Pharmacokinetics, Biotransformation, and Excretion of [14C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis
Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven d-aminoacids with an l-cysteine linked to a d-cysteine by a disulfide bond. A single intravenous dose of [14C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [14C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide d-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and l-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.
Hemodialysis was the predominant clearance and elimination pathway of etelcalcetide following a single dose of [14C]etelcalcetide in chronic kidney disease patients on hemodialysis.
Biotransformation resulted from reversible disulfide exchange with endogenous thiols, and the etelcalcetide d-amino acid backbone was preserved.
The majority of circulating etelcalcetide-related biotransformed moieties existed as serum albumin peptide conjugate (SAPC).
After removal of plasma etelcalcetide by dialysis, re-equilibration between SAPC and l-cysteine present in blood partially restored predialysis concentrations of etelcalcetide.
Calcimimetics are a class of drugs that activate the parathyroid calcium-sensing receptor (CaSR) to inhibit parathyroid hormone (PTH) secretion [1, 2]. Dysregulation of CaSR signaling plays an important role in the development of secondary hyperparathyroidism (SHPT), a frequent comorbidity for patients with chronic kidney disease (CKD) that is characterized by elevated PTH levels, mineral disturbances, and increased risk of complications and death .
Pharmacokinetic profiles of etelcalcetide and [14C]etelcalcetide-derived radioactivity (referred to as ‘total C-14’) in rat plasma showed a multiphase decline with a long terminal half-life (t½) . In rats with intact kidneys, total C-14 following a single intravenous dose was predominantly excreted in urine (77–84 % of administered dose; approximately 90 % of recovered dose). In bilaterally nephrectomized rats, recovery of total C-14 was low and elimination by nonrenal pathways was slow. Etelcalcetide biotransformation occurred in whole blood primarily by disulfide exchange with endogenous thiol-containing molecules; the d-amino acid backbone was unaltered. The predominant biotransformation product present in plasma was a covalently bound serum albumin peptide conjugate (SAPC) .
In clinical studies, the importance of renal clearance was indicated by a prolonged etelcalcetide t½ in patients with CKD on hemodialysis (81.7–175 h) compared with healthy volunteers (18.4–20.0 h) [6, 7, 8]. These findings were consistent with the role of renal clearance determined in rats . Based on the nonclinical findings that biotransformation of etelcalcetide only occurs by reversible disulfide exchange , and because renal clearance is the primary mechanism of elimination in animals and humans with intact renal function [5, 7], dialytic clearance was expected to be the main elimination pathway in patients with limited or no kidney function undergoing hemodialysis. In previous clinical studies [8, 10, 11], the duration of pharmacokinetic data collections was limited and the effect of hemodialysis on the pharmacokinetics of etelcalcetide was unknown.
This study was conducted to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in patients with CKD on hemodialysis. A therapeutic dose was administered that contained a microtracer quantity of [14C]etelcalcetide in order to limit patient exposure to C-14 and to facilitate study conduct in a dialysis clinic. The microtracer approach necessitated using accelerator mass spectrometry (AMS) to achieve the sensitivity required for quantification of the low concentrations of radioactivity excreted in the large volumes of dialysate and other biomatrices over the long study duration.
2 Materials and Methods
2.1 Radiolabeled Drug and Formulation
[14C]etelcalcetide drug substance (Fig. 1; hydrochloride salt; specific activity 70.9 nCi/mg of etelcalcetide freebase; high-performance liquid chromatography [LC] purity 99.5 %) was synthesized at Amgen Inc. (Thousand Oaks, CA, USA). The C-14 label was placed on the carbonyl carbon of the N-acetyl moiety in the d-amino acid backbone and the stability of the radiolabel at this position was demonstrated in nonclinical studies . The drug substance was formulated as a single 10 mg dose of etelcalcetide with 26.3 kBq (710 nCi; approximately 10 µg) of [14C]etelcalcetide in 2 mL liquid solution for bolus intravenous administration at the end of hemodialysis. The formulation was a sterile, preservative-free, aqueous solution containing 0.85 % sodium chloride, and 10 mM succinic acid, in a single-use 5 mL type 1 glass vial. The drug product vial for each patient was prepared at the clinical site by combining the drug substance in the liquid formulation and contained 4 mL of clear, colorless solution with AMG 416 concentration of 5 mg/mL at a final pH of 3.3.
2.2 Study Design and Objectives
The specific objectives of the study were (i) to determine the rate, extent, and routes of radioactivity excretion of [14C]etelcalcetide in feces, dialysate, and urine over time; and (ii) to measure radioactivity concentrations in whole blood and plasma over time. Secondary objectives were to (i) measure etelcalcetide concentrations in plasma for comparison with total C-14 concentrations; (ii) evaluate the safety and tolerability of a single intravenous dose (10 mg) of etelcalcetide; and (iii) assess the effect of hemodialysis on the pharmacokinetics of etelcalcetide and total C-14.
2.2.1 Patient Selection
Six patients aged ≥18 years with stage 5 CKD on hemodialysis were enrolled in this study. Each patient had a stable dialysis prescription that was not anticipated to change significantly during the course of the study; a body mass index between 18 and 38 kg/m2; corrected calcium >8.3 mg/dL; and PTH between 300 and 1200 pg/mL. Patients were excluded if they had received etelcalcetide or cinacalcet (a small molecule calcimimetic ) within 30 days. Patients were also excluded if any [14C]-labeled drug substance within 1 year to ensure that no residual drug-related C-14 is present in the samples from these subjects, which may confound the results obtained through AMS analysis.
2.2.2 Study Treatment
Patients were resident in the clinical study site for 12 days (i.e. study day −1 until completion of procedures on study day 11) and underwent hemodialysis three times per week for the duration of the study (Fig. 2). The hemodialysis time was fixed as per the patient prescription and its duration ranged from 3 to 4 h across the study subjects. All patients used the same dialyzer model (Optiflux® F180NR; Fresenius Medical Care, Waltham, MA, USA). At the end of hemodialysis on study day 1, patients received a single intravenous bolus dose of [14C]etelcalcetide into the arm opposite the arm used for hemodialysis, followed by a 5 mL saline flush.
2.3 Sample Collection
Blood, dialysate (entire amounts from each hemodialysis session), urine, feces from each discharge, and vomit from each emesis were collected (Fig. 2) and processed as described in the electronic supplementary methods. Blood samples were also collected from predialyzer and postdialyzer (arterial and venous) lines during the hemodialysis session on study day 4 and after completion of hemodialysis. After the in-clinic period, patients returned to the site on an outpatient basis in accordance with their routine hemodialysis sessions up to study day 39. Four patients returned for two extended collection periods, each comprising three consecutive hemodialysis sessions (collection period 1: study days 129–148; collection period 2: approximately 1 month after collection period 1, corresponding to study days 157–176). Blood and dialysate were collected during each outpatient day visit. Blood samples were collected into potassium-EDTA (Fig. 2) for C-14 analysis, etelcalcetide and total M11 (TM11; described in Sect. 2.4) bioanalysis, and biotransformation product profiling. Blood, dialysate, urine, and feces were collected, processed, and stored for additional analyses as described (Fig. 2). Dialyzer cartridges were collected after each hemodialysis session for each patient. Serum for anti-etelcalcetide antibody analysis was collected on study days −1 and 39.
2.4 Bioanalysis of Etelcalcetide and TM11
Plasma concentrations of etelcalcetide and TM11 were determined by LC–tandem mass spectrometry (MS/MS) as described in the electronic supplementary methods. TM11 is the sulfhydryl (reduced) form of the d-amino acid peptide backbone in etelcalcetide .
2.5 Accelerator Mass Spectrometry Analysis
The C-14 content in whole blood, plasma, dialysate, urine, and fecal samples was determined by AMS at Xceleron Inc. (Germantown, MD, USA) following a graphitization procedure as described in the electronic supplementary methods.
2.6 Biotransformation Product Profiling
Radioprofiles and biotransformation product identification were performed on pooled samples of plasma, urine, and dialysate with and without tris(2-carboxyethyl phosphine) (TCEP) reduction as described in the electronic supplementary methods. Structure assignments of etelcalcetide and its biotransformation products were based on comparisons to known structures from nonclinical studies , authentic standards, calculations, and interpretations from high-resolution MS and LC–MS/MS data.
2.7 Pharmacokinetic Analysis
All patients who received a single dose of etelcalcetide were included in the pharmacokinetic analysis set. Noncompartmental analyses were performed on individual plasma etelcalcetide, plasma C-14, and plasma TM11 concentration–time data from samples taken from the patient’s nonhemodialysis arm during the nonhemodialysis period using Phoenix WinNonlin v.6.3 software on Citrix (Pharsight®, St. Louis, MO, USA). Mean (standard deviation) concentration–time profiles were generated using Phoenix WinNonlin v.6.3 (Pharsight®), as were all descriptive statistics. Pharmacokinetic parameters (e.g. maximum observed drug concentration [Cmax], time to reach Cmax [tmax], area under the plasma concentration–time curve [AUC], hemodialysis clearance [CLHD], and extraction ratio [EHD]) were estimated as described in the electronic supplementary methods.
2.8 Estimation of Carbon-14 Excretion on Nonsampled Days
The total C-14 recovery in dialysate over the period between day 39 and the start of the extended collection period was estimated by interpolation. The total C-14 excretion rate on nonsampled days was estimated with the assumption that the dialysis excretion rate was a first-order process (electronic supplementary Fig. 1). A straight line (Y = slope·X + intercept) regression was applied to the log-transformed excretion rate (Y) versus time (X) profile. Regression analysis was applied for the measured data from study day 27 to the last time point; these correspond to six time points from study days 27 to 39, and six time points in the two extended pharmacokinetic collection periods.
2.9 Safety Analysis
All patients in the study were included in the safety analysis set. Adverse events were classified according to the Medical Dictionary for Regulatory Activities version 17.0 , and graded according to the Common Terminology Criteria for Adverse Events version 4.0 . Adverse events were reported through study day 39 or the last visit of the extended pharmacokinetic collection period.
2.10 Anti-Etelcalcetide Antibody Analysis
A validated biosensor immunoassay was used to screen for and confirm the presence of binding anti-etelcalcetide and anti-SAPC antibodies (electronic supplementary methods).
3.1 Pharmacokinetic Analyses
[N = 6]
Sex, n (%)
Median age, years (range)
Race, n (%)
Black (or African American)
Median height (range), cm
Median weight (range), kg
Median body mass index (range), kg/m2
Summary of pharmacokinetic parameters during the nonhemodialysis period for analytes total C-14, etelcalcetide, and total M11 in plasma after a single intravenous bolus administration of [14C] etelcalcetide (10 mg; 26.3 kBq) in patients with CKD on hemodialysis
Ratio to 14C
Summary of pharmacokinetic parameter values during hemodialysis for etelcalcetide in arterial and venous plasma after a single intravenous bolus administration of [14C]etelcalcetide (10 mg; 26.3 kBq) in patients with CKD during the first hemodialysis period postdose on study day 4
Analyte etelcalcetide [N = 6]
Etelcalcetide concentrations in plasma were lower than the corresponding concentration of total C-14 in plasma, indicating the presence of circulating biotransformation products (Fig. 3a, b). TM11 concentrations in plasma were similar to the concentrations of total C-14 in plasma. A regression analysis of the pooled data in which TM11 and total C-14 concentrations were available for a given time point across all patients demonstrated a goodness of fit (R2) value of 0.97. Plasma AUC ratios between TM11 and total C-14 were also close to unity (Table 2), indicating that all [14C]-labeled components were quantitatively converted to TM11 by chemical reduction; therefore, the d-amino acid backbone in etelcalcetide was predominantly intact in the C-14 products present in plasma.
Cumulative excretion of radioactivity following administration of a single intravenous dose of [14C]etelcalcetide (10 mg; 26.3 kBq) in patients with CKD on hemodialysis
Estimated cumulative recovery from study days 1–176, mean (SD) %
Administered C-14 dosea
Summary of representative LC-HRMS data for etelcalcetide and its biotransformation products
Calculated m/z (2+)e
Observed m/z (2+)e
Product ion data
448, 464, 481
299, 448, 714, 742, 770, 795
448, 465, 481
448, 465, 481
448, 465, 481
448, 464, 481, 524
448, 464, 481
448, 464, 481, 617
448, 464, 481
448, 465, 481
448, 464, 481, 524
448, 464, 481
Summary of biotransformation product profile in plasma, dialysate, and urine following intravenous administration of [14C]etelcalcetide (10 mg; 26.3 kBq) in patients with CKD on hemodialysis
Summary of biotransformation product profile in TCEP-treated plasma, dialysate, and urine following intravenous administration of [14C]etelcalcetide (10 mg; 26.3 kBq) in patients with CKD on hemodialysis
% C-14 chromatograma
Sulfhydryl (reduced form) of etelcalcetide backbone
In dialysate (Fig. 6c), the biotransformation product profile consisted of all components observed in plasma, except the protein conjugates. TCEP reduction of the dialysate resulted in a major TM11 peak (77.8 %) and a minor amount of reduced M5 (1.1 %) (Table 7). Several unidentified peaks were observed in the pooled day 4 dialysate before and after TCEP, each individually <7 and <5 %, respectively. No desacetylated biotransformation product or the corresponding reduced form was observed in dialysate or TCEP-reduced dialysate. In urine, the most abundant component was intact etelcalcetide (approximately 25 % of the 14C-chromatogram). In addition to etelcalcetide, 12 known biotransformation products were detected in urine (electronic supplementary Fig. 2). Peaks from unidentified components were each <1 % of the administered dose. TCEP reduction of the urine resulted in formation of, predominantly, a single TM11 peak (67.4 %) (Table 7). Several unidentified peaks were observed in the TCEP-reduced urine, each individually <5 % of the 14C-chromatogram. No desacetylated biotransformation product or its reduced form was observed in urine or TCEP-reduced urine. Feces were not profiled for biotransformation products because of the low amount of fecally excreted radioactivity. Cumulative excretion ratios in urine and feces on nonsampled days were estimated for each patient (electronic supplementary Table 1).
Treatment-emergent adverse events occurred in five patients and included constipation (n = 2), contact dermatitis, flatulence, nausea, pneumonia, upper respiratory tract infection, and vomiting (each n = 1); events were mild in intensity, with the exception of one serious adverse event of severe pneumonia. Of these, only constipation and flatulence were considered treatment-emergent adverse events.
3.5 Anti-Etelcalcetide Antibodies
No antibodies against either etelcalcetide or SAPC were detected in six predose and six postdose (study day 39) samples.
Etelcalcetide is a novel synthetic peptide composed almost entirely of d-amino acids. Minimal literature is available on the human disposition of peptides predominantly composed of d-amino acids, since there is no approved drug in this chemical class. The objective of this study was to characterize the pharmacokinetics, biotransformation, and excretion following a single microtracer intravenous dose of [14C]etelcalcetide to patients with CKD on hemodialysis. Higher quantities of C-14 more typical for human drug disposition studies were considered but not pursued because of the difficulty in controlling radioactivity contamination if hospitalizations were required during the study. One patient required hospitalization, and microtracer labeling obviated the need for contamination controls. The microtracer approach required the use of AMS for C-14 measurement in biofluids and dialysate. Remarkable detection limits were enabled by AMS, with C-14 concentrations of approximately 0.25 mBq (approximately 6.7 fCi/g) of 14C (approximately 0.06 ng equivalents of etelcalcetide/g) quantified in an approximately 0.35 g dialysate sample prepared from approximately 150 kg of dialysate collected on study day 176.
Nonclinical investigations indicated that etelcalcetide and its biotransformation products exist in a dynamic equilibrium in blood . Etelcalcetide undergoes biotransformation to form conjugates by disulfide exchange with endogenous thiols present in blood [5, 9]. These products were previously observed in vitro (human and rat) and in vivo (rat) . In rats, a majority of etelcalcetide-related moieties in circulation existed in the form of covalent protein conjugates inferred to be SAPC. SAPC was characterized in plasma following in vitro incubations of etelcalcetide in whole blood; it was demonstrated to be a disulfide conjugation of the etelcalcetide d-amino acid backbone to the l-cysteine 34 of serum albumin . In vitro kinetic studies showed that under the conditions tested, the rate of etelcalcetide CLHD was >16-fold faster than its rate of conversion to SAPC, and the rate of conversion of SAPC to etelcalcetide was approximately 200-fold slower than the dialytic rate constant . Re-equilibration to form etelcalcetide from SAPC occurred at a slow rate compared with etelcalcetide elimination by dialysis . Formation of etelcalcetide from SAPC is possible because of abundant quantities of l-cysteine present in plasma .
Based on the nonclinical findings, we hypothesized that etelcalcetide biotransformation in humans would predominately result from disulfide exchange . Moreover, with a dialyzer molecular weight cutoff of 10 kDa, we hypothesized that in patients with CKD on hemodialysis the drug-related species that would be eliminated during dialysis would be parent etelcalcetide and low-molecular-weight biotransformation products. Little change in total C-14 was expected during dialysis due to restricted dialysis of SAPC and the slow rate at which SAPC converts back to etelcalcetide or to any other low-molecular-weight products. Finally, we anticipated that upon cessation of dialysis, re-equilibration would occur and partially restore plasma etelcalcetide concentrations. To test these hypotheses, drug-derived products in plasma and dialysate were characterized and the pharmacokinetics of total C-14 and etelcalcetide in blood and plasma were determined. In addition, the dialyzer input and output blood was sampled during the first dialysis session, and intensive blood sampling was conducted after dialysis cessation.
The shape of the pharmacokinetic profiles of etelcalcetide and total C-14 were similar. The concentration–time courses of plasma etelcalcetide and SAPC (inferred from the total C-14 pharmacokinetic profile) outside the hemodialysis periods paralleled each other. In general, the SAPC concentration was approximately fivefold higher than the etelcalcetide concentration. The etelcalcetide to SAPC ratio decreased during the hemodialysis session when etelcalcetide and other low-molecular-weight biotransformation products were cleared. After dialysis, a partial restoration of circulating etelcalcetide concentrations in plasma occurred (Fig. 6b). These observations were consistent with the hypothesis that most of the radiolabeled, etelcalcetide-related species maintain a state of dynamic equilibrium with etelcalcetide, and that re-equilibration occurs following dialytic removal of etelcalcetide. This was further corroborated by direct determination of etelcalcetide and total C-14 clearance by dialysis, as measured by their respective concentrations entering and exiting the dialyzer during hemodialysis (Fig. 4). Only a small proportion (approximately 5 %) of the total C-14 that entered the dialyzer was removed. The nonclinical characterization of SAPC , the partial characterization of SAPC in these patients with CKD, and the near quantitative conversion of total C-14 to TM11 in plasma, are all consistent with a presumption that most of the total C-14 present in blood was in the form of SAPC. Accordingly, little removal of total C-14 occurred because SAPC has a molecular weight of approximately 67 kDa, which is well above the dialyzer cutoff and thus prevented its removal. In contrast to limited removal of total C-14, approximately 50 % of the etelcalcetide that entered the dialyzer was removed, which was consistent with the proportion of unbound etelcalcetide in plasma. Etelcalcetide noncovalent binding to plasma proteins (fraction unbound) in patients with CKD was 0.59 . These findings and the equilibrium that exists are consistent with the high volume of distribution for etelcalcetide reported in a previous population pharmacokinetic analysis , which can be attributed in part to reversible disulfide exchange of the etelcalcetide d-amino acid backbone between all available endogenous thiols and the l-cysteine readily available in plasma.
Recovery of total C-14 was estimated to be 67 % at study termination (day 176). The recovery is an estimate because the dose excreted in dialysate had to be partially interpolated. In the later part of the study, patients were released from the clinic and received some hemodialyses in settings where radioactivity was not quantified. The majority of the radioactivity was directly quantified. The predominant clearance pathway of total C-14 was hemodialysis, with the balance recovered in urine and feces. The parent drug was the predominant species present in dialysate and urine. Approximately 60 % of the [14C]etelcalcetide dose (approximately 89 % of total C-14 eliminated) was removed by dialysis as the parent drug. The radiolabeled species in feces was not determined because of the relatively small quantities of total C-14 present. The lack of higher recovery is likely due to the long C-14 elimination half-life in patients with stage 5 CKD. Extension of the study to increase recovery of the C-14 dose was not feasible. The recovery of thiol-containing drugs in disposition studies is generally low , particularly in patients undergoing hemodialysis for thiol-containing drugs normally cleared in the urine. For example, recovery of captopril, an angiotensin-converting enzyme inhibitor, was inversely proportional to the stage of renal impairment . Compliance with sample collection in this study was high; only two dialyses were missed in one patient due to hospitalization. Loss of C-14 as carbon dioxide was unlikely because there was no evidence of acetyl moiety loss in any etelcalcetide biotransformation products, and <0.2 % of an [acetyl-14C]etelcalcetide dose in rats was recovered in expired air .
Previous in vitro assessments demonstrated that etelcalcetide was unlikely to be metabolized by cytochromes P450 (CYP450) or peptidases, or subject to excretion by transporters . The biotransformation products detected in this study confirmed etelcalcetide was not metabolized by CYP450 or peptidases, little or no direct excretion of the drug occurred, and biotransformation occurred by disulfide exchange.
No unanticipated safety events were detected in this study. Antibody formation has the potential to alter the exposure and safety profile of therapeutics with a molecular weight <10 kDa [17, 18]. No anti-etelcalcetide antibodies were detected in serum using an assay designed to detect etelcalcetide or SAPC-reactive antibodies.
The current study provided insight into the complex pharmacokinetics of etelcalcetide that was not available from previous clinical studies. The majority of radioactivity (67 %) that was eliminated from a single dose of [14C]-labeled etelcalcetide 176 days after administration was removed by hemodialysis. Biotransformation was by disulfide exchange with endogenous thiols, and no alteration of the d-amino acid backbone was detected. Most of the circulating etelcalcetide-related biotransformed moieties existed as SAPC. After removal of plasma etelcalcetide by hemodialysis, re-equilibration between SAPC and l-cysteine in blood resulted in partial restoration of etelcalcetide plasma concentrations between hemodialysis sessions.
The authors gratefully acknowledge the CKD patients who participated in this clinical research study; Nicole Breese, John Jent, and members of the clinical study planning team for providing study management support; Scott Roberts, PhD, Jeroen Bezemer, PhD, Derek Maclean, PhD, and Merill Goldenberg, PhD, for drug product manufacture and dose administration protocol; Stephen English, BS, Marie Croft, PhD, and Mark Seymour, PhD, from Xceleron; and Frank Terschan, BS, Victoria Schilling, AAS, Jolene Berg, MD, and Harry Alcorn, PharmD, from DaVita Clinical Research. The authors thank James Balwit, MS, CMPP (Complete Healthcare Communications, LLC, an ICON plc company, Chadds Ford, PA, USA), whose work was funded by Amgen Inc., and Holly Tomlin, PhD (Amgen Inc.), for assistance in writing this manuscript.
Compliance with Ethical Standards
This study was funded by Amgen Inc.
Disclosure of potential conflict of interest
Raju Subramanian, Xiaochun Zhu, M. Benjamin Hock, Bethlyn J. Sloey, Benjamin Wu, Sarah F. Wilson, Ogo Egbuna, J. Greg Slatter, Jim Xiao, and Gary L. Skiles are employees of and shareholders in Amgen Inc.
Research involving human participants
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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