Otsuka Pharmaceutical, Teijin Pharma, Torii, Taisho Toyama Pharmaceutical, and Sanofi. A.M. has also received speaker honorarium from Ono Pharmaceutical, Kyowa Hakko Kirin, Takeda Pharmaceutical, Otsuka Pharmaceutical, MSD, Novartis Pharma, Kissei Pharmaceutical, Boehringer Ingelheim, Chugai Pharmceutical, Kowa, and Mylan. This work was supported by JSPS KAKENHI Grant Number 17K09720.

References

Herzog

Asinger

Berger

et al . Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80: 572–586. PubMed PMID: 21750584.

Papademetriou

Lovato

Doumas

et al . Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int 2015; 87: 649–659. PubMed PMID: 25229335.

Reinecke

Nabauer

Gerth

et al . Morbidity and treatment in patients with atrial fibrillation and chronic kidney disease. Kidney Int 2015; 87: 200–209. PubMed PMID: 24897032.

Torres

De Broe

Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease.

Kidney Int 2012; 82: 19–25. PubMed PMID: 22437409.

Cunningham

Locatelli

Rodriguez

Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.

Clin J Am Soc Nephrol 2011; 6: 913–921. PubMed PMID: 21454719.

Drueke

TB.

The pathogenesis of parathyroid gland hyperplasia in chronic renal failure.

Kidney Int 1995; 48: 259–272. PubMed PMID: 7564087.

Fraser

WD.

Hyperparathyroidism.

Lancet 2009; 374: 145–158. PubMed PMID: 19595349.

Schumock

Andress

Marx

et al . Association of secondary hyperparathyroidism with CKD progression, health care costs and survival in diabetic predialysis CKD patients. Nephron Clin Pract 2009; 113: c54–c61. PubMed PMID: 19590235.

Garside

Pitt

Anderson

et al . The cost-utility of cinacalcet in addition to standard care compared to standard care alone for secondary hyperparathyroidism in end-stage renal disease: a UK perspective. Nephrol Dial Transplant 2007; 22: 1428–1436. PubMed PMID: 17308322.

10.

Garside

Pitt

Anderson

et al . The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation. Health Technol Assess 2007; 11: iii, xi–xiii, 1–167. PubMed PMID: 17462168.

11.

Garside

Pitt

Anderson

et al . The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technol Assess 2007; 11: iii–iv, ix–221. PubMed PMID: 17999840.

12.

Ketteler

Block

Evenepoel

et al . Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney Int 2017; 92: 26–36. PubMed PMID: 28646995.

13.

Patel

Singh

AK.

Role of vitamin D in chronic kidney disease.

Semin Nephrol 2009; 29: 113–121. PubMed PMID: 19371802. Pubmed Central PMCID: 2696155.

14.

Edson

Iyer

et al . Determination of etelcalcetide biotransformation and hemodialysis kinetics to guide the timing of Its dosing. Kidney Int Rep 2016; 1: 24–33. PubMed PMID: 29318205. Pubmed Central PMCID: 5720529.

15.

Block

Bushinsky

Cheng

et al . Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: a randomized clinical trial. JAMA 2017; 317: 156–164. PubMed PMID: 28097356.

16.

Yokoyama

Fukagawa

Shigematsu

et al . A single- and multiple-dose, multicenter study of etelcalcetide in Japanese hemodialysis patients with secondary hyperparathyroidism. Kidney Int Rep 2017; 2: 634–644. PubMed PMID: 29142982. Pubmed Central PMCID: 5678849.

17.

Shigematsu

Fukagawa

Yokoyama

et al . Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism. Clin Exp Nephrol 2018; 22: 426–436. PubMed PMID: 28836058.

18.

Yokoyama

Fukagawa

Shigematsu

et al . A 12-week dose-escalating study of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese hemodialysis patients. Clinical Nephrol 2017; 88: 68–78. PubMed PMID: 28671062.

19.

Fukagawa

Yokoyama

Shigematsu

et al.

A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients. Nephrol Dial Transplant 2017; 32: 1723–1730. PubMed PMID: 28057872.

20.

Mima

Ohshiro

Kitada

et al . Glomerular-specific protein kinase C-beta-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. Kidney Int 2011; 79: 883–896. PubMed PMID: 21228767. Pubmed Central PMCID: 3612886.

21.

Ari

Kaya

Demir

et al . Cinacalcet may improve oxidative DNA damage in maintenance hemodialysis patients: an observational study. Int Urol Nephrol 2014; 46: 1843–1849. PubMed PMID: 24811568.

22.

Raggi

Chertow

Torres

et al . The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 2011; 26: 1327–1339. PubMed PMID: 21148030.

23.

Bellasi

Cozzolino

Adragao

et al . Phosphate binders in moderate chronic kidney disease: where do we stand? J Nephrol 2013; 26: 993–1000. PubMed PMID: 23543481.

24.

Urena-Torres

Floege

Hawley

et al . Protocol adherence and the progression of cardiovascular calcification in the ADVANCE study. Nephrol Dial Transplant 2013; 28: 146–152. PubMed PMID: 23028103.

25.

Bellasi

Cozzolino

Russo

et al . Cinacalcet but not vitamin D use modulates the survival benefit associated with sevelamer in the INDEPENDENT study. Clin Nephrol 2016; 86: 113–124. PubMed PMID: 27443567.

26.

Strippoli

Palmer

Tong

et al . Meta-analysis of biochemical and patient-level effects of calcimimetic therapy. Am J Kidney Dis 2006; 47: 715–726. PubMed PMID: 16632010.

27.

Fliser

Kollerits

Neyer

et al . Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007; 18: 2600–2608. PubMed PMID: 17656479.

28.

Isakova

Xie

Yang

et al . Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305: 2432–2439. PubMed PMID: 21673295. Pubmed Central PMCID: 3124770.

29.

Nasrallah

El-Shehaby

Salem

et al . Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients. Nephrol Dial Transplant 2010; 25: 2679–2685. PubMed PMID: 20176609.

30.

Gutierrez

Januzzi

Isakova

et al . Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119: 2545–2552. PubMed PMID: 19414634. Pubmed Central PMCID: 2740903.

31.

Seiler

Reichart

Roth

et al . FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant 2010; 25: 3983–3989. PubMed PMID: 20525642.

32.

Nakano

Hamano

Fujii

et al . Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 2012; 50: 1266–1274. PubMed PMID: 22425694.

33.

Moe

Chertow

Parfrey

et al . Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. Circulation 2015; 132: 27–39. PubMed PMID: 26059012.

34.

Pereira

Meng

Marques

et al . Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes. Clin Kidney J 2018; 11: 80–88. PubMed PMID: 29423207. Pubmed Central PMCID: 5798074.

35.

Stollenwerk

Iannazzo

Akehurst

et al.

A decision-analytic model to assess the cost-effectiveness of etelcalcetide vs. cinacalcet

. Pharmacoeconomics 2018; 36: 603–612. PubMed PMID: 29392552.

36.

Rose

Shepherd

Harris

et al . Etelcalcetide for treating secondary hyperparathyroidism: an evidence review group evaluation of a nice single technology appraisal. Pharmacoeconomics 2018. PubMed PMID: 29691773.