http://www.kidney-international.

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clinical investigation

& 2013 International Society of Nephrology

AMG 416 (velcalcetide) is a novel peptide for the

treatment of secondary hyperparathyroidism in a
single-dose study in hemodialysis patients
Kevin J. Martin1, Karen Pickthorn2, Saling Huang2, Geoffrey A. Block3, Andrew Vick4, Peter F. Mount5,
David A. Power5 and Gregory Bell2,6
1

Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA; 2Amgen, Inc, Thousand Oaks,
California, USA; 3Denver Nephrology, Denver, Colorado, USA; 4WIL Research, Ashland, Ohio, USA; 5Austin Hospital, Melbourne,
Victoria, Australia and 6University of California, San Francisco, California, USA

AMG 416 (velcalcetide), a novel peptide agonist of the

calcium-sensing receptor, lowers plasma parathyroid hormone
in preclinical uremic animal models and in normal healthy
individuals. Here, we studied its efficacy in hemodialysis
patients suffering from secondary hyperparathyroidism. Major
inclusion criteria were hemodialysis for at least 3 months,
serum parathyroid hormone over 300 pg/ml, a corrected
serum calcium of 9.0 mg/dl or more, and stable doses of
vitamin D analogs for at least 3 weeks prior to screening.
Twenty-eight patients were enrolled in one of five cohorts
(5, 10, 20, 40, 60 mg). Cohorts 13 (four patients each) were
treated in a two-period crossover design, while cohorts 4 and
5 (eight patients each) were randomized 1:1 to AMG 416 or
placebo. Patients were admitted to a clinical research unit
following hemodialysis and studied for 3 days prior to
discharge for hemodialysis. Single intravenous doses of AMG
416 from 5 to 60 mg were well tolerated, and plasma levels
increased in a dose-related manner. AMG 416 treatment was
associated with significant, dose-dependent reductions in
serum parathyroid hormone and fibroblast growth factor 23.
Compared with placebo, all dose groups of 10 mg or more
were associated with attenuation in the rise in serum
phosphate during the interdialytic period. Dose-dependent
reductions in serum calcium were observed and were well
tolerated. Thus, AMG 416 represents a novel therapeutic
approach for the treatment of secondary hyperparathyroidism
in hemodialysis patients.
Kidney International (2013) 85, 191197; doi:10.1038/ki.2013.289;
published online 31 July 2013
KEYWORDS: bone; calcium; calcium-sensing receptor; hemodialysis; hyperparathyroidism; parathyroid hormone

Correspondence: Kevin J. Martin, Division of Nephrology, Saint Louis

University School of Medicine, Saint Louis, Missouri 63107, USA.
E-mail: martinkj@slu.edu
Received 27 March 2013; revised 5 June 2013; accepted 13 June 2013;
published online 31 July 2013
Kidney International (2014) 85, 191197

Secondary hyperparathyroidism (SHPT) is a complex

disorder associated with chronic kidney disease (CKD) in
which the impairment of mineral homeostasis (calcium and
phosphate) and vitamin D (1,25(OH)2D3) metabolism leads
to excessive parathyroid hormone (PTH) levels. These
changes begin early in CKD and gradually worsen as CKD
progresses to end-stage renal disease.1 Elevated PTH levels
further exacerbate the disturbances in mineral metabolism
and are linked to a variety of deleterious physiological effects
including bone remodeling disorders, vascular calcification,
and left ventricular hypertrophy. Increased levels of PTH,
calcium, and phosphate are associated with an increased risk
for cardiovascular events, hospitalization, all-cause and cardiovascular mortality.29 The importance of the appropriate
management of SHPT and the associated mineral disturbances is underscored by the various clinical practice
guidelines used to manage this disorder.1014
Treatment of SHPT in dialysis patients is complex and
has relied on several approaches, including normalization of
serum calcium, control of hyperphosphatemia, and treatment with nutritional and active vitamin D.1,3 Dietary phosphorus restriction and oral phosphate binders are typically
prescribed to reduce serum phosphate levels; however, they do
not consistently normalize serum phosphate. Exogenously
administered vitamin D analogs can decrease PTH gene
transcription as well as increase calcium (and phosphate)
absorption from the gut, thereby decreasing PTH synthesis
and secretion.15,16 However, vitamin D use is often limited by
the development of hypercalcemia and hyperphosphatemia,
leaving many patients with elevated PTH levels and poorly
controlled calcium and phosphorus. PTH secretion by the
parathyroid gland is primarily controlled by the action of
a cell-surface calcium-sensing receptor (CaSR) residing on
parathyroid chief cells.17,18 Activation of the CaSR by calcium
or by calcimimetics reduces PTH secretion from the
parathyroid gland, lowering serum intact PTH (iPTH). Thus,
with the introduction of the calcimimetic, cinacalcet
hydrochloride, in 2004, a more direct approach to control
PTH in SHPT became available. Treatment with cinacalcet, an
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KJ Martin et al.: AMG 416 (velcalcetide) in hemodialysis subjects

Table 1 | Demographics and baseline chemistries

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Total N 28

4
54.3 (10.4)
56 (4065)

4
59.0 (14.5)
60.5 (4075)

4
52.8 (21.2)
46.5 (3583)

8
52.9 (14.6)
53.5 (2878)

8
47.5 (10.9)
49.0 (2860)

28
52.4 (13.6)
53.0 (2883)

Sex (n, %)
Male
Female

3 (75)
1 (25)

4 (100)
0

3 (75)
1 (25)

4 (50)
4 (50)

6 (75)
2 (25)

20 (71)
8 (29)

Race (n, %)
White
African American
Asian

1 (25)
2 (50)
1 (25)

0
4 (100)
0

1 (25)
3 (75)
0

0
8 (100)
0

1 (13)
7 (88)
0

3 (11)
24 (86)
1 (4)

4
7.15 (4.51)
6.48 (2.712.9)

4
9.43 (3.96)
11.31 (3.511.6)

8
5.45 (6.72)
3.35 (0.721.8)

8
4.59 (2.57)
4.02 (0.98.9)

28
6.35 (5.01)
4.35 (0.721.8)

4 (100)
0

2 (50)
2 (50)

3 (75)
1 (25)

8 (100)
0

6 (75)
2 (75)

23 (82)
5 (18)

449.8 (96.4)
419.7 (373.5586.5)

632.0 (254.8)
562.7 (420.0982.5)

1609.8 (1577.4)
880.2 (711.53967.5)

910.8 (934.7)
645.2 (315.53179.5)

820.9 (213.1)
830.7 (496.51116.5)

879.3 (799.8)
704.5 (315.53967.5)

1.10 (0.05)
1.11 (1.01.1)

1.13 (0.09)
1.13 (1.01.2)

1.04 (0.05)
1.03 (1.01.1)

1.01 (0.05)
1.01 (0.91.1)

1.06 (0.06)
1.04 (0.91.2)

10.0 (0.14)
10.05 (9.810.1)

10.5 (0.89)
10.2 (9.811.8)

9.45 (0.4)
9.4 (8.810.0)

9.46 (0.77)
9.35 (8.510.9)

9.68 (0.68)
9.8 (8.511.8)

Age (years)
N
Mean (s.d.)
Median (range)

Duration of hemodialysis (years)

N
4
Mean (s.d.)
7.76 (6.48)
Median (range)
5.36 (3.117.2)
Active vitamin D use (n, %)
Yes
No
iPTH (pg/ml)
Mean (s.d.)
Median (range)

Ionized calcium (mmol/l)

Mean (s.d.)
Median (range)

1.08 (0.02)
1.07 (1.11.1)

Corrected calcium (mg/dl)

Mean (s.d.)
9.45 (0.5)
Median (range)
9.5 (8.810.0)
Phosphate (mg/dl)
Mean (s.d.)
Median (range)

3.15 (0.26)
3.07 (2.93.5)

3.28 (1.37)
3.01 (2.05.1)

3.92 (0.66)
3.76 (3.34.8)

3.02 (0.84)
3.07 (1.84.1)

3.74 (0.65)
3.76 (2.54.8)

3.41 (0.83)
3.5 (1.85.1)

Log FGF23
Mean (s.d.)
Median (range)

8.87 (1.86)
9.27 (5.1611.85)

7.43 (2.09)
6.87 (5.7610.21)

9.14 (2.37)
10.08 (6.4510.89)

9.29 (2.20)
10.16 (6.0610.79)

9.02 (0.74)
8.94 (8.2110.00)

9.65 (0.77)
9.89 (8.5510.27)

Abbreviations: FGF23, fibroblast growth factor 23; iPTH, intact parathyroid hormone.
Subjects in cohort 1 received 5 mg AMG 416 and placebo in a crossover design.
Subjects in cohort 2 received 10 mg AMG 416 and placebo in a crossover design.
Subjects in cohort 3 received 20 mg AMG 416 and placebo in a crossover design.
In cohort 4, four subjects received 40 mg AMG 416 and four subjects received placebo.
In cohort 5, four subjects received 60 mg AMG 416 and four subjects received placebo.

allosteric agonist of the CaSR, results in an immediate left shift

in the calciumPTH curve. It has been demonstrated in
numerous clinical trials that cinacalcet reduces PTH levels,
while simultaneously reducing serum calcium and phosphate.19
AMG 416 is a novel, long-acting 8-amino-acid peptide
agonist of the CaSR.20,21 AMG 416 directly activates the CaSR
with activity in the presence or absence of ambient serum
calcium, a mechanism of action distinct from that of cinacalcet
hydrochloride. Intravenous administration of AMG 416 to
uremic animals reduced serum PTH and attenuated
parathyroid hyperplasia and soft tissue calcification in a
dose-dependent manner.20,21 Furthermore, intravenous
administration of AMG 416 to healthy male subjects was
shown to be safe, well tolerated, and to reduce serum iPTH
in a dose-dependent manner.22 Similarly, AMG 416 reduced
serum fibroblast growth factor 23 (FGF23) levels, a
phosphaturic hormone, in a dose-dependent manner in
healthy male subjects. FGF23, acting via the Klotho-FGF
receptor 1,23,24 is important in the bonekidney axis control192

ling phosphorus homeostasis and vitamin D metabolism but

more recently appears to have a role in the pathogenesis of
SHPT and left ventricular hypertrophy.2527
The present study was conducted, therefore, to assess
the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single doses of AMG 416 administered
by intravenous (IV) bolus injection to hemodialysis subjects
with SHPT.
RESULTS

Twenty-eight male and female subjects were randomized into

five dose cohorts. Dose escalation was stopped when the
maximum dose, 60 mg, was reached. Demographics and
baseline blood chemistries (obtained post-dialysis and within
30 min before dosing) varied across cohorts consistent with
the small sample size (Table 1). Baseline serum phosphate
levels ranged from 1.8 to 5.1 mg/dl (mean 3.41 mg/dl),
reflecting phosphate clearance during hemodialysis. To
control for the variability in baseline chemistry levels and
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KJ Martin et al.: AMG 416 (velcalcetide) in hemodialysis subjects

Table 2 | Adverse events

Dose cohort
Placebo

5 mg

10 mg

20 mg

40 mg

60 mg

Number of subjects dosed

Number of subjects with X1 adverse event

20
2 (10%)

4
1 (25%)

3
1 (33%)

4
1 (25%)

4
4 (100%)

4
2 (50%)

Adverse event (preferred term)

Calcium ionized decreased
Paresthesias
Gastroesophageal reflux
Toothache
Anemia
Cardiac failure, congestive
Injection site pruritis
Pneumonia

0
1
0
0
1
1
0
1

0
1
1
0
0
0
0
0

1
0
0
0
0
0
0
0

0
0
0
1
0
0
0
0

(0%)
(0%)
(0%)
(25%)
(0%)
(0%)
(0%)
(0%)

4
1
0
0
0
0
1
0

2
0
0
0
0
0
0
0

Placebo
5 mg
10 mg

20 mg
40 mg
60 mg

(0%)
(5%)
(0%)
(0%)
(5%)
(5%)
(0%)
(5%)

(0%)
(25%)
(25%)
(0%)
(0%)
(0%)
(0%)
(0%)

(100%)
(25%)
(0%)
(0%)
(0%)
(0%)
(25%)
(0%)

(50%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%)

20
Placebo
5 mg
10 mg

40

20 mg
40 mg
60 mg

Percent change from baseline in

ionized calcium

Percent change from baseline in

intact PTH (%)

60

(33%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%)

20
0
20
40
60
80

10

10

20

100
0

10

20

30
40
Hours

50

60

70

10

20

30
40
Hours

50

60

70

Figure 1 | Percentage change from baseline in serum intact

parathyroid hormone (iPTH) levels. Time 0 h is 24 h after
hemodialysis and before dosing. Data are shown as means.e.m.

Figure 2 | Percentage change from baseline in plasma-ionized

calcium following single intravenous doses of AMG 416 or
placebo. Time 0 h is 24 h after hemodialysis and before dosing.
Data are shown as means.e.m.

facilitate between-group comparisons, the treatment effect is

presented as a percentage change from baseline.
Single doses of AMG 416 administered by IV bolus were
well tolerated (Table 2). No serious AEs were reported in
subjects receiving AMG 416. One serious AE of severe
congestive heart failure complicated by uncontrolled hypertension and anemia occurred in a subject following treatment
with placebo in Cohort 2; the subject was withdrawn from
the study and did not receive treatment with AMG 416. The
most frequent treatment-emergent adverse event (TEAE) was
asymptomatic decreased ionized calcium level, an expected
consequence of the pharmacological effect of AMG 416 on
the CaSR. Seven subjects treated with AMG 416 developed
asymptomatic hypocalcemia, six of whom received a dose of
either 40 or 60 mg. Two subjects reported paresthesia as a
TEAE; one subject reported paresthesia during both the
AMG 416 and placebo treatment periods in Cohort 1. In
both subjects, paresthesia was mild in intensity and resolved
without treatment.
Mean baseline iPTH values varied across the treatment
groups ranging from 431 to 1555 pg/ml. Treatment with AMG

416 resulted in dose-dependent decreases in iPTH (Figure 1).

The decreases in iPTH occurred within 30 min of dosing, as
decreases were observed at the first post-dose sampling time
point. The mean maximal change from baseline in iPTH was
 64%,  73%,  75%,  84%, and  86% at the 5, 10, 20,
40, and 60 mg dose levels, respectively. These decreases were
most pronounced during the first 2448 h post dose and
persisted longer as the dose increased. At discharge from the
clinical research unit, the mean percentage change values from
baseline in iPTH were  48.5%,  49.3%, and  62.6% for
the 20, 40, and 60 mg dose groups, respectively. Consistent
with the long terminal half-life (see below), the mean serum
iPTH in the 40- and 60-mg treatment groups remained below
baseline levels 4 weeks post dose.
There were no changes in the mean plasma-ionized
calcium level in the placebo or the AMG 416 5-mg group
over the 3-day observation period. Decreases in plasmaionized calcium were observed in the 10 mg (up to B6%),
20 mg (up to B7%), 40 mg (up to B5%), and 60 mg (up to
B13%) dose groups (Figure 2). In general, plasma-ionized
calcium levels had decreased by the 8-h time point and had

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KJ Martin et al.: AMG 416 (velcalcetide) in hemodialysis subjects

10,000
Placebo
5 mg
10 mg

140

20 mg
40 mg
60 mg

AMG 416 concentration (g/l)

Percent change from baseline in

phosphorus (%)

160

120
100
80
60
40
20
0
0

10

20

30
40
Hours

50

60

70

Figure 3 | Percentage change from baseline in serum phosphate

levels following single intravenous doses of AMG 416 or placebo
over the course of the study. Data are shown as means.e.m.

Percent change from baseline in

log of FGF23

40 mg
60 mg

1000

100

10

20

Placebo
5 mg
10 mg

10

20 mg
40 mg
60 mg

10
0

10

20

30
40
Hours

50

60

70

Figure 4 | Percentage change from baseline in serum log

fibroblast growth factor 23 (FGF23) levels following single
intravenous doses of AMG 416 or placebo. Data are shown as
means.e.m.

returned toward baseline by discharge, except in the 60-mg

group where plasma-ionized calcium levels remained
below pre-dose levels at discharge. Three (75%) subjects in
the AMG 416 40- and 60-mg treatment groups had
at least one plasma-ionized calcium level below 0.9 mmol/l
at any time during the study. Changes in serum albumincorrected calcium were consistent with the changes observed
in plasma-ionized calcium. Changes in QT interval were
observed to correlate with hypocalcemia and not with drug
concentration.
Baseline serum phosphate level, measured at the end of
dialysis and before dosing, was low, reflecting the effects of
hemodialysis on phosphate clearance. Serum phosphate levels
increased from pre-dose levels throughout the sampling
period in the placebo group and all active dose groups.
Compared with placebo, treatment with AMG 416 at doses
194

5 mg
10 mg
20 mg

10

20

30
40
Hours

50

60

70

Figure 5 | Mean AMG 416 plasma concentrations (ng/ml) time

course following single intravenous doses of AMG 416 to
hemodialysis subjects with secondary hyperparathyroidism
(SHPT). Data are shown as means.e.m.

X10 mg reduced the increase in serum phosphate levels over

the observation period. In placebo-treated subjects, mean
serum phosphate levels increased rapidly during the first 32 h
post dose, after which mean serum phosphate levels appeared
to plateau (Figure 3). When expressed as a percentage change
from baseline in serum phosphate levels, administration of
AMG 416 at doses X10 mg was associated with an
attenuation of the initial increase in serum phosphate levels
and a lower plateau level during the 3-day observation
period. At discharge from the clinical research unit, the
percentage increase in serum phosphate levels in subjects
receiving 1060 mg AMG 416 was 2460% lower than
placebo. The mean absolute increase in serum phosphate
levels during the observation period (i.e., change from
baseline at discharge) was 2.56, 2.58, 0.89, 1.95, 1.84, and
2.09 mg/dl for the placebo and 5, 10, 20, 40, and 60 mg/dl for
the AMG 416 groups.
Intravenous administration of AMG 416 at doses X10 mg
to hemodialysis subjects with SHPT was associated with
sustained dose-dependent decreases in serum FGF23 levels
(Figure 4).
Pharmacokinetics

Following IV bolus administration to hemodialysis subjects,

AMG 416 was eliminated from plasma in a polyphasic
manner. Plasma AMG 416 concentrations quickly declined
from peak levels initially but remained detectable over a
sampling period of B65 h post dose across the dose range
evaluated (Figure 5). Systemic plasma exposure of AMG 416
(as assessed by Cmax and interdialytic AUC065 h) increased in
a dose-related manner over the dose range evaluated, and the
observed increase in total exposure (as assessed by AUC065 h)
appeared to be reasonably proportional to dose (Table 3).
Estimates of elimination half-life over the interdialytic
period (over a sampling period of B65 h) appeared to be
dose independent over the dose range evaluated with
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KJ Martin et al.: AMG 416 (velcalcetide) in hemodialysis subjects

Table 3 | Summary of human plasma AMG 416 pharmacokinetic parameters from hemodialysis subjects
Dose (mg)

No. of subjects

Parameter

Cmax (lg/l)

AUC065 h(lg h/l)

t1/2 (h)

Cohort

10

20

40

60

Geometric mean
CV% geometric mean
Geometric mean
CV% geometric mean
Geometric mean
CV% geometric mean
Geometric mean
CV% geometric mean
Geometric mean
CV% geometric mean

133
55.8
257
25.8
479
41.0
686
40.8
1080
39.6

1080
16.9
2770
15.6
4680
31.8
8890
31.3
14,800
41.3

121
43.6
81.7
31.9
175
44.4
NC
NC
115
27.4

Abbreviations: AUC065 h, area under the curve between the time of dose and the last time point; Cmax, maximum observed plasma concentration; CV, coefficient of
variation; NC, not calculated; t1/2, terminal elimination phase half-life.

geometric mean values ranging from 81.7 to 175 h (Table 3).

On the basis of limited PK sampling through 4 weeks post
dose in cohorts 4 and 5, the terminal elimination half-life
exceeds 7 days.
AMG 416 clearance during hemodialysis generally followed a first-order elimination process with an estimated
mean hemodialysis clearance value of B33 l/h across the
doses evaluated. Residual plasma drug levels were observed
after repeat hemodialysis sessions, consistent with the long
terminal half-life of AMG 416 in this patient population and
incomplete clearance of drug by hemodialysis.
No subject developed antibodies to AMG 416 during the
treatment or follow-up period.
DISCUSSION

Our current findings demonstrate that IV injection of AMG

416 effectively reduces serum iPTH levels in hemodialysis
subjects with SHPT. Treatment with AMG 416 resulted in
profound, dose-dependent decreases in serum iPTH levels.
These decreases were evident 8 h post dose, were most
pronounced during the first 2448 h post dose, and persisted
longer as the dose increased. The duration of serum iPTH
suppression tended to increase with dose and exceeded the
3-day interdialytic period following single doses of AMG 416
X20 mg. Consistent with the sustained suppression of serum
iPTH, the geometric mean elimination half-life was estimated
to be ranging from 3 to 7 days over the interdialytic sampling
period with true terminal elimination phase half-life value
greater than 7 days. The long half-life and sustained duration
of PTH suppression are distinct from the effects of cinacalcet
hydrochloride and suggest that a three-times-weekly dosing
of AMG 416 is likely to result in consistent, sustained PTH
reductions throughout the interdialytic interval. The reduction in serum iPTH was associated with modest reductions in
ionized calcium and with an attenuation in the increase in
serum phosphate levels that occurs during the interdialytic
period. These data indicate that AMG 416 may be an effective
treatment of SHPT in hemodialysis patients by simultaneously improving the control of serum iPTH, calcium, and
phosphate levels.
Single doses of AMG 416 administered as an IV bolus
to hemodialysis subjects with SHPT appeared to be well
Kidney International (2014) 85, 191197

tolerated. One serious AE occurred in a subject treated with

placebo and the subject was discontinued from the study
before receiving AMG 416. The most common AE in the
AMG 416 treatment groups was asymptomatic hypocalcemia,
which is consistent with the mechanism of action at the
CaSR.19 Importantly, despite substantial and sustained
reductions in serum iPTH, nausea and vomiting were not
observed in this study in AMG 416-treated subjects.19,28
Potential mechanisms to be considered might be the failure
of AMG 416 to cross the bloodbrain barrier (if nausea and
vomiting are centrally mediated) and/or whether IV administration did not result in activation luminal gastric CaSRs
(if the symptoms are locally mediated). Long-term exposure
to AMG 416 will be required to assess whether the lack
of symptomatic gastrointestinal side effects is consistently
observed. Given the common occurrence of nausea and
vomiting with chronic administration of cinacalcet hydrochloride, this may be an important distinction of AMG 416.
AMG 416 substantially lowered serum FGF23 levels
concomitantly with reductions in serum calcium, phosphate,
and iPTH levels. This is consistent with a previous study with
cinacalcet in hemodialysis patients and with emerging data
that PTH directly stimulates osteoblast production of
FGF23.29 Active vitamin D is a potent stimulator of FGF23
production in osteoblasts;30,31 however, it is unlikely that the
decrease in FGF23 levels can be attributed to lower exposure
to active vitamin D, as active vitamin D was maintained at
stable doses during the study. Increases in serum FGF23 levels
in CKD patients have been associated with progression of
CKD,32 vascular calcification,33 left ventricular hypertrophy,27 and increased mortality.34
AMG 416 has several characteristics that may improve
the management of mineral and bone disorders associated
with CKD. AMG 416 is a long-acting CaSR agonist resulting
in sustained suppression of iPTH throughout the interdialytic period. The long duration of action could potentially
provide more consistent control of serum iPTH, phosphate,
and FGF23 levels over the 2- to 3-day dosing interval.
In addition, the IV route of administration will improve compliance and ensure appropriate utilization of AMG 416. The
IV route also allows flexibility in dose titration and is likely to
have more consistent and predictable pharmacokinetics
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clinical investigation

compared with oral therapy. Compared with oral calcimimetics, the IV route of administration for AMG 416 will be
associated with lower luminal gastrointestinal exposure,
potentially reducing gastrointestinal AEs, a major reason
for discontinuing oral therapy in this patient population.28
Animal studies indicate that AMG 416 does not cross the
bloodbrain barrier, potentially reducing the risk of central
nervous systemrelated toxicity. In addition, in vivo and
in vitro studies demonstrate that AMG 416 neither inhibits
nor induces any of the major hepatic P450 isoforms
potentially reducing the risk of drugdrug interactions in a
patient population with significant comorbidities and concomitant medications.
In summary, the present study indicates that single IV
bolus doses of AMG 416 from 5 to 60 mg were well tolerated.
AMG 416 was associated with dose-dependent suppression of
serum iPTH and FGF23 levels and a significant attenuation in
the increase in serum phosphate levels during the interdialytic
period. Both the extent and duration of iPTH suppression
coupled with a prolonged plasma half-life support a threetimes-weekly dosing, likely toward the lower end of the range
of doses used in the present studies to avoid oversuppression
of iPTH. Further studies will be required to evaluate dose and
dose interval in this patient group. The present clinical finding
supports the continued development of AMG 416 to manage
disturbances in iPTH, calcium, phosphate, and FGF23 levels
in hemodialysis patients with SHPT.

MATERIALS AND METHODS

The study protocols were reviewed and approved by Austin Health
Human Research Ethics Committee and Schulman Associates
Institutional Review Board. Written informed consent was obtained
from each subject before screening. Subjects enrolled in this
study were 18 years of age or older, receiving hemodialysis three
times a week for at least 3 months, and on stable doses of active
vitamin D analogs for at least 3 weeks before screening. The
main eligibility criteria were a screening iPTH level X300 and
o1200 pg/ml for cohorts 13, serum-corrected calcium level
X9.0 mg/dl, and a hemoglobin level X9.5 g/dl. For cohorts 4 and
5, screening iPTH level was changed toX400 pg/ml because of
the profound decrease in iPTH observed in the prior cohorts and
the desire not to oversuppress iPTH for a prolonged period of time.
In cohorts 13, dialysate calcium levels were 1.25 mmol/l in eight
patients, 1.3 mmol/l in three, and 1.75 mmol/l in one and remained
unchanged in the crossover in all but one patient in whom the
dialysate calcium level was changed from 1.3 to 1.25 mmol/l for the
placebo arm (one patient did not crossover due to a serious AE). In
cohorts 4 and 5 (16 patients), five patients had a dialysate calcium of
1 mmol/l in the AMG 416 group compared with six in the placebo
arm, three used 1.25 mmol/l in the AMG 416 arm compared with
one in the placebo group. One patient used dialysate calcium of
1.75 mmol/l in the placebo arm.
Dialysis times varied from 3.5 to 5 h in individual patients and did
not change significantly between the arms. The dialysers used were
Optiflux (FMC, Waltham, MA) 180 NR in 21 patients, Optiflux 200
in 3 patients, Gambro (Lund, Sweden) 210H in 3 patients, and
Optiflux 160 NR in 1 patient and did not change between arms.
196

KJ Martin et al.: AMG 416 (velcalcetide) in hemodialysis subjects

Dialysis dose was not quantitated for these treatments, although

dialysis times and dialyzers were not changed.
Major exclusion criteria included symptomatic ventricular
dysrhythmias or Torsades de Pointes, uncontrolled hypertension,
and a history of angina pectoris or congestive heart failure (New
York Heart Association Class III or IV). Subjects were also excluded
for having a history of myocardial infarction, coronary angioplasty,
or coronary arterial bypass grafting in the last 6 months, seizures in
the last 12 months, parathyroidectomy in the last 3 months, significant pre-study clinical or laboratory safety abnormalities, or treatment with cinacalcet in the 3 weeks before the first dose of study drug.
The study was a double-blind, randomized, placebo-controlled,
multicenter study in subjects with SHPT receiving hemodialysis.
The starting dose, 5 mg, was the dose from a phase 1 study in
healthy volunteers that resulted in a modest mean maximal
reduction in corrected calcium (9.8%) and iPTH with minimal
adverse effects. Dose escalation proceeded to 10, 20, 40, and 60 mg.
AMG 416 or placebo (sterile 0.9% NaCl) was administered by IV
bolus injection 24 h following completion of hemodialysis.
Subjects remained confined in the clinical research unit until
their next regularly scheduled dialysis session (B72 h). This allowed
for the assessment of the effects of AMG 416 in the long interdialytic
period without the influence of dialysis. In addition, intravenous
drugs are typically administered at the end of a dialysis treatment.
Thus, the administration of the drug at this time would be relevant to
clinical practice.
Cohorts 13 were conducted with a two-period crossover design.
Each crossover cohort enrolled four subjects randomized 1:1 to
AMG 416 followed by placebo or placebo followed by AMG 416.
There were 714 days between study drug administrations in period
1 and period 2. Because of the detection of residual AMG 416
following the first post-dose hemodialysis session and the potential
for carryover effects with the crossover design, the study design was
modified for cohorts 4 and 5 with eight subjects randomized 1:1 to
either AMG 416 or placebo in each cohort.
Subjects were observed in the clinical research unit for B3 days
after study drug administration in each period. Clinical AEs, physical
examinations, vital signs, and 12-lead electrocardiographies were
monitored during the confinement period and for up to 4 weeks
following dosing. Hematology, coagulation, and serum chemistry,
iPTH (ECLIA on the Roche Elecsys analyzer (Roche Diagnostics
USA, Indianapolis, IN) (normal range 1565 pg/ml)) and FGF23
(FGF23 ELISA Kit, Kainos Labs, Tokyo, Japan) were assayed at
clinical reference laboratories according to the vendors instructions.
Blood was collected into heparin-evacuated tubes and ionized
calcium analyzed within 10 min using the i-STAT System (Abbott
Labs, Abbott Point of Care, Princeton, NJ) (normal range
1.121.32 mmol/l). Plasma samples for pharmacokinetics were
drawn at pre-specified time points, including a sample after the
hemodialysis session that followed discharge from the phase 1 unit
(all cohorts) and on days 8, 15, and 29 (cohorts 4 and 5), and
were analyzed using a validated liquid chromatography/mass
spectrometry method. Pharmacokinetic parameters were estimated
using a model-independent method using WinNonlin, version 5.2
(Pharsight Corp, Mountain View, CA).
Serum samples for antibodies to AMG 416 were drawn at four
time points for cohorts 13: before study drug administration in the
first period, 710 days after study drug administration in each
period, and 2128 days after study drug administration in the
second period. For cohorts 4 and 5, serum samples for antibodies
to AMG 416 were drawn at three time points: before study drug
Kidney International (2014) 85, 191197

clinical investigation

KJ Martin et al.: AMG 416 (velcalcetide) in hemodialysis subjects

administration and 710 days and 2128 days after study drug
administration. Evaluation of the safety data for each cohort
preceded randomization to the next higher-dose cohort.
Statistical analysis
Data from all randomized subjects were included in the analyses.
Summaries of subject disposition, demographics, and baseline
characteristics were examined by dose group.
All reported AEs were coded to a standard set of terms, using the
Medical Dictionary for Regulatory Activities. A TEAE was defined as
an AE that occurred after the start of study medication administration or that was present before the start of study medication
administration but increased in severity or frequency after treatment.
Summaries of the incidence of TEAEs were presented by dose group.
The mean percentage change in serum iPTH, calcium, and
phosphate concentrations were plotted versus time for each AMG
416 dose level and for the pooled placebo group. Calcium levels were
adjusted for albumin levels below 4.0 mg/dl with the equation:
corrected calcium (cCa) [measured calcium (Ca) in mg/dl]
[4  (albumin in g/dl)]0.8. The doseresponse trend in iPTH,
FGF23, cCa, and phosphate reductions was examined by fitting a
first-order regression equation where percentage change from
baseline is modeled as a function of AMG 416 dose.
DISCLOSURE

The original work presented in this manuscript was sponsored by KAI

Pharmaceuticals, a wholly owned subsidiary of Amgen. KJM, GAB,
PFM, DAP, and AV and have received consulting fees from KAI
Pharmaceuticals. GB, KP, and SH were employees of KAI Pharmaceuticals, a wholly owned subsidiary of Amgen, Thousand Oaks, CA,
at the time this study was conducted. The other authors declare no
competing interests.
ACKNOWLEDGMENTS

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

We thank the investigators, staff, and patients who participated in the

study. David Martin, PhD, assisted in the preparation of the manuscript.

23.

DISCLAIMER

24.

This work has not been presented elsewhere except in the abstract
form at American Society of Nephrology 2011.

25.
26.

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