- Email: [email protected]
A Single- and Multiple-Dose, Multicenter Study of Etelcalcetide in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism
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A Single- and Multiple-Dose, Multicenter Study of Etelcalcetide in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism Keitaro Yokoyama1, Masafumi Fukagawa2, Takashi Shigematsu3, Takashi Akiba4, Akifumi Fujii5, Akinori Yamauchi6, Motoi Odani7, Tadao Akizawa8 and the ONO-5163 Study Group
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Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan; 2Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan; 3 Department of Nephrology, Wakayama Medical University, Wakayama, Japan; 4Sekikawa Hospital, Tokyo, Japan; 5Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan; 6Clinical Pharmacology, Ono Pharmaceutical Co., Ltd., Osaka, Japan; 7Data Science, Ono Pharmaceutical Co., Ltd., Osaka, Japan; and 8Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Introduction: The pharmacokinetics, pharmacodynamics, and safety and tolerability profile of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous, long-acting calcium-sensing receptor agonist, were studied in Japanese hemodialysis patients with secondary hyperparathyroidism. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisted of a single dose part and a multiple dose (3 times weekly for 4 weeks) part. Major inclusion criteria were hemodialysis for at least 90 days, serum intact parathyroid hormone (iPTH) $ 300 pg/ml, and serum albumin-corrected Ca (cCa) $ 9.0 mg/dl. There were 3 single-dose cohorts (n ¼ 6 each) randomized 2:1 to 5, 10, or 20 mg etelcalcetide or placebo, and 2 multiple-dose cohorts (n ¼ 11 each) randomized 8:3 to 2.5 or 5 mg etelcalcetide or placebo. Results: Etelcalcetide plasma concentration decreased rapidly after intravenous administration, generally remained stable from 24 hours postdose to the next dialysis, and then decreased by dialysis. Etelcalcetide exposure increased dose proportionally. Etelcalcetide plasma predialysis concentration reached almost steady state at week 4. A single dose of etelcalcetide dose-dependently reduced serum iPTH in 30 minutes, and the reduction reached a plateau at 1 hour that lasted until 8 hours. The percent change from baseline serum iPTH thereafter showed a trend to gradually decrease; it was still 30% or greater on day 3. Similar results were obtained at the last injection (days 27–29) of the multiple dose. The effect of the multiple dose was sustained during the interdialytic period. Etelcalcetide decreased serum cCa in a more gradual but dose-dependent and sustained manner. Discussion: Etelcalcetide dose-dependently reduced serum iPTH and serum cCa. Moreover, the effect was sustained in the interdialytic period. Kidney Int Rep (2017) -, -–-; http://dx.doi.org/10.1016/j.ekir.2017.01.016 KEYWORDS: calcium-sensing receptor agonist (calcimimetics); clinical trial; etelcalcetide (ONO-5163/AMG 416); secondary hyperparathyroidism ª 2017 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
econdary hyperparathyroidism (SHPT) is a complex disorder associated with chronic kidney disease (CKD), in which impaired mineral homeostasis and reduced synthesis of calcitriol, the active form of vitamin D, leads to excessive
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Correspondence: Keitaro Yokoyama, Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. E-mail: [email protected] Received 30 November 2016; revised 29 January 2017; accepted 31 January 2017; published online 18 February 2017
parathyroid hormone (PTH) levels.1–3 Elevated PTH levels and impaired mineral metabolism are linked to a variety of pathological changes, including parathyroid hyperplasia,1–3 metabolic bone disease,1–3 vascular calcification,4 and left ventricular hypertrophy.5 These pathological changes increase the risk of cardiovascular events, the leading cause of morbidity and mortality in these patients.6 Thus, the importance of appropriate management of SHPT is underscored by various clinical practice guidelines.7,8
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Active vitamin D analogues and cinacalcet are major treatment options for SHPT.7,8 Although active vitamin D analogues inhibit PTH secretion, these analogues also stimulate intestinal calcium transport and bone resorption, thereby increasing the risk of hypercalcemia, leaving many patients with elevated PTH levels.9 Cinacalcet, a calcium-sensing receptor (CaSR) agonist, is recommended for such patients. Cinacalcet reduces PTH secretion by binding to CaSR located on parathyroid chief cells, without increasing extracellular calcium.10,11 Numerous clinical trials have demonstrated that cinacalcet reduces not only PTH levels, but also serum calcium and phosphorus (P).12 Despite the beneficial clinical properties of cinacalcet, use of the drug has been limited by gastrointestinal adverse events (AEs), including nausea and vomiting, leading to poor compliance.12–14 Thus, there is a need for other calcimimetic agents with good efficacy and better tolerability that promote increased compliance. Etelcalcetide (ONO-5163/AMG 416) is a novel peptide consisting of 7 D-amino acids, is administered intravenously, is an agonist of CaSR,15 and has a long action in hemodialysis patients with limited or no kidney function because renal clearance is the main elimination pathway in healthy individuals.16 Etelcalcetide lowers the threshold for CaSR activation in response to extracellular calcium, and directly activates CaSR itself in the absence or presence of extracellular calcium as well as cinacalcet.17 Phase I and II studies demonstrated that etelcalcetide quickly reduced serum intact PTH (iPTH) and serum albumin-corrected calcium (cCa) in a dose-dependent manner in nonJapanese hemodialysis patients with SHPT.18–20 The effects were sustained during the interdialytic period when the drug was administered 3 times weekly for 4 weeks. Their studies supported clinical efficacy, demonstrating sustained etelcalcetide plasma concentrations throughout the study. In addition, the desirable timing to evaluate serum PTH and Ca for etelcalcetide may be different from that for cinacalcet, considering the pharmacokinetics of each. The present study was conducted to evaluate the pharmacokinetics, pharmacodynamics including the time-course changes and daily fluctuations, safety, and tolerability of etelcalcetide in Japanese hemodialysis patients with SHPT. The possible treatment of less severe SHPT with different doses of etelcalcetide was also evaluated, because Japanese patients have lower baseline iPTH compared to non-Japanese patients.21 MATERIALS AND METHODS Study Patients This was a randomized, double-blind, placebocontrolled, parallel-group study. The study population
comprised Japanese patients $20 years of age in medically stable condition with CKD who had been treated with hemodialysis 3 times a week for at least 90 days. The primary inclusion criteria were mean serum iPTH $ 300 pg/ml and serum cCa $ 9.0 mg/dl at screening, and calcium concentrations of dialysate stable ($2.25 mEq/l) for at least 2 weeks prior to screening. The major exclusion criteria were as follows: primary hyperparathyroidism; parathyroidectomy within 90 days or parathyroid intervention within 28 days before the start of screening; symptomatic angina pectoris or chronic heart failure; history of myocardial infarction within 180 days of the first dose of study drug; uncontrollable diabetes; and bisphosphonate therapy within 24 weeks of the first dose of study drug. Informed consent was obtained from all participants included in the study. All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (Institutional Review Board approval number ONO-5163-02) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was registered as JapicCTI-121978. Study Design This study comprised 2 parts: a single-dose study at 1 study center, and a multiple-dose study at 16 centers. Doses of 5, 10, and 20 mg (S1, S2, and S3) and of 2.5 and 5 mg (M1 and M2) were selected for the single-dose and multiple-dose parts, respectively, based on the following considerations: (i) a single intravenous injection at 5 to 60 mg was tolerable in non-Japanese SHPT patients18; (ii) 3-times-weekly 5- and 10-mg doses for 4 weeks were tolerable in non-Japanese patients19; (iii) a single injection of 5 mg was tolerable in healthy Japanese subjects with pharmacokinetics similar to those of non-Japanese subjects (unpublished data); and (iv) a possibility that a lower dose might benefit patients with lower baseline iPTH. The patients were randomly assigned via a centralized randomization system to receive either etelcalcetide or placebo. For the single-dose part, 6 patients each were enrolled in 3 cohorts and randomized 2:1 to receive etelcalcetide or placebo. The first cohort (S1) received a 5-mg IV injection of etelcalcetide via the venous blood line after dialysis. After all patients in cohort S1 or S2 met the safety criteria, the cohort S2 or S3 was started. The safety criteria included the following: serum cCa $ 7.5 mg/dl; no occurrence of Kidney International Reports (2017) -, -–-
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hypocalcemia requiring treatment; no occurrence of corrected QT interval (QTc) prolongation on 12-lead electrocardiograms (ECGs); iPTH $ 60 pg/ml; QTc by the Fridericia formula # 450 ms; and no occurrence of moderate- or higher-grade AEs that were not determined to be unrelated to the study drug. For the multiple-dose part, 11 patients each were enrolled in 2 cohorts and randomized 8:3 to receive etelcalcetide or placebo. After the safety criteria were met for cohort S1, the first cohort (M1) received a 2.5-mg IV injection of etelcalcetide 3 times weekly for 4 weeks. The second cohort (M2) followed the same treatment schedule with 5 mg after the safety criteria were met for cohorts S3 and M1. Bisphosphonates were prohibited from 24 weeks before the start of screening to the final visit. Calcitonin, estrogens, synthetic estrogens, selective estrogen receptor modulators, and cinacalcet hydrochloride were prohibited 14 days prior to iPTH determination at screening and from 28 days before the first dose to the final visit. Phosphate binders, active vitamin D derivatives, and calcium formulations were allowed if the dosage and administration schedules were unchanged from that at 14 days and 7 days before screening, respectively. Biochemical Determinations All samples were analyzed by SRL Medisearch Inc. (Tokyo, Japan) for laboratory tests and determination of serum iPTH, cCa, P, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase5b (TRACP-5b), and fibroblast growth factor 23 (FGF23). Antibodies Against Etelcalcetide Antibodies against etelcalcetide were determined by Eurofins Pharma Bioanalytics Service US Inc. (St. Charles, MO) using a validated enzyme-linked immunosorbent assay (performed between 2013 and 2014). Determination of Plasma Etelcalcetide Concentration The plasma concentration of etelcalcetide was determined by Quintiles BioSciences, Inc. (Ithaca, NY) using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). Safety and Tolerability The safety and tolerability profiles of etelcalcetide were assessed in terms of AEs, vital signs, clinical laboratory measurements, and antietelcalcetide antibodies. Vital signs were monitored at each institution, and 12-lead ECGs were monitored and analyzed by Suzuken Co. Ltd (Nagoya, Japan).
Statistical Analyses There was no hypothesis to be verified a priori in this study. Therefore, the planned sample sizes were determined based on practical considerations. All pharmacodynamic and safety analyses were performed in a descriptive manner, and no statistical inferences were made in this study. The pharmacokinetic analysis set included all patients who received etelcalcetide and from whom plasma etelcalcetide concentration data were obtained. The maximum plasma concentration (Cmax) and area under the plasma concentrationtime curve (AUC) from time 0 to the last time point with quantifiable concentration before the next hemodialysis (AUClast) were calculated for each subject using a noncompartmental analysis method. Descriptive statistics were calculated for both pharmacokinetic parameters. RESULTS Single-Dose Study Patients
Demographic and clinical characteristics of patients are summarized in Table 1. The mean serum iPTH Q2 at screening was 414.0 396.5, 338.3 34.2, 516.6 224.1, and 392.3 91.6 pg/ml for the placebo (S1þS2þS3) and etelcalcetide (S1, S2, and S3) groups, respectively. Pharmacokinetics
The time course of plasma etelcalcetide concentrations after a single dose is shown in Figure 1a. Injected etelcalcetide quickly decreased with time, but remained fairly constant from 24 hr to the next dialysis. AUClast and Cmax increased dose-proportionally (Table 2). Pharmacodynamics
Serum iPTH was quickly reduced in 30 minutes after a single dose, and a plateau was reached at 1 hour in the etelcalcetide groups (Figure 1b). The effect was sustained until day 4, and the percent change from the baseline was approximately 30% with 20 mg at 56 hours. The effect was also dose dependent, with a mean maximum change from the baseline of 16.21% 8.51% for placebo, 50.43% 12.63% for 5 mg, 69.26% 11.35% for 10 mg, and 74.47% 11.12% for 20 mg. On the other hand, serum cCa did not change appreciably for 8 hours, then gradually decreased after 18 hours, and reached a plateau at 56 hours in the etelcalcetide groups (Figure 1c). The mean maximum change from the baseline was 4.13% 5.41% for placebo, 7.26% 3.48% for 5 mg, 6.79% 5.86% for 10 mg, and 14.26% 6.01% for 20 mg. No patients developed hypocalcemia with cCa < 7.5 mg/dl in both groups. Serum P followed a similar time course in the
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Table 1. Demographic and clinical characteristics of patients in single-dose study Groups
Cohort S1
Cohort S2
Cohort S3
Placebo (S1DS2DS3)
5 mg/person
10 mg/person
20 mg/person
6
4
4
4
Male Female
3 (50.0%) 3 (50.0%)
4 (100.0%) 0 (0.0%)
3 (75.0%) 1 (25.0%)
3 (75.0%) 1 (25.0%)
Age (yr)
Mean SD Median Range
58.2 17.4 59.5 35–79
54.0 11.1 54.0 41–67
60.5 18.4 62.0 40–78
55.3 4.9 57.5 48–58
Body weight (kg) (postdialysis)
Mean SD Median Range
64.28 9.51 62.05 53.0–79.3
84.65 26.30 74.60 66.4–123.0
62.95 6.34 64.30 54.5–68.7
64.78 16.65 63.80 46.0–85.5
BMI (kg/m2)
Mean SD Median Range
24.69 5.05 22.39 19.8–32.6
28.71 7.36 26.80 22.4–38.8
23.56 2.20 22.64 22.1–26.8
24.13 4.79 23.19 20.2–29.9
Duration of dialysis (yr)
Mean SD Median Range
6.400 6.253 5.500 0.27–17.00
5.250 3.304 4.000 3.00–10.00
8.875 8.910 7.500 0.50–20.00
8.250 3.202 7.000 6.00–13.00
Vitamin D treatment
Yes No
5 (83.3%) 1 (16.7%)
3 (75.0%) 1 (25.0%)
4 (100.0%) 0 (0.0%)
4 (100.0%) 0 (0.0%)
Phosphate binder treatment
Yes No
6 (100.0%) 0 (0.0%)
4 (100.0%) 0 (0.0%)
3 (75.0%) 1 (25.0%)
4 (100.0%) 0 (0.0%)
Serum iPTH (pg/ml)
Mean SD Median Range
414.0 61.3 396.5 342–499
338.3 34.2 328.5 309–387
516.6 224.1 460.5 321–825
392.3 91.6 393.0 309–474
Serum cCa (mg/dl)
Mean SD Median Range
9.52 0.38 9.45 9.1–10.2
9.55 0.44 9.65 9.0–9.9
10.08 0.56 10.10 9.4–10.7
9.83 0.30 9.80 9.5–10.2
Serum P (mg/dl)
Mean SD Median Range
4.82 1.35 5.40 2.4–6.1
5.88 1.04 6.20 4.4–6.7
5.48 2.01 6.00 2.6–7.3
5.53 0.54 5.50 4.9–6.2
Dose No. of patients, n Sex
BMI, body mass index; cCa, albumin-corrected Ca; iPTH, serum intact parathyroid hormone; P, phosphorus; S, single-dose.
placebo and etelcalcetide groups until 4 hours after drug administration. From 4 hours to day 4, serum P remained lower in the etelcalcetide groups compared with the placebo group. Safety and Tolerability
No deaths or serious adverse events (AEs) were reported during the study. AEs were reported in 1 patient (25.0%) each in the etelcalcetide 5-mg group (abnormal activated partial thromboplastin time [APTT] and abnormal prothrombin) and 10-mg group (APTT) group, and in 2 patients (33.3%) in the placebo group (atrial flutter in 1 patient, and fatigue, peripheral pain, and dermatitis in the other). With the exception of atrial flutter in the placebo group, all AEs were considered unrelated to treatment. No antietelcalcetide antibodies were detected during the study period. Multiple-Dose Study Patients
Demographic and clinical characteristics of patients are summarized in Table 3. The mean serum iPTH at screening was 636.7 183.0, 695.0 345.7, and 453.5 127.5 pg/ml for the placebo (M1þM2), etelcalcetide M1, and M2 group, respectively. Pharmacokinetics
Etelcalcetide plasma concentration reached a plateau by 4 weeks (Figure 2a). AUClast and Cmax at week 4 were
up to 3.05 and 1.18 times higher than those after the initial dose, respectively. AUClast and Cmax increased dose-dependently (Table 4). Pharmacodynamics
Etelcalcetide injections resulted in marked dosedependent reductions in serum iPTH 30 minutes later (6.68% 22.97% for placebo, 41.65% 19.36% for 2.5 mg, and 58.60% 6.47% for 5 mg) and stayed at the same level up to 4 hours, remaining 24.25% 13.36% for 2.5 mg and 32.64% 18.20% for 5 mg lower than baseline on day 3 compared with placebo at 6.94% 13.00%. Similar results were obtained at the last injection (day 27 to day 29) in the etelcalcetide groups (Figure 3a). The reductions in serum iPTH were sustained throughout the study period, with a percent change from the baseline of 26.25% 26.94% for 2.5 mg, 45.65% 20.06% for 5 mg, and 0.25% 21.17% for placebo at the end of the study or at study withdrawal (Figure 2b). Etelcalcetide also dosedependently reduced serum cCa from day 2 through day 41 (Figure 2c). The mean percent change from the baseline at the end of the study or at withdrawal was 0.41% 2.73% for placebo, 7.05% 4.60% for 2.5 mg, and 12.75% 4.88% for 5 mg. No patients experienced hypocalcemia with serum cCa < 7.5 mg/dl in both groups. The mean percent changes from the baseline in serum P were greater in the etelcalcetide Kidney International Reports (2017) -, -–-
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
a
10000
1000
5 mg (S1)
Plasma etelcalcetideconcentration (ng/mL)
10 mg (S2) 20 mg (S3) 100
1000
10
100
0
12
24
36
48
60
72
10
1 0
48
96
144 192 240 288 336 384 432 480 528 576 624 672 Time after dose (hr)
b Percent changes in serum iPTH level (%)
Placebo
Etelcalcetide 5 mg (S1)
Etelcalcetide 10 mg (S2)
Etelcalcetide 20 mg (S3)
60.00 40.00 20.00 0.00 -20.00 -40.00 -60.00 -80.00 -100.00
-20 10 40 Day 1 Before dosing 10 min 30 min
70
100
130
1 hr
4 hr
8 hr
160 190 220 250 280 310 340 370 400 430 460 Day 2 Day 3 Day 4 Day 8 Day 15 Day 29 18 hr 24 hr 32 hr 42 hr 48 hr 56 hr (discharge) (follow-up)
After dosing
c
Placebo
Etelcalcetide 5 mg (S1)
Etelcalcetide 10 mg (S2)
Etelcalcetide 20 mg (S3)
10.00 Percent change in cCa level (%)
427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480
5.00 0.00 -5.00 -10.00 -15.00 -20.00 -25.00
-20 Day 1
Before dosing
10
40 30 min
70 1 hr
100 4 hr
130 8 hr
160 190 220 250 Day 2 Day 3 18 hr 24 hr 32 hr 42 hr
280 48 hr
310 56 hr
340 Day 4
370 400 430 Day 8 Day 15 Day 29
(discharge) (follow-up)
After dosing
Figure 1. Single-dose study. Etelcalcetide was injected via the venous blood line after dialysis in hemodialysis patients with secondary hyperparathyroidism (SHPT). (a) Mean (þSD) plasma concentration of etelcalcetide following single-dose IV injection. (Inset) First 65 hours of the plasma concentration curve. (b) Percent changes in serum intact parathyroid hormone (iPTH) after single-dose IV injection. Data are expressed as mean SD. (c) Percent changes in serum albumin-corrected calcium (cCa) after single-dose IV injection. Data are expressed as mean SD.
groups compared with the placebo group. At the end of the treatment or withdrawal from the study, the percent changes from the baseline were 5.75% 11.71% for placebo, 14.68% 13.38% for 2.5 mg, and 13.79% 18.18% for 5 mg. Serum BAP, TRACP-5b, and FGF23 levels did not change in the placebo group throughout the study period (Figure 4ac). Concentrations of BAP before
hemodialysis also remained unchanged on day 29 in the etelcalcetide groups, but showed trends toward decreases on day 55. On the other hand, for TRACP-5b, a trend toward decreases in the etelcalcetide groups on day 29 and a return to baseline on day 55 was shown. Etelcalcetide tended to decrease FGF23 on day 29, showing a trend toward a return to baseline levels on day 55.
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Table 2. Pharmacokinetic parameters (summary statistics) in singledose study AUClast (ng$h/ml)
Cmax (ng/ml)
Cohort (dosage level)
n
S1 (5 mg)
4
1110 360
236 89
S2 (10 mg)
4
2550 110
589 88
S3 (20 mg)
4
5460 680
999 135
Mean ± SD
AUC last, area under the curve from time 0 to last time point with quantifiable concentration before the next hemodialysis; S, single-dose.
Safety and Tolerability
AEs were reported in 7 patients (87.5%) in the etelcalcetide 2.5-mg group (atrial fibrillation, bradycardia, cardiopulmonary arrest, supraventricular extrasystoles, paroxysmal tachycardia, ventricular extrasystoles, edema peripheral, APTT prolonged, increased blood creatine phosphokinase, prothrombin time prolonged, white blood cell count increased, neutrophil percentage increased, lymphocyte percentage decreased, and upper respiratory tract inflammation),
3 patients (37.5%) in the 5-mg group (vertigo positional, decrease in blood calcium, and hypotension), and 2 patients (33.3%) in the placebo group (blood creatine phosphokinase increased, blood potassium increased, and heat rash). For bradycardia and cardiopulmonary arrest, supraventricular extrasystoles and ventricular extrasystoles, paroxysmal tachycardia, and increased blood creatine phosphokinase, 1 patient each in the 2.5-mg group, and a decrease in blood calcium in the 5-mg group, the relationships to treatment were not ruled out. With the exception of cardiopulmonary arrest in the 2.5-mg group, most of these AEs were mild and disappeared during the study period. No deaths occurred during the study period. No antietelcalcetide antibodies were detected during the study period. DISCUSSION The present study demonstrated that single- and multiple-dose intravenous injections of etelcalcetide
Table 3. Demographic and clinical characteristics of patients in multiple-dose study Groups Dose
Placebo (M1DM2)
No. of patients, n
Cohort M1
Cohort M2
2.5 mg/person
5 mg/person
6
8
8
Male Female
2 (33.3%) 4 (66.7%)
4 (50.0%) 4 (50.0%)
3 (37.5%) 5 (62.5%)
Age (yr)
Mean SD Median Range
54.2 16.9 54.0 30–74
64.4 9.4 61.5 54–81
54.0 14.6 53.5 37–83
Body weight (kg) (postdialysis)
Mean SD Median Range
52.13 6.56 48.80 46.3–60.5
48.05 11.47 46.25 33.2–67.4
63.88 18.52 63.90 38.9–88.4
BMI (kg/m2)
Mean SD Median Range
21.16 1.21 20.99 19.6–22.9
19.63 2.83 18.74 16.5–24.2
25.16 6.09 23.69 17.0–35.9
Duration of dialysis (yr)
Mean SD Median Range
8.2 5.6 8.0 1–17
13.1 6.2 11.0 7–24
9.6 6.0 10.0 2–21
Active vitamin D treatment
Yes No
4 (66.7%) 2 (33.3%)
7 (87.5%) 1 (12.5%)
7 (87.5%) 1 (12.5%)
Phosphate binder treatment
Yes No
5 (83.3%) 1 (16.7%)
8 (100.0%) 0 (0.0%)
8 (100.0%) 0 (0.0%)
Serum iPTH (pg/ml)
Mean SD Median Range
636.7 183.0 655.5 350–813
695.0 345.7 556.5 408–1420
453.5 127.5 415.0 341–726
Serum cCa (mg/dl)
Mean SD Median Range
9.62 0.79 9.25 9.0–10.9
9.80 0.50 9.75 9.2–10.7
Serum P (mg/dl)
Mean SD Median Range
4.95 0.80 4.95 4.0–5.8
5.48 1.35 5.35 3.9–7.5
5.36 1.22 5.60 3.3–6.9
Serum BAP (mg/l)a
Mean SD Median Range
27.90 7.26 27.55 20.2–40.2
35.58 40.78 21.85 10.8–135.0
17.30 9.68 15.70 8.0–37.3
Serum TRACP-5b (mU/dl)a
Mean SD Median Range
821.0 178.1 838.5 504–1050
697.6 355.8 572.0 328–1390
548.5 297.7 488.0 188–1090
Serum FGF23 (pg/ml)a (logarithm)
Mean SD Median Range
7.81 1.53 7.96 5.7–10.2
8.66 2.31 9.64 5.5–11.0
9.54 1.64 9.67 6.6–11.8
Sex
10.20 0.79 10.05 9.4–11.8
BAP, bone alkaline phosphatase; BMI, body mass index; cCa, albumin-corrected Ca; FGF23, fibroblast growth factor23; iPTH, serum intact parathyroid hormone; M, multiple-dose; P, phosphorus; TRACP-5b, tartrate-resistant acid phosphatase5b. a Data obtained for baseline measurements. Kidney International Reports (2017) -, -–-
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
a
Plasma etelcalcetide concentration (ng/mL)
1000 2.5 mg (M1) 5 mg (M2)
100
10
1
1
8
15
22 29 36 Day of the study
43
57
50
b Placebo
Etelcalcetide 5 mg (M2)
Etelcalcetide 2.5 mg (M1)
Percent changes in serum iPTH (%)
60.00 40.00
↓↓ ↓ ↓↓ ↓↓ ↓ ↓ ↓↓↓
20.00 0.00 -20.00 -40.00 -60.00 -80.00 1
3
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20 22
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27 29
34 41 55
E
Day of the study
c Placebo
Etelcalcetide 2.5 mg (M1)
Etelcalcetide 5 mg (M2)
15.00 10.00
Percent changes in serum cCa (%)
643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696
↓↓ ↓ ↓↓ ↓↓ ↓ ↓ ↓↓↓
5.00 0.00 -5.00 -10.00 -15.00 -20.00
1
3
6
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10 13
15 17 20 22
24 27 29
34 41 55
E
Day of the study
Figure 2. Multiple-dose study. Etelcalcetide was injected via the venous blood line after dialysis on days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, and 27 (arrows in b and c) in hemodialysis patients with secondary hyperparathyroidism (SHPT). Blood samples were obtained before each dialysis. (a) Mean (þSD) plasma concentration of etelcalcetide following multiple-dose IV injections. (b) Percent changes in serum intact parathyroid hormone (iPTH) during the study period (multiple-dose IV injections and follow-up). iPTH levels over the study period (from day 1 to day 55). Data are expressed as mean SD. E denotes at the end of the study (day 55) or at withdrawal from the study. (c) Percent changes in serum albumincorrected calcium (cCa) during the study period (multiple-dose IV injections and follow-up). cCa levels over the study period (from day 1 to day 55). Data are expressed as means SD. E denotes at the end of the study (day 55) or at withdrawal from the study. Kidney International Reports (2017) -, -–-
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Table 4. Pharmacokinetic parameters (summary statistics) in multiple-dose study AUClast (ng$h/ml) Cohort (dosage level) n Evaluation date
Cmax (ng/ml)
Mean ± SD
M1 (2.5 mg)
8 7 7
Day 1a Day 27b Day 27/day 1
600 133 151 56 1830 380 168 24 c 3.05 (2.91–3.19) 1.18 (0.86–1.62)c
M2 (5 mg)
8 8 8
Day 1 Day 27 Day 27/day 1
1200 560 315 89 3860 1840 356 143 c 3.20 (2.87–3.57) 1.09 (0.90–1.32)c
AUClast, area under the curve from time 0 to last time point with quantifiable concentration before the next hemodialysis; M, multiple-dose. a First administration day of multiple-dose part of study. b Last administration day of multiple-dose part of study. c Geometric mean (95% confidence interval).
resulted in dose-dependent and sustained reductions of serum iPTH and cCa in Japanese hemodialysis patients with SHPT as well as in a non-Japanese patient population.18–20 Compared with previous studies in non-Japanese patients, this study included patients with serum iPTH much lower than 500 pg/ml, which is the threshold for treatment with calcimimetics such as cinacalcet, according to the guidelines.7 The dosage levels in this study, the single dose at 5, 10, or 20 mg and the multiple dose at 2.5 or 5 mg 3 times weekly for 4 weeks, were also relatively lower compared with previous studies of a single dose at 5 to 60 mg and multiple doses at 5 to 10 mg 3 times weekly for 4 weeks.18,19 There was a consideration to evaluate the possibility that a lower dose might benefit patients with less severe SHPT, thereby preventing disease progression and leading to better prognosis. This study clearly indicated that a multiple doses of 2.5 mg 3 times weekly were effective in reducing serum iPTH in Japanese patients with moderate to severe SHPT. Etelcalcetide lowers PTH and is expected to affect bone metabolism and to lower Ca. It is important to clarify the relation between pharmacokinetics and pharmacodynamic parameters of etelcalcetide to appropriately assess its efficacy and safety. If unstable fluctuations of PTH and Ca are observed, the timing for assessment of efficacy and safety needs to be considered. Etelcalcetide plasma concentrations remained constant from 24 hours after administration to the next dialysis, and were increased with repeated administration. Accordingly, the mean AUClast following the day 27 injection was approximately 3 times higher than the AUClast following the day 1 injection, whereas the mean Cmax following both injections was approximately the same. In the present study, dialysis reduced etelcalcetide plasma concentrations to 30% to 40%. Based on the pharmacokinetics profile of etelcalcetide, a single dose resulted in sustained reductions of serum iPTH and cCa. Similarly, multiple doses for 4 weeks showed sustained reductions despite changes in bone
metabolism biomarkers, such as BAP and TRACP-5b, and marked daily fluctuations of PTH and Ca did not occur. Although cinacalcet has a short half-life and therefore induces diurnal fluctuation of serum iPTH, etelcalcetide may maintain a stable level of serum iPTH. In addition, oral administration of cinacalcet is often associated with gastrointestinal AEs, causing poor patient adherence to the therapy.12–14 To avoid these AEs, various timings of cinacalcet dosing, such as dosing after a meal or before sleep, have been attempted. However, changing the dose timing also affects measured values of serum iPTH and cCa, owing to diurnal fluctuation.22 To ascertain the effects and safety of cinacalcet, iPTH measurements are recommended to be performed before drug administration. Such a requirement might not be necessary for etelcalcetide, because etelcalcetide is administered via the venous blood line after dialysis and because diurnal changes in serum iPTH and cCa in etelcalcetide-treated patients are small. In contrast to the quick reduction in serum iPTH, the effect of etelcalcetide on serum Ca appeared gradually and steadily. It is therefore possible to predict possible hypocalcemia in advance through careful observation. This is an advantage over cinacalcet, which reduces serum Ca 8 to 12 hours after oral administration, expected to be during sleep. Because the timing of blood sampling and measurement affects the evaluation of drug effects, serum Ca was suggested to be evaluated 8 to 12 hours after administration of cinacalcet.23 FGF23 serum level is a known factor that predicts CKD progression and prognosis.1,2 In addition, high FGF23 is associated with mortality, left ventricular hypertrophy, and cardiovascular events independent of P, iPTH, and other clinical factors.5 Although trends toward decreases in FGF23 were shown with etelcalcetide, the amount of exposure was limited in the present study; further investigation with clinical doses will be necessary. Good safety and tolerability profiles were demonstrated for etelcalcetide. In terms of serious AEs, cardiopulmonary arrest reported in the 2.5-mg group of the multiple-dose study, the relationship to treatment was not ruled out, although possible causes included patient background such as aortic valve stenosis/incompetence, and long-term dialysis history of 19 years as well as the increased fluid volume. The event promptly recovered with heart massage and pharmacotherapy. No other AE that led to drug discontinuation was reported except for this patient, and no serious AE was reported in the 5-mg group. Although AEs of nausea and vomiting were not Kidney International Reports (2017) -, -–-
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
a Placebo
Etelcalcetide 5 mg (M2)
Etelcalcetide 2.5 mg (M1)
Percent changes in serum iPTH (%)
60.00 40.00
Day 27
↓ Day 1
↓
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0.5 1
1.5
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48 0 0.5 1 Time after dose (hr)
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b Placebo
Etelcalcetide 5 mg (M2)
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15.00 Percent changes in serum cCa (%)
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10.00
↓Day 1
↓Day 27
5.00 0.00 -5.00 -10.00 -15.00 -20.00
0
1
1.5
4
18 48 0 Time after dose (hr)
1
1.5
4
18
48
Figure 3. Percent changes in serum intact parathyroid hormone (iPTH) and albumin-corrected calcium (cCa) during the study period (multipledose IV injections and follow-up). Etelcalcetide was injected via the venous blood line after dialysis on days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, and 27 in hemodialysis patients with secondary hyperparathyroidism (SHPT). Blood samples were obtained before each dialysis. Data are expressed as mean SD. (a) iPTH levels following drug administration (from day 1 to day 3, and from day 27 to day 29). (b) cCa levels following drug administration (from day 1 to day 3, and from day 27 to day 29).
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reported, the amount of exposure was limited in the study; further investigation with clinical doses will be needed. This is the first study in Japanese patients. Study limitations include the small number of patients and the short period of dosing, as the patients had to be hospitalized for frequent and accurate blood collection timing to clarify the relationship between the pharmacokinetics of etelcalcetide and pharmacodynamics. Therefore, more definite quantitative data from a subsequent phase 2 or 3 study extending patient numbers
and treatment duration are required to confirm these observations with statistical evaluation. In conclusion, the present study clarified the relationship between the pharmacokinetics and pharmacodynamics of etelcalcetide, and demonstrated that etelcalcetide produced dose-dependent and sustained reductions in serum iPTH and cCa in Japanese hemodialysis patients with SHPT. The IV injection of etelcalcetide will provide a new alternative drug therapy offering increased compliance and benefits for SHPT in dialysis patients.
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a
Placebo
Percent changes in BAP (%)
40.00
Etelcalcetide 5 mg (M2)
20.00 10.00 0.00 -10.00 -20.00 -30.00
b Percent changes in TRACP-5b (%)
Etelcalcetide 2.5 mg (M1)
30.00
-25
5
35
Day 1 Predialysis
Placebo
30.00
65
Day 29 Predialysis
Etelcalcetide 2.5 mg (M1)
Day 55 Predialysis
Etelcalcetide 5 mg (M2)
20.00 10.00 0.00 -10.00 -20.00 -30.00 -40.00 -50.00
-25
c Percent changes in FGF-23 (%)
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
10.00
5 Day 1 Predialysis
Placebo
Day35 29 Predialysis
Etelcalcetide 2.5 mg (M1)
Day65 55 Predialysis
Etelcalcetide 5 mg (M2)
5.00 0.00 -5.00 -10.00 -15.00 -20.00 -25.00
Day 1 Predialysis
Day 29 Predialysis
Day 55 Predialysis
Figure 4. Percent changes in bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase5b (TRACP-5b), and fibroblast growth factor 23 (FGF23) serum levels during the study period (multiple-dose IV injection and follow-up). Etelcalcetide was injected via the venous blood line after dialysis on days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, and 27 in hemodialysis patients with secondary hyperparathyroidism (SHPT). Data are expressed as mean SD. (a) BAP; (b) TRACP-5b; (c) FGF 23.
DISCLOSURE KY, MF, TS, TA, and TA report consultancies with Ono Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin; AF, AY, and MO report employment with Ono Pharmaceutical Co., Ltd.
ACKNOWLEDGMENTS
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This work was funded by Ono Pharmaceutical Co., Ltd., including writing and editing services were provided by ASCA Corporation. The authors thank the Clinical Development Department, Ono Pharmaceutical Co., Ltd., for their assistance in preparing and writing this paper. The investigators were as follows: T. Iitsuka, Ibaraki Seinan Medical Center Hospital; H. Ogura, Kurosawa
Hospital, Bishinkai Medical Corporation; Y. Kanamaru, Clinique Soigner; K. Oguchi, Ikegami General Hospital, Medical Corporation Showakai; T. Suzuki, Suzuki Urology Clinic; Y. Kanno, Kanno Dialysis & Vascular Access Clinic; H. Shimosaka, Tajimi Clinic, Hakuyoukai Medical Corporation; M. Horie, Daiyukai Daiichi Hospital; H. Kasuga, Nagoya Kyoritsu Hospital and Kaikoukai Central Clinic, Kaikoukai Medical Group; K. Harada, Kasaoka Daiichi Hospital; and S. Funakoshi, Nagasaki Jin Hospital, Japan.
SUPPLEMENTARY MATERIAL Q5 Figure S1. Participant flow. Supplementary material is linked to the online version of the paper at http://www.kireports.org. Kidney International Reports (2017) -, -–-
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REFERENCES 1. Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011;6:913–921. 2. Fraser WD. Hyperparathyroidism. Lancet. 2009;374:145–158. 3. Drüeke TB. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure. Kidney Int. 1995;48:259–272. 4. Jean G, Bresson E, Terrat JC, et al. Peripheral vascular calcification in long-haemodialysis patients: associated factors and survival consequences. Nephrol Dial Transplant. 2009;24:948–955.
14. Fukagawa M, Yumita S, Akizawa T, et al. Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients. Nephrol Dial Transplant. 2008;23:328–335. 15. Walter S, Baruch A, Dong J, et al. Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J Pharmacol Exp Ther. 2013;346: 229–240.
5. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–4408.
16. Shen J, Xiao J, Pickthorn K, et al. A pharmacokinetic/ pharmacodynamic model for AMG 416, a novel calcimimetic peptide, following a single intravenous dose in healthy subjects. J Clin Pharmacol. 2014;54:1125–1133.
6. Ganesh SK, Stack AG, Levin NW, et al. Association of elevated serum PO(4), Ca PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol. 2001;12:2131–2138.
17. Alexander ST, Hunter T, Walter S, et al. Critical cysteine residues in both the calcium-sensing receptor and the allosteric activator AMG 416 underlie the mechanism of action. Mol Pharmacol. 2015;88:853–865.
7. Kidney Disease: Improving Global Outcomes (KDIGO) CKDMBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CDK-MBD). Kidney Int. 2009;76(Suppl 113):S1–S130. 8. Guideline Working Group, Japanese Society for Dialysis Therapy. Clinical practice guideline for the management of secondary hyperparathyroidism in chronic dialysis patients. Ther Apher Dial. 2008;12:514–525. 9. Goodman WG. The consequences of uncontrolled secondary hyperparathyroidism and its treatment in chronic kidney disease. Semin Dial. 2004;17:209–216. 10. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2þ)-sensing receptor from bovine parathyroid. Nature. 1993;366:575–580. 11. Nemeth EF, Heaton WH, Miller M, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther. 2004;308:627–635. 12. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. New Engl J Med. 2004;350:1516–1525. 13. Gincherman Y, Moloney K, McKee C, et al. Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients. Hemodial Int. 2010;14:68–72.
18. Martin KJ, Pickthorn K, Huang S, et al. AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients. Kidney Int. 2014;85:191–197. 19. Bell G, Huang S, Martin KJ, et al. A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients. Curr Med Res Opin. 2015;31:943–952. 20. Bushinsky DA, Block GA, Martin KJ, et al. Treatment of secondary hyperparathyroidism: results of a phase 2 trial evaluating an intravenous peptide agonist of the calcium-sensing receptor. Am J Nephrol. 2015;42:379–388. 21. Tentori F, Wang M, Bieber BA, et al. Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. Clin J Am Soc Nephrol. 2015;10:98–109. 22. Bover J, Ureña P, Ruiz-Garcia C, et al. Clinical and practical use of calcimimetics in dialysis patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2016;11:161–174. 23. Okuno S, Ishimura E, Inaba M, et al. Cinacalcet for mineral metabolism management: is it possible to achieve the goal set in the JSDT guideline? In: Akiba T, Akizawa T, eds. Hemodialysis Therapy IX. Tokyo: Igaku Tosho Shuppan, Japan; 2009:32–44.
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A Single- and Multiple-Dose, Multicenter Study of Etelcalcetide in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism Keitaro Yokoyama1, Masafumi Fukagawa2, Takashi Shigematsu3, Takashi Akiba4, Akifumi Fujii5, Akinori Yamauchi6, Motoi Odani7, Tadao Akizawa8 and the ONO-5163 Study Group
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Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan; 2Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan; 3 Department of Nephrology, Wakayama Medical University, Wakayama, Japan; 4Sekikawa Hospital, Tokyo, Japan; 5Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan; 6Clinical Pharmacology, Ono Pharmaceutical Co., Ltd., Osaka, Japan; 7Data Science, Ono Pharmaceutical Co., Ltd., Osaka, Japan; and 8Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Introduction: The pharmacokinetics, pharmacodynamics, and safety and tolerability profile of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous, long-acting calcium-sensing receptor agonist, were studied in Japanese hemodialysis patients with secondary hyperparathyroidism. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisted of a single dose part and a multiple dose (3 times weekly for 4 weeks) part. Major inclusion criteria were hemodialysis for at least 90 days, serum intact parathyroid hormone (iPTH) $ 300 pg/ml, and serum albumin-corrected Ca (cCa) $ 9.0 mg/dl. There were 3 single-dose cohorts (n ¼ 6 each) randomized 2:1 to 5, 10, or 20 mg etelcalcetide or placebo, and 2 multiple-dose cohorts (n ¼ 11 each) randomized 8:3 to 2.5 or 5 mg etelcalcetide or placebo. Results: Etelcalcetide plasma concentration decreased rapidly after intravenous administration, generally remained stable from 24 hours postdose to the next dialysis, and then decreased by dialysis. Etelcalcetide exposure increased dose proportionally. Etelcalcetide plasma predialysis concentration reached almost steady state at week 4. A single dose of etelcalcetide dose-dependently reduced serum iPTH in 30 minutes, and the reduction reached a plateau at 1 hour that lasted until 8 hours. The percent change from baseline serum iPTH thereafter showed a trend to gradually decrease; it was still 30% or greater on day 3. Similar results were obtained at the last injection (days 27–29) of the multiple dose. The effect of the multiple dose was sustained during the interdialytic period. Etelcalcetide decreased serum cCa in a more gradual but dose-dependent and sustained manner. Discussion: Etelcalcetide dose-dependently reduced serum iPTH and serum cCa. Moreover, the effect was sustained in the interdialytic period. Kidney Int Rep (2017) -, -–-; http://dx.doi.org/10.1016/j.ekir.2017.01.016 KEYWORDS: calcium-sensing receptor agonist (calcimimetics); clinical trial; etelcalcetide (ONO-5163/AMG 416); secondary hyperparathyroidism ª 2017 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
econdary hyperparathyroidism (SHPT) is a complex disorder associated with chronic kidney disease (CKD), in which impaired mineral homeostasis and reduced synthesis of calcitriol, the active form of vitamin D, leads to excessive
S
Correspondence: Keitaro Yokoyama, Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. E-mail: [email protected] Received 30 November 2016; revised 29 January 2017; accepted 31 January 2017; published online 18 February 2017
parathyroid hormone (PTH) levels.1–3 Elevated PTH levels and impaired mineral metabolism are linked to a variety of pathological changes, including parathyroid hyperplasia,1–3 metabolic bone disease,1–3 vascular calcification,4 and left ventricular hypertrophy.5 These pathological changes increase the risk of cardiovascular events, the leading cause of morbidity and mortality in these patients.6 Thus, the importance of appropriate management of SHPT is underscored by various clinical practice guidelines.7,8
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Active vitamin D analogues and cinacalcet are major treatment options for SHPT.7,8 Although active vitamin D analogues inhibit PTH secretion, these analogues also stimulate intestinal calcium transport and bone resorption, thereby increasing the risk of hypercalcemia, leaving many patients with elevated PTH levels.9 Cinacalcet, a calcium-sensing receptor (CaSR) agonist, is recommended for such patients. Cinacalcet reduces PTH secretion by binding to CaSR located on parathyroid chief cells, without increasing extracellular calcium.10,11 Numerous clinical trials have demonstrated that cinacalcet reduces not only PTH levels, but also serum calcium and phosphorus (P).12 Despite the beneficial clinical properties of cinacalcet, use of the drug has been limited by gastrointestinal adverse events (AEs), including nausea and vomiting, leading to poor compliance.12–14 Thus, there is a need for other calcimimetic agents with good efficacy and better tolerability that promote increased compliance. Etelcalcetide (ONO-5163/AMG 416) is a novel peptide consisting of 7 D-amino acids, is administered intravenously, is an agonist of CaSR,15 and has a long action in hemodialysis patients with limited or no kidney function because renal clearance is the main elimination pathway in healthy individuals.16 Etelcalcetide lowers the threshold for CaSR activation in response to extracellular calcium, and directly activates CaSR itself in the absence or presence of extracellular calcium as well as cinacalcet.17 Phase I and II studies demonstrated that etelcalcetide quickly reduced serum intact PTH (iPTH) and serum albumin-corrected calcium (cCa) in a dose-dependent manner in nonJapanese hemodialysis patients with SHPT.18–20 The effects were sustained during the interdialytic period when the drug was administered 3 times weekly for 4 weeks. Their studies supported clinical efficacy, demonstrating sustained etelcalcetide plasma concentrations throughout the study. In addition, the desirable timing to evaluate serum PTH and Ca for etelcalcetide may be different from that for cinacalcet, considering the pharmacokinetics of each. The present study was conducted to evaluate the pharmacokinetics, pharmacodynamics including the time-course changes and daily fluctuations, safety, and tolerability of etelcalcetide in Japanese hemodialysis patients with SHPT. The possible treatment of less severe SHPT with different doses of etelcalcetide was also evaluated, because Japanese patients have lower baseline iPTH compared to non-Japanese patients.21 MATERIALS AND METHODS Study Patients This was a randomized, double-blind, placebocontrolled, parallel-group study. The study population
comprised Japanese patients $20 years of age in medically stable condition with CKD who had been treated with hemodialysis 3 times a week for at least 90 days. The primary inclusion criteria were mean serum iPTH $ 300 pg/ml and serum cCa $ 9.0 mg/dl at screening, and calcium concentrations of dialysate stable ($2.25 mEq/l) for at least 2 weeks prior to screening. The major exclusion criteria were as follows: primary hyperparathyroidism; parathyroidectomy within 90 days or parathyroid intervention within 28 days before the start of screening; symptomatic angina pectoris or chronic heart failure; history of myocardial infarction within 180 days of the first dose of study drug; uncontrollable diabetes; and bisphosphonate therapy within 24 weeks of the first dose of study drug. Informed consent was obtained from all participants included in the study. All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (Institutional Review Board approval number ONO-5163-02) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was registered as JapicCTI-121978. Study Design This study comprised 2 parts: a single-dose study at 1 study center, and a multiple-dose study at 16 centers. Doses of 5, 10, and 20 mg (S1, S2, and S3) and of 2.5 and 5 mg (M1 and M2) were selected for the single-dose and multiple-dose parts, respectively, based on the following considerations: (i) a single intravenous injection at 5 to 60 mg was tolerable in non-Japanese SHPT patients18; (ii) 3-times-weekly 5- and 10-mg doses for 4 weeks were tolerable in non-Japanese patients19; (iii) a single injection of 5 mg was tolerable in healthy Japanese subjects with pharmacokinetics similar to those of non-Japanese subjects (unpublished data); and (iv) a possibility that a lower dose might benefit patients with lower baseline iPTH. The patients were randomly assigned via a centralized randomization system to receive either etelcalcetide or placebo. For the single-dose part, 6 patients each were enrolled in 3 cohorts and randomized 2:1 to receive etelcalcetide or placebo. The first cohort (S1) received a 5-mg IV injection of etelcalcetide via the venous blood line after dialysis. After all patients in cohort S1 or S2 met the safety criteria, the cohort S2 or S3 was started. The safety criteria included the following: serum cCa $ 7.5 mg/dl; no occurrence of Kidney International Reports (2017) -, -–-
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hypocalcemia requiring treatment; no occurrence of corrected QT interval (QTc) prolongation on 12-lead electrocardiograms (ECGs); iPTH $ 60 pg/ml; QTc by the Fridericia formula # 450 ms; and no occurrence of moderate- or higher-grade AEs that were not determined to be unrelated to the study drug. For the multiple-dose part, 11 patients each were enrolled in 2 cohorts and randomized 8:3 to receive etelcalcetide or placebo. After the safety criteria were met for cohort S1, the first cohort (M1) received a 2.5-mg IV injection of etelcalcetide 3 times weekly for 4 weeks. The second cohort (M2) followed the same treatment schedule with 5 mg after the safety criteria were met for cohorts S3 and M1. Bisphosphonates were prohibited from 24 weeks before the start of screening to the final visit. Calcitonin, estrogens, synthetic estrogens, selective estrogen receptor modulators, and cinacalcet hydrochloride were prohibited 14 days prior to iPTH determination at screening and from 28 days before the first dose to the final visit. Phosphate binders, active vitamin D derivatives, and calcium formulations were allowed if the dosage and administration schedules were unchanged from that at 14 days and 7 days before screening, respectively. Biochemical Determinations All samples were analyzed by SRL Medisearch Inc. (Tokyo, Japan) for laboratory tests and determination of serum iPTH, cCa, P, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase5b (TRACP-5b), and fibroblast growth factor 23 (FGF23). Antibodies Against Etelcalcetide Antibodies against etelcalcetide were determined by Eurofins Pharma Bioanalytics Service US Inc. (St. Charles, MO) using a validated enzyme-linked immunosorbent assay (performed between 2013 and 2014). Determination of Plasma Etelcalcetide Concentration The plasma concentration of etelcalcetide was determined by Quintiles BioSciences, Inc. (Ithaca, NY) using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). Safety and Tolerability The safety and tolerability profiles of etelcalcetide were assessed in terms of AEs, vital signs, clinical laboratory measurements, and antietelcalcetide antibodies. Vital signs were monitored at each institution, and 12-lead ECGs were monitored and analyzed by Suzuken Co. Ltd (Nagoya, Japan).
Statistical Analyses There was no hypothesis to be verified a priori in this study. Therefore, the planned sample sizes were determined based on practical considerations. All pharmacodynamic and safety analyses were performed in a descriptive manner, and no statistical inferences were made in this study. The pharmacokinetic analysis set included all patients who received etelcalcetide and from whom plasma etelcalcetide concentration data were obtained. The maximum plasma concentration (Cmax) and area under the plasma concentrationtime curve (AUC) from time 0 to the last time point with quantifiable concentration before the next hemodialysis (AUClast) were calculated for each subject using a noncompartmental analysis method. Descriptive statistics were calculated for both pharmacokinetic parameters. RESULTS Single-Dose Study Patients
Demographic and clinical characteristics of patients are summarized in Table 1. The mean serum iPTH Q2 at screening was 414.0 396.5, 338.3 34.2, 516.6 224.1, and 392.3 91.6 pg/ml for the placebo (S1þS2þS3) and etelcalcetide (S1, S2, and S3) groups, respectively. Pharmacokinetics
The time course of plasma etelcalcetide concentrations after a single dose is shown in Figure 1a. Injected etelcalcetide quickly decreased with time, but remained fairly constant from 24 hr to the next dialysis. AUClast and Cmax increased dose-proportionally (Table 2). Pharmacodynamics
Serum iPTH was quickly reduced in 30 minutes after a single dose, and a plateau was reached at 1 hour in the etelcalcetide groups (Figure 1b). The effect was sustained until day 4, and the percent change from the baseline was approximately 30% with 20 mg at 56 hours. The effect was also dose dependent, with a mean maximum change from the baseline of 16.21% 8.51% for placebo, 50.43% 12.63% for 5 mg, 69.26% 11.35% for 10 mg, and 74.47% 11.12% for 20 mg. On the other hand, serum cCa did not change appreciably for 8 hours, then gradually decreased after 18 hours, and reached a plateau at 56 hours in the etelcalcetide groups (Figure 1c). The mean maximum change from the baseline was 4.13% 5.41% for placebo, 7.26% 3.48% for 5 mg, 6.79% 5.86% for 10 mg, and 14.26% 6.01% for 20 mg. No patients developed hypocalcemia with cCa < 7.5 mg/dl in both groups. Serum P followed a similar time course in the
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Table 1. Demographic and clinical characteristics of patients in single-dose study Groups
Cohort S1
Cohort S2
Cohort S3
Placebo (S1DS2DS3)
5 mg/person
10 mg/person
20 mg/person
6
4
4
4
Male Female
3 (50.0%) 3 (50.0%)
4 (100.0%) 0 (0.0%)
3 (75.0%) 1 (25.0%)
3 (75.0%) 1 (25.0%)
Age (yr)
Mean SD Median Range
58.2 17.4 59.5 35–79
54.0 11.1 54.0 41–67
60.5 18.4 62.0 40–78
55.3 4.9 57.5 48–58
Body weight (kg) (postdialysis)
Mean SD Median Range
64.28 9.51 62.05 53.0–79.3
84.65 26.30 74.60 66.4–123.0
62.95 6.34 64.30 54.5–68.7
64.78 16.65 63.80 46.0–85.5
BMI (kg/m2)
Mean SD Median Range
24.69 5.05 22.39 19.8–32.6
28.71 7.36 26.80 22.4–38.8
23.56 2.20 22.64 22.1–26.8
24.13 4.79 23.19 20.2–29.9
Duration of dialysis (yr)
Mean SD Median Range
6.400 6.253 5.500 0.27–17.00
5.250 3.304 4.000 3.00–10.00
8.875 8.910 7.500 0.50–20.00
8.250 3.202 7.000 6.00–13.00
Vitamin D treatment
Yes No
5 (83.3%) 1 (16.7%)
3 (75.0%) 1 (25.0%)
4 (100.0%) 0 (0.0%)
4 (100.0%) 0 (0.0%)
Phosphate binder treatment
Yes No
6 (100.0%) 0 (0.0%)
4 (100.0%) 0 (0.0%)
3 (75.0%) 1 (25.0%)
4 (100.0%) 0 (0.0%)
Serum iPTH (pg/ml)
Mean SD Median Range
414.0 61.3 396.5 342–499
338.3 34.2 328.5 309–387
516.6 224.1 460.5 321–825
392.3 91.6 393.0 309–474
Serum cCa (mg/dl)
Mean SD Median Range
9.52 0.38 9.45 9.1–10.2
9.55 0.44 9.65 9.0–9.9
10.08 0.56 10.10 9.4–10.7
9.83 0.30 9.80 9.5–10.2
Serum P (mg/dl)
Mean SD Median Range
4.82 1.35 5.40 2.4–6.1
5.88 1.04 6.20 4.4–6.7
5.48 2.01 6.00 2.6–7.3
5.53 0.54 5.50 4.9–6.2
Dose No. of patients, n Sex
BMI, body mass index; cCa, albumin-corrected Ca; iPTH, serum intact parathyroid hormone; P, phosphorus; S, single-dose.
placebo and etelcalcetide groups until 4 hours after drug administration. From 4 hours to day 4, serum P remained lower in the etelcalcetide groups compared with the placebo group. Safety and Tolerability
No deaths or serious adverse events (AEs) were reported during the study. AEs were reported in 1 patient (25.0%) each in the etelcalcetide 5-mg group (abnormal activated partial thromboplastin time [APTT] and abnormal prothrombin) and 10-mg group (APTT) group, and in 2 patients (33.3%) in the placebo group (atrial flutter in 1 patient, and fatigue, peripheral pain, and dermatitis in the other). With the exception of atrial flutter in the placebo group, all AEs were considered unrelated to treatment. No antietelcalcetide antibodies were detected during the study period. Multiple-Dose Study Patients
Demographic and clinical characteristics of patients are summarized in Table 3. The mean serum iPTH at screening was 636.7 183.0, 695.0 345.7, and 453.5 127.5 pg/ml for the placebo (M1þM2), etelcalcetide M1, and M2 group, respectively. Pharmacokinetics
Etelcalcetide plasma concentration reached a plateau by 4 weeks (Figure 2a). AUClast and Cmax at week 4 were
up to 3.05 and 1.18 times higher than those after the initial dose, respectively. AUClast and Cmax increased dose-dependently (Table 4). Pharmacodynamics
Etelcalcetide injections resulted in marked dosedependent reductions in serum iPTH 30 minutes later (6.68% 22.97% for placebo, 41.65% 19.36% for 2.5 mg, and 58.60% 6.47% for 5 mg) and stayed at the same level up to 4 hours, remaining 24.25% 13.36% for 2.5 mg and 32.64% 18.20% for 5 mg lower than baseline on day 3 compared with placebo at 6.94% 13.00%. Similar results were obtained at the last injection (day 27 to day 29) in the etelcalcetide groups (Figure 3a). The reductions in serum iPTH were sustained throughout the study period, with a percent change from the baseline of 26.25% 26.94% for 2.5 mg, 45.65% 20.06% for 5 mg, and 0.25% 21.17% for placebo at the end of the study or at study withdrawal (Figure 2b). Etelcalcetide also dosedependently reduced serum cCa from day 2 through day 41 (Figure 2c). The mean percent change from the baseline at the end of the study or at withdrawal was 0.41% 2.73% for placebo, 7.05% 4.60% for 2.5 mg, and 12.75% 4.88% for 5 mg. No patients experienced hypocalcemia with serum cCa < 7.5 mg/dl in both groups. The mean percent changes from the baseline in serum P were greater in the etelcalcetide Kidney International Reports (2017) -, -–-
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
a
10000
1000
5 mg (S1)
Plasma etelcalcetideconcentration (ng/mL)
10 mg (S2) 20 mg (S3) 100
1000
10
100
0
12
24
36
48
60
72
10
1 0
48
96
144 192 240 288 336 384 432 480 528 576 624 672 Time after dose (hr)
b Percent changes in serum iPTH level (%)
Placebo
Etelcalcetide 5 mg (S1)
Etelcalcetide 10 mg (S2)
Etelcalcetide 20 mg (S3)
60.00 40.00 20.00 0.00 -20.00 -40.00 -60.00 -80.00 -100.00
-20 10 40 Day 1 Before dosing 10 min 30 min
70
100
130
1 hr
4 hr
8 hr
160 190 220 250 280 310 340 370 400 430 460 Day 2 Day 3 Day 4 Day 8 Day 15 Day 29 18 hr 24 hr 32 hr 42 hr 48 hr 56 hr (discharge) (follow-up)
After dosing
c
Placebo
Etelcalcetide 5 mg (S1)
Etelcalcetide 10 mg (S2)
Etelcalcetide 20 mg (S3)
10.00 Percent change in cCa level (%)
427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480
5.00 0.00 -5.00 -10.00 -15.00 -20.00 -25.00
-20 Day 1
Before dosing
10
40 30 min
70 1 hr
100 4 hr
130 8 hr
160 190 220 250 Day 2 Day 3 18 hr 24 hr 32 hr 42 hr
280 48 hr
310 56 hr
340 Day 4
370 400 430 Day 8 Day 15 Day 29
(discharge) (follow-up)
After dosing
Figure 1. Single-dose study. Etelcalcetide was injected via the venous blood line after dialysis in hemodialysis patients with secondary hyperparathyroidism (SHPT). (a) Mean (þSD) plasma concentration of etelcalcetide following single-dose IV injection. (Inset) First 65 hours of the plasma concentration curve. (b) Percent changes in serum intact parathyroid hormone (iPTH) after single-dose IV injection. Data are expressed as mean SD. (c) Percent changes in serum albumin-corrected calcium (cCa) after single-dose IV injection. Data are expressed as mean SD.
groups compared with the placebo group. At the end of the treatment or withdrawal from the study, the percent changes from the baseline were 5.75% 11.71% for placebo, 14.68% 13.38% for 2.5 mg, and 13.79% 18.18% for 5 mg. Serum BAP, TRACP-5b, and FGF23 levels did not change in the placebo group throughout the study period (Figure 4ac). Concentrations of BAP before
hemodialysis also remained unchanged on day 29 in the etelcalcetide groups, but showed trends toward decreases on day 55. On the other hand, for TRACP-5b, a trend toward decreases in the etelcalcetide groups on day 29 and a return to baseline on day 55 was shown. Etelcalcetide tended to decrease FGF23 on day 29, showing a trend toward a return to baseline levels on day 55.
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
Table 2. Pharmacokinetic parameters (summary statistics) in singledose study AUClast (ng$h/ml)
Cmax (ng/ml)
Cohort (dosage level)
n
S1 (5 mg)
4
1110 360
236 89
S2 (10 mg)
4
2550 110
589 88
S3 (20 mg)
4
5460 680
999 135
Mean ± SD
AUC last, area under the curve from time 0 to last time point with quantifiable concentration before the next hemodialysis; S, single-dose.
Safety and Tolerability
AEs were reported in 7 patients (87.5%) in the etelcalcetide 2.5-mg group (atrial fibrillation, bradycardia, cardiopulmonary arrest, supraventricular extrasystoles, paroxysmal tachycardia, ventricular extrasystoles, edema peripheral, APTT prolonged, increased blood creatine phosphokinase, prothrombin time prolonged, white blood cell count increased, neutrophil percentage increased, lymphocyte percentage decreased, and upper respiratory tract inflammation),
3 patients (37.5%) in the 5-mg group (vertigo positional, decrease in blood calcium, and hypotension), and 2 patients (33.3%) in the placebo group (blood creatine phosphokinase increased, blood potassium increased, and heat rash). For bradycardia and cardiopulmonary arrest, supraventricular extrasystoles and ventricular extrasystoles, paroxysmal tachycardia, and increased blood creatine phosphokinase, 1 patient each in the 2.5-mg group, and a decrease in blood calcium in the 5-mg group, the relationships to treatment were not ruled out. With the exception of cardiopulmonary arrest in the 2.5-mg group, most of these AEs were mild and disappeared during the study period. No deaths occurred during the study period. No antietelcalcetide antibodies were detected during the study period. DISCUSSION The present study demonstrated that single- and multiple-dose intravenous injections of etelcalcetide
Table 3. Demographic and clinical characteristics of patients in multiple-dose study Groups Dose
Placebo (M1DM2)
No. of patients, n
Cohort M1
Cohort M2
2.5 mg/person
5 mg/person
6
8
8
Male Female
2 (33.3%) 4 (66.7%)
4 (50.0%) 4 (50.0%)
3 (37.5%) 5 (62.5%)
Age (yr)
Mean SD Median Range
54.2 16.9 54.0 30–74
64.4 9.4 61.5 54–81
54.0 14.6 53.5 37–83
Body weight (kg) (postdialysis)
Mean SD Median Range
52.13 6.56 48.80 46.3–60.5
48.05 11.47 46.25 33.2–67.4
63.88 18.52 63.90 38.9–88.4
BMI (kg/m2)
Mean SD Median Range
21.16 1.21 20.99 19.6–22.9
19.63 2.83 18.74 16.5–24.2
25.16 6.09 23.69 17.0–35.9
Duration of dialysis (yr)
Mean SD Median Range
8.2 5.6 8.0 1–17
13.1 6.2 11.0 7–24
9.6 6.0 10.0 2–21
Active vitamin D treatment
Yes No
4 (66.7%) 2 (33.3%)
7 (87.5%) 1 (12.5%)
7 (87.5%) 1 (12.5%)
Phosphate binder treatment
Yes No
5 (83.3%) 1 (16.7%)
8 (100.0%) 0 (0.0%)
8 (100.0%) 0 (0.0%)
Serum iPTH (pg/ml)
Mean SD Median Range
636.7 183.0 655.5 350–813
695.0 345.7 556.5 408–1420
453.5 127.5 415.0 341–726
Serum cCa (mg/dl)
Mean SD Median Range
9.62 0.79 9.25 9.0–10.9
9.80 0.50 9.75 9.2–10.7
Serum P (mg/dl)
Mean SD Median Range
4.95 0.80 4.95 4.0–5.8
5.48 1.35 5.35 3.9–7.5
5.36 1.22 5.60 3.3–6.9
Serum BAP (mg/l)a
Mean SD Median Range
27.90 7.26 27.55 20.2–40.2
35.58 40.78 21.85 10.8–135.0
17.30 9.68 15.70 8.0–37.3
Serum TRACP-5b (mU/dl)a
Mean SD Median Range
821.0 178.1 838.5 504–1050
697.6 355.8 572.0 328–1390
548.5 297.7 488.0 188–1090
Serum FGF23 (pg/ml)a (logarithm)
Mean SD Median Range
7.81 1.53 7.96 5.7–10.2
8.66 2.31 9.64 5.5–11.0
9.54 1.64 9.67 6.6–11.8
Sex
10.20 0.79 10.05 9.4–11.8
BAP, bone alkaline phosphatase; BMI, body mass index; cCa, albumin-corrected Ca; FGF23, fibroblast growth factor23; iPTH, serum intact parathyroid hormone; M, multiple-dose; P, phosphorus; TRACP-5b, tartrate-resistant acid phosphatase5b. a Data obtained for baseline measurements. Kidney International Reports (2017) -, -–-
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a
Plasma etelcalcetide concentration (ng/mL)
1000 2.5 mg (M1) 5 mg (M2)
100
10
1
1
8
15
22 29 36 Day of the study
43
57
50
b Placebo
Etelcalcetide 5 mg (M2)
Etelcalcetide 2.5 mg (M1)
Percent changes in serum iPTH (%)
60.00 40.00
↓↓ ↓ ↓↓ ↓↓ ↓ ↓ ↓↓↓
20.00 0.00 -20.00 -40.00 -60.00 -80.00 1
3
6
8
10
13
15 17
20 22
24
27 29
34 41 55
E
Day of the study
c Placebo
Etelcalcetide 2.5 mg (M1)
Etelcalcetide 5 mg (M2)
15.00 10.00
Percent changes in serum cCa (%)
643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696
↓↓ ↓ ↓↓ ↓↓ ↓ ↓ ↓↓↓
5.00 0.00 -5.00 -10.00 -15.00 -20.00
1
3
6
8
10 13
15 17 20 22
24 27 29
34 41 55
E
Day of the study
Figure 2. Multiple-dose study. Etelcalcetide was injected via the venous blood line after dialysis on days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, and 27 (arrows in b and c) in hemodialysis patients with secondary hyperparathyroidism (SHPT). Blood samples were obtained before each dialysis. (a) Mean (þSD) plasma concentration of etelcalcetide following multiple-dose IV injections. (b) Percent changes in serum intact parathyroid hormone (iPTH) during the study period (multiple-dose IV injections and follow-up). iPTH levels over the study period (from day 1 to day 55). Data are expressed as mean SD. E denotes at the end of the study (day 55) or at withdrawal from the study. (c) Percent changes in serum albumincorrected calcium (cCa) during the study period (multiple-dose IV injections and follow-up). cCa levels over the study period (from day 1 to day 55). Data are expressed as means SD. E denotes at the end of the study (day 55) or at withdrawal from the study. Kidney International Reports (2017) -, -–-
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Table 4. Pharmacokinetic parameters (summary statistics) in multiple-dose study AUClast (ng$h/ml) Cohort (dosage level) n Evaluation date
Cmax (ng/ml)
Mean ± SD
M1 (2.5 mg)
8 7 7
Day 1a Day 27b Day 27/day 1
600 133 151 56 1830 380 168 24 c 3.05 (2.91–3.19) 1.18 (0.86–1.62)c
M2 (5 mg)
8 8 8
Day 1 Day 27 Day 27/day 1
1200 560 315 89 3860 1840 356 143 c 3.20 (2.87–3.57) 1.09 (0.90–1.32)c
AUClast, area under the curve from time 0 to last time point with quantifiable concentration before the next hemodialysis; M, multiple-dose. a First administration day of multiple-dose part of study. b Last administration day of multiple-dose part of study. c Geometric mean (95% confidence interval).
resulted in dose-dependent and sustained reductions of serum iPTH and cCa in Japanese hemodialysis patients with SHPT as well as in a non-Japanese patient population.18–20 Compared with previous studies in non-Japanese patients, this study included patients with serum iPTH much lower than 500 pg/ml, which is the threshold for treatment with calcimimetics such as cinacalcet, according to the guidelines.7 The dosage levels in this study, the single dose at 5, 10, or 20 mg and the multiple dose at 2.5 or 5 mg 3 times weekly for 4 weeks, were also relatively lower compared with previous studies of a single dose at 5 to 60 mg and multiple doses at 5 to 10 mg 3 times weekly for 4 weeks.18,19 There was a consideration to evaluate the possibility that a lower dose might benefit patients with less severe SHPT, thereby preventing disease progression and leading to better prognosis. This study clearly indicated that a multiple doses of 2.5 mg 3 times weekly were effective in reducing serum iPTH in Japanese patients with moderate to severe SHPT. Etelcalcetide lowers PTH and is expected to affect bone metabolism and to lower Ca. It is important to clarify the relation between pharmacokinetics and pharmacodynamic parameters of etelcalcetide to appropriately assess its efficacy and safety. If unstable fluctuations of PTH and Ca are observed, the timing for assessment of efficacy and safety needs to be considered. Etelcalcetide plasma concentrations remained constant from 24 hours after administration to the next dialysis, and were increased with repeated administration. Accordingly, the mean AUClast following the day 27 injection was approximately 3 times higher than the AUClast following the day 1 injection, whereas the mean Cmax following both injections was approximately the same. In the present study, dialysis reduced etelcalcetide plasma concentrations to 30% to 40%. Based on the pharmacokinetics profile of etelcalcetide, a single dose resulted in sustained reductions of serum iPTH and cCa. Similarly, multiple doses for 4 weeks showed sustained reductions despite changes in bone
metabolism biomarkers, such as BAP and TRACP-5b, and marked daily fluctuations of PTH and Ca did not occur. Although cinacalcet has a short half-life and therefore induces diurnal fluctuation of serum iPTH, etelcalcetide may maintain a stable level of serum iPTH. In addition, oral administration of cinacalcet is often associated with gastrointestinal AEs, causing poor patient adherence to the therapy.12–14 To avoid these AEs, various timings of cinacalcet dosing, such as dosing after a meal or before sleep, have been attempted. However, changing the dose timing also affects measured values of serum iPTH and cCa, owing to diurnal fluctuation.22 To ascertain the effects and safety of cinacalcet, iPTH measurements are recommended to be performed before drug administration. Such a requirement might not be necessary for etelcalcetide, because etelcalcetide is administered via the venous blood line after dialysis and because diurnal changes in serum iPTH and cCa in etelcalcetide-treated patients are small. In contrast to the quick reduction in serum iPTH, the effect of etelcalcetide on serum Ca appeared gradually and steadily. It is therefore possible to predict possible hypocalcemia in advance through careful observation. This is an advantage over cinacalcet, which reduces serum Ca 8 to 12 hours after oral administration, expected to be during sleep. Because the timing of blood sampling and measurement affects the evaluation of drug effects, serum Ca was suggested to be evaluated 8 to 12 hours after administration of cinacalcet.23 FGF23 serum level is a known factor that predicts CKD progression and prognosis.1,2 In addition, high FGF23 is associated with mortality, left ventricular hypertrophy, and cardiovascular events independent of P, iPTH, and other clinical factors.5 Although trends toward decreases in FGF23 were shown with etelcalcetide, the amount of exposure was limited in the present study; further investigation with clinical doses will be necessary. Good safety and tolerability profiles were demonstrated for etelcalcetide. In terms of serious AEs, cardiopulmonary arrest reported in the 2.5-mg group of the multiple-dose study, the relationship to treatment was not ruled out, although possible causes included patient background such as aortic valve stenosis/incompetence, and long-term dialysis history of 19 years as well as the increased fluid volume. The event promptly recovered with heart massage and pharmacotherapy. No other AE that led to drug discontinuation was reported except for this patient, and no serious AE was reported in the 5-mg group. Although AEs of nausea and vomiting were not Kidney International Reports (2017) -, -–-
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
a Placebo
Etelcalcetide 5 mg (M2)
Etelcalcetide 2.5 mg (M1)
Percent changes in serum iPTH (%)
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15.00 Percent changes in serum cCa (%)
859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912
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↓Day 1
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5.00 0.00 -5.00 -10.00 -15.00 -20.00
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Figure 3. Percent changes in serum intact parathyroid hormone (iPTH) and albumin-corrected calcium (cCa) during the study period (multipledose IV injections and follow-up). Etelcalcetide was injected via the venous blood line after dialysis on days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, and 27 in hemodialysis patients with secondary hyperparathyroidism (SHPT). Blood samples were obtained before each dialysis. Data are expressed as mean SD. (a) iPTH levels following drug administration (from day 1 to day 3, and from day 27 to day 29). (b) cCa levels following drug administration (from day 1 to day 3, and from day 27 to day 29).
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reported, the amount of exposure was limited in the study; further investigation with clinical doses will be needed. This is the first study in Japanese patients. Study limitations include the small number of patients and the short period of dosing, as the patients had to be hospitalized for frequent and accurate blood collection timing to clarify the relationship between the pharmacokinetics of etelcalcetide and pharmacodynamics. Therefore, more definite quantitative data from a subsequent phase 2 or 3 study extending patient numbers
and treatment duration are required to confirm these observations with statistical evaluation. In conclusion, the present study clarified the relationship between the pharmacokinetics and pharmacodynamics of etelcalcetide, and demonstrated that etelcalcetide produced dose-dependent and sustained reductions in serum iPTH and cCa in Japanese hemodialysis patients with SHPT. The IV injection of etelcalcetide will provide a new alternative drug therapy offering increased compliance and benefits for SHPT in dialysis patients.
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a
Placebo
Percent changes in BAP (%)
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K Yokoyama et al.: Etelcalcetide in Hemodialysis Patients With SHPT
10.00
5 Day 1 Predialysis
Placebo
Day35 29 Predialysis
Etelcalcetide 2.5 mg (M1)
Day65 55 Predialysis
Etelcalcetide 5 mg (M2)
5.00 0.00 -5.00 -10.00 -15.00 -20.00 -25.00
Day 1 Predialysis
Day 29 Predialysis
Day 55 Predialysis
Figure 4. Percent changes in bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase5b (TRACP-5b), and fibroblast growth factor 23 (FGF23) serum levels during the study period (multiple-dose IV injection and follow-up). Etelcalcetide was injected via the venous blood line after dialysis on days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, and 27 in hemodialysis patients with secondary hyperparathyroidism (SHPT). Data are expressed as mean SD. (a) BAP; (b) TRACP-5b; (c) FGF 23.
DISCLOSURE KY, MF, TS, TA, and TA report consultancies with Ono Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin; AF, AY, and MO report employment with Ono Pharmaceutical Co., Ltd.
ACKNOWLEDGMENTS
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This work was funded by Ono Pharmaceutical Co., Ltd., including writing and editing services were provided by ASCA Corporation. The authors thank the Clinical Development Department, Ono Pharmaceutical Co., Ltd., for their assistance in preparing and writing this paper. The investigators were as follows: T. Iitsuka, Ibaraki Seinan Medical Center Hospital; H. Ogura, Kurosawa
Hospital, Bishinkai Medical Corporation; Y. Kanamaru, Clinique Soigner; K. Oguchi, Ikegami General Hospital, Medical Corporation Showakai; T. Suzuki, Suzuki Urology Clinic; Y. Kanno, Kanno Dialysis & Vascular Access Clinic; H. Shimosaka, Tajimi Clinic, Hakuyoukai Medical Corporation; M. Horie, Daiyukai Daiichi Hospital; H. Kasuga, Nagoya Kyoritsu Hospital and Kaikoukai Central Clinic, Kaikoukai Medical Group; K. Harada, Kasaoka Daiichi Hospital; and S. Funakoshi, Nagasaki Jin Hospital, Japan.
SUPPLEMENTARY MATERIAL Q5 Figure S1. Participant flow. Supplementary material is linked to the online version of the paper at http://www.kireports.org. Kidney International Reports (2017) -, -–-
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