Saling Huang

AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients

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 1-3 (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.

Velcalcetide (AMG 416), a novel peptide agonist of the calcium sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects

Context Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease—mineral and bone disorder. Objective To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. Methods The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18–45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo. Intervention Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously. Outcomes Measurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study. Results Intravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P < 0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h. Conclusion Single IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients.

A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients

Abstract Objective: Secondary hyperparathyroidism (SHPT) is a frequent complication of chronic kidney disease. We evaluated AMG 416, a long-acting peptide agonist of the calcium-sensing receptor, to assess its safety, tolerability, and efficacy and to determine a safe and effective starting dose for subsequent phase 2 studies. The study was not designed to titrate AMG 416 dosing to achieve a specific PTH treatment goal. Research design and methods: This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation study designed to evaluate the safety and efficacy of AMG 416 administered thrice weekly by IV bolus at the end of hemodialysis for up to 4 weeks. Eligible subjects were enrolled in one of three cohorts and treated with 5 mg of AMG 416 or placebo for 2 weeks (Cohort 1) or 5 or 10 mg of AMG 416 or placebo for 4 weeks (Cohorts 2 and 3). The primary endpoint was mean percentage change from baseline in PTH during the efficacy assessment phase (EAP) in Cohorts 2 and 3. Results: Analysis of the primary endpoint showed that treatment with AMG 416 at 10 mg (Cohort 2) and 5 mg (Cohort 3) for up to 4 weeks resulted in mean 49.4% and 33.0% reductions from baseline in PTH during the efficacy assessment phase, respectively (p < 0.05 for both cohorts compared to placebo group within the cohort). A substantial proportion of subjects treated with AMG 416 achieved PTH ≤300 pg/mL and ≥30% reduction in PTH from baseline in both cohorts. The observed decreases in serum-corrected calcium were well tolerated and serum phosphate levels also tended to decrease. Conclusions: The present clinical findings support the continued development of AMG 416 as a treatment for SHPT in hemodialysis patients.

The Safety and Efficacy of KAI-1678— An Inhibitor of Epsilon Protein Kinase C (εPKC)—Versus Lidocaine and Placebo for the Treatment of Postherpetic Neuralgia: A Crossover Study Design

OBJECTIVE Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. DESIGN The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI-1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). PATIENTS A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for ≥3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of ≥4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. RESULTS Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. CONCLUSIONS We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study.

Treatment of Secondary Hyperparathyroidism: Results of a Phase 2 Trial Evaluating an Intravenous Peptide Agonist of the Calcium-Sensing Receptor

Background/Aims: This study evaluated the efficacy and safety of AMG416 (etelcalcitide), a novel peptide agonist of the calcium (Ca)-sensing receptor given intravenously (IV) after each hemodialysis session for the treatment of secondary hyperparathyroidism (SHPT). Methods: Adult subjects with SHPT on hemodialysis enrolled in a 12-week, dose titration (parent) study followed by an open-label extension phase. AMG416 was administered IV, thrice weekly starting at 5 mg/session and titrated based on the subjects parathyroid hormone (PTH) and albumin-corrected Ca (cCa) to target a PTH of 150-300 pg/ml. Efficacy (percent PTH change from baseline to the efficacy analysis period during the parent study) and safety (open-label extension phase) endpoints were evaluated. Results: Baseline (n = 37) mean (standard error [SE]) PTH was 853 (106 pg/ml). The mean (95% CI) percent change from baseline to the efficacy analysis period in PTH concentration was -53.6% (-60.8, -46.4). The proportion of subjects with ≥30% reduction in PTH from baseline to the efficacy assessment period (EAP) was 89% (32/36; 95% CI 73.9, 96.9). Results by the baseline PTH subgroup (≤700 vs. >700 pg/ml) were comparable for both analyses. The proportion of subjects achieving a PTH ≤300 pg/ml was 56% (n = 20/36) at the efficacy assessment period. The mean (SE) percent changes from baseline to EAP were observed for cCa -15% (1.0%) and phosphorus -10% (3.3%). Adverse events were mild to moderate in severity. The PTH reductions achieved in the parent study were maintained in the open-label extension phase. Conclusion: AMG416 was well tolerated and appears to be an effective agent for the treatment of SHPT in patients on hemodialysis.

A pharmacokinetic/pharmacodynamic model for AMG 416, a novel calcimimetic peptide, following a single intravenous dose in healthy subjects

AMG 416 is a novel peptide agonist of the calcium‐sensing receptor. In support of the clinical development program, a pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to describe the relationship between plasma AMG 416 levels and serum intact parathyroid hormone (iPTH) concentrations in healthy male subjects. AMG 416 plasma concentrations were characterized by a three‐compartment linear PK model, while serum iPTH levels were described by an indirect response model with drug effect on the production of iPTH characterized with an inhibitory Emax model. The production of iPTH was modeled by a circadian rhythm function. The systemic clearance of plasma AMG 416 was estimated to be 6.94 L/h. Two sine functions best described iPTH circadian rhythm with an amplitude estimated to be 0.15 and 0.08, respectively. The maximum response Emax and the potency parameter EC50 were estimated to be 0.69 and 21.0 ng/mL, respectively. This work improved our understanding of the interaction between AMG 416 PK and iPTH concentrations in healthy adult male subjects. Data suggest additional PK/PD studies with AMG 416 are warranted in the hemodialysis population.

Population Pharmacokinetic Evaluation of a Fully Human IgG2 Monoclonal Antibody in Patients with Inflammatory Diseases

ABX-IL8 is a fully human IgG₂ monoclonal antibody generated using transgenic mouse technology (Xenomouse®) that binds to human Interleukin-8 with high affinity and specificity. The objective of this study was to evaluate the pharmacokinetic (PK) properties of ABX-IL8 in patients with active inflammatory diseases. Patients with psoriasis and rheumatoid arthritis received single or multiple short intravenous infusions of ABX-IL8 or placebo. Serum concentrations of ABX-IL8, baseline serum IgG and IgG₂ concentrations and Anti-Drug Antibody (ADA) response to ABX-IL8 were determined using relevant immunoassays. Pharmacokinetic analyses of the serum ABX-IL8 concentration-time data were performed. Following single-dose administration of ABX-IL8, dose proportional increases in drug exposure were observed. Consistent with the disposition properties of the endogenous IgG antibodies, ABX-IL8 appeared to be primarily distributed into the plasma compartment and the extra-vascular fluid and the steady-sate volume of distribution (61 ± 14 to 71 ± 14 mL/kg) was comparable to that for the endogenous antibodies. Following the multiple-dose administration, PK properties of the antibody were linear with dose and time. Steady-state clearance (2.6 ± 1.1 to 2.7 ± 1.4 mL/day/kg) was similar to that observed following the single dose administration and no ADA response was detected throughout the study. PK variability and serum exposure to ABX-IL8 following administration of the fixed doses were comparable to those observed following administration of the weight-adjusted doses; the impact of body weight on clearance was minimal and this correlation did not translate into requirements for body weight-adjusted dosing. Additionally, age and disease type (psoriasis or RA) had no impact on ABX-IL8 pharmacokinetics.

A Single-Center, Randomized, Double-Blind, Active, and Placebo-Controlled Study of KAI-1678, a Novel PKC-Epsilon Inhibitor, in the Treatment of Acute Postoperative Orthopedic Pain

OBJECTIVE KAI-1678, a novel inhibitor of the interaction of the epsilon isoform of protein kinase C (εPKC) with its intracellular receptor, has demonstrated activity in countering hyperalgesia in several models of pain. In this controlled randomized trial, KAI-1678 was tested for analgesic activity in an orthopedic acute postoperative pain setting. DESIGN Following hip or knee replacement surgery, subjects were treated with KAI-1678, ketorolac, or saline. Subjects recorded their pain intensity on a visual analog scale and rated their quality of analgesia. The pain intensity differences between baseline and the evaluations were summed over the first 4 hours. RESULTS The analysis revealed that, while ketorolac displayed good analgesic activity, KAI-1678 was not significantly different than placebo. Analgesia quality ratings similarly did not show a difference between KAI-1678 and placebo in this pain model. A small excess of infusion site erythema was seen with KAI-1678, but otherwise the drug was safe and well tolerated. CONCLUSIONS We investigated the safety and efficacy of a novel inhibitor of εPKC and provide clinical evidence that inhibition of εPKC with KAI-1678 is not effective in the treatment of acute postoperative orthopedic pain.

Utility of CMR Markers of Myocardial Injury in Predicting LV Functional Recovery: Results from PROTECTION AMI CMR Sub-study

BACKGROUND Adverse left ventricular (LV) remodelling following acute ST-segment elevation myocardial infarction (STEMI) has prognostic importance. We aimed to predict 90-day left ventricular (LV) function following acute STEMI using variables from clinical presentation, biomarkers, and cardiovascular magnetic resonance imaging (CMR). METHODS Consecutive patients undergoing primary percutaneous coronary intervention for anterior STEMI as part of the Selective Inhibition of Delta-protein Kinase C for the Reduction of Infarct Size in Acute Myocardial Infarction (PROTECTION-AMI) trial were enrolled into the CMR sub-study at selected sites. CMR was performed at baseline (days 3 to 5) and 90 days and used to evaluate infarct size, myocardial salvage index, infarct heterogeneity, microvascular obstruction and global LV function. Biochemical markers including creatinine kinase area under the curve (CK AUC), peak CK, peak CK-myocardial band (CK-MB) and AUC, and troponin I were collected at specific time-points. RESULTS Ninety-six patients were enrolled in the CMR sub study and 85 completed the 90-day follow-up, across 24 centres worldwide. LV ejection fraction (EF) was 56% (46-63%) at baseline and 60% (49-67%) at 90 days (p<0.001). Infarct size had moderate inverse correlation with 90-day EF (Spearmans rho=-0.7, p < 0.001) and had the strongest correlation when compared to myocardial salvage index (Spearmans rho=0.5, p=0.001), infarct heterogeneity (Spearmans rho=-0.4, p=0.02 or microvascular obstruction (Spearmans rho=-0.4, p<0.001). All biochemical markers had similar moderate relationship to LVEF at 90 days (Spearmans rho -0.6 to -0.8, p=0.001). In a multivariable model, only baseline LVEF, CMR infarct size and infarct heterogeneity independently predicted 90-day LVEF. CONCLUSION This study reports findings of a combined CMR protocol (including myocardial oedema imaging) in a multi-centre, multi-vendor setting. We found infarct size, infarct heterogeneity and myocardial salvage index correlated favourably with 90-day LVEF, however only the former two were independently predictive.

Correlation of cardiac magnetic resonance imaging and biochemical markers of myocardial injury in a multi-centre study: PROTECTION AMI CMR substudy

The purpose of this study was to determine predictors of 90-day left ventricular function following acute ST-segment elevation myocardial infarction (STEMI) using variables from clinical presentation, biomarker testing, and cardiovascular magnetic resonance imaging (CMR).