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.

ContextVelcalcetide, 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.ObjectiveTo assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers.MethodsThe 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.InterventionVelcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously.OutcomesMeasurements 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.ResultsIntravenous 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.ConclusionSingle 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.

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.

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.

Brief summary of article: Nociceptive properties of protein kinase C (PKC) has been studied for nearly two decades. We found that KAI-1678-a novel inhibitor of epsilon PKC-was not an analgesic for patients with postoperative pain following total hip or total knee replacement surgery. However, a different PKC inhibitor may prove to be a safe and effective analgesic. AbstractObjective. KAI-1678, a novel inhibitor of the interaction of the epsilon isoform of protein kinase C (ePKC) 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 ePKC and provide clinical evidence that inhibition of ePKC with KAI-1678 is not effective in the treatment of acute postoperative orthopedic pain.

Background:The Tauriel Study (NCT03289143) was a Phase 2 randomized, doubleblind, placebo-controlled, parallel-group clinical trial that assessed the safety and efficacy of semorinemab in patients with prodromal-to-mild Alzheimer's disease. We examined the concordance of fluid tau biomarkers with Tau PET for the identification of patients with high tau burden at enrollment.Method: Tau at baseline was assessed by [18F]GTP1 PET imaging and assays for multiple CSF and plasma tau indices, including pTau181 and mid-domain tTau (Elecsys assays), tau peptides 2-24 and 93-105 (anti-peptide capture mass-spec assay), and phosphotau/unphosphorylated tau217 ratio (mass-spec assay). The association between imaging and fluid tau levels were assessed with Spearman correlations. AUC, sensitivity and specificity are reported in the context of predicting tau burden with a single fluid biomarker, where 'high tau' is defined as GTP1 temporal meta-ROI SUVR ≥1.3. Cutoffs were derived using Youden's index.Result: 354 participants had both PET and plasma samples; 68 subjects had paired PET and CSF data. GTP1 significantly correlated with each fluid marker, highly with pT217 (r = 0.78), moderately with other CSF assays (r = 0.44 -0.56) and weakly with plasma tTau (r = 0.19) (Table 1). Discrimination was highest for CSF pTau217 ( AUC = 0.909). Specificity was 0.862 and 0.84 for pTau181 and pTau217 respectively, while sensitivity was 0.564 and 0.868 (Figure 1). Empirically defined cutoffs were 36.88 pg/mL for pTau181 and 0.052 for pT217. Conclusion:Baseline Tau PET is shown to be prognostic for future cognitive decline and thus could be included in enrollment criteria for future clinical studies in AD. Alternative approaches include the use of fluid biomarkers for tau. While pTau181 and nterminal tau indices can only be optimized for either high specificity or high sensitivity, both can be concurrently optimized using pTau217, thus positioning it as a potential alternative marker for Tau pathology. Additional CSF and plasma tau indices are pending similar analyses.

BackgroundSeveral radiotracers targeting tau pathology in Alzheimer’s disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620.MethodsTo date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1).ResultsTracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4.ConclusionsThe tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets.Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask.Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images.Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions.Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM).

BackgroundSeveral radiotracers targeting tau pathology in Alzheimer’s disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620.MethodsTo date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1).ResultsTracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4.ConclusionsThe tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets.Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask.Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images.Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions.Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM).