A Single- and Multiple-Dose, Multicenter Study of Etelcalcetide in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism

To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients. In this multicenter study, IV injections of etelcalcetide (3 times a week for 12weeks) were administered, with dose escalation every 4 weeks depending on changes in serum intact parathyroid hormone (iPTH) and corrected calcium (cCa). A total of 24 patients participated in this study. Serum iPTH was reduced in a time- and dose-dependent manner, with reductions (in pg/mL) at 12 weeks of -226.1 ± 125.3, -362.5 ± 161.5, and -412.4 ± 130.2, respectively, for maximum doses of 5, 10, and 15mg. At the end of the treatment, 50% of patients had serum iPTH levels within the target range (60-240 pg/mL). Serum cCa and phosphorus were reduced in parallel with iPTH. Adverse events (AEs) occurred in 20 patients (83.3%). The most frequently observed AEs (>10%) were either mild or moderate nasopharyngitis (29.2%), decreased serum calcium (16.7%), and vomiting (12.5%). Dose-escalated triweekly etelcalcetide was effective for SHPT in Japanese hemodialysis patients and was satisfactorily tolerated. .

Plain Language SummaryCalcimimetics are widely used for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. However, conventional calcimimetics have risks of upper gastrointestinal disturbances and hypocalcemia. Upacicalcet, a novel intravenous calcimimetic, is expected to reduce these risks. To assess the long-term efficacy and safety of upacicalcet, a phase 3 open-label, 52-week study in HD patients with SHPT was conducted in Japan. A total of 157 Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels ≥8.4 mg/dL were enrolled. Of those, 138 completed the 52-week upacicalcet treatment. Upacicalcet achieved the target serum iPTH level (60–240 pg/mL) in 94.2% of patients at 52 weeks. Moreover, upacicalcet decreased bone metabolism markers, intact fibroblast growth factor-23 levels, and parathyroid gland volume. Upacicalcet reduced corrected calcium-phosphate product levels even in patients with mild SHPT, i.e., serum iPTH level ≤300 pg/mL. Upacicalcet caused neither symptomatic hypocalcemia nor cCa levels <7.5 mg/dL despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Gastrointestinal symptoms leading to upacicalcet dose reduction were not occurred. In conclusion, upacicalcet stably reduced the serum iPTH levels in HD patients with mild-to-severe SHPT, with few safety concerns. Serum cCa and P levels were well controlled, with a low incidence of hypocalcemia. Upacicalcet is a novel calcimimetic that may provide safe and appropriate long-term treatment of SHPT.

Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis. This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH)>240pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52weeks, with an initial dose of 5mg and flexibility to adjust the dose between 2.5 and 15mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60-240pg/mL). Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4-92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related. Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52weeks in Japanese hemodialysis patients, and was safe and well tolerated. JapicCTI-142665.

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Calcium (Ca) overload by Ca-containing phosphorus (P) binder has been suggested to be implicated in the pathogenesis of soft tissue and vascular calcification, which contribute to increased morbidity and mortality of cardiovascular disease in patients undergoing dialysis. Recently, a noncalcium P binder, sevelamer hydrochloride (sevelamer), has become available in Japan. However, Japanese patients undergoing dialysis might be less tolerant of sevelamer treatment, and it is likely to cause hypocalcemia because their dietary Ca intake is less than that in European and American patients. We evaluated the effects of combination therapy with sevelamer and calcium carbonate (CC) on mineral metabolism in Japanese hemodialysis patients, as an alternative form of P management. A total of 210 hemodialysis patients were enrolled, and were given a small dose of sevelamer (0.75-1.5 g/day) on CC treatment. Sevelamer dose was gradually increased, while CC decreased during 24 weeks. Five patients discontinued sevelamer treatment because of severe constipation, anorexia, and parathyroidectomy for severe secondary hyperparathyroidism. After 24 weeks, the dose of sevelamer was significantly increased to 3.29 g/day (initial dose: 1.47 g/day), while CC was decreased by 54%. Adjusted serum Ca significantly decreased (9.63 +/- 0.57-9.45 +/- 0.67 mg/dL; P = 0.0012), although serum P increased (5.89 +/- 1.32-6.25 +/- 1.32 mg/dL; P = 0.017). Serum intact PTH (iPTH) significantly increased in patients with a low or normal iPTH level (< or =300 pg/mL), while it did not change in patients with secondary hyperparathyroidism (>300 pg/mL). The results suggest that the therapeutic regimen is more tolerant and reduces Ca load in Japanese hemodialysis patients while avoiding hypocalcemia. In addition, the mitigated Ca overload could improve PTH hyposecretion in patients with adynamic bone disease, which is associated with soft tissue calcification and higher mortality in uremia.

BackgroundSecondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT.MethodsIn this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60–240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline.ResultsThe proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed.ConclusionsThis study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.

Upacicalcet is a novel small-molecule calcimimetic agent developed for intravenous injection. Here, we evaluated the long-term efficacy and safety of upacicalcet treatment via intraindividual dose adjustment in haemodialysis patients with secondary hyperparathyroidism (SHPT). A phase 2, multicentre, open-label, single-arm study was conducted. Upacicalcet was administered for 52weeks; the starting dose was 50μg thrice a week, and then adjusted to 25, 50, 100, 150, 200, 250, or 300μg, according to the dose-adjustment method set in the protocol. The primary endpoint was the percentage of patients with serum intact parathyroid hormone (iPTH) level achieving a target range of 60-240pg/mL (target achievement rate) at week 18. A total of 58 patients were administered upacicalcet. The target achievement rate of serum iPTH level at week 18 was 57.9%, which increased to 80.8% at week 52. The serum-corrected calcium (cCa) level decreased immediately after upacicalcet administration, but no further decrease was observed. Adverse events were observed in 94.8% of patients, and adverse drug reactions (ADRs) occurred in 20.7% of patients. The most common ADR was decreased adjusted calcium in eight patients; dizziness occurred as a serious ADR in one patient. The serum cCa level of patients who interrupted upacicalcet treatment at a serum cCa level of <7.5mg/dL recovered to ≥7.5mg/dL immediately after the interruption. In haemodialysis patients with SHPT, upacicalcet doses of 25-300μg for 52 weeks were found to be highly effective and well-tolerated, with minor safety concerns.

Background: Jaktinib is a novel selective janus kinase 1/2 inhibitor. The phase I first-in-human study evaluated the tolerance and pharmacokinetics of jaktinib in healthy Chinese subjects. Methods: A randomized, double-blind, placebo-controlled study were designed. A total of 126 healthy subjects were enrolled into the single ascending dose, multiple ascending dose and food effect study. Safety endpoints included adverse events, abnormal vital signs, 12-lead ECGs, abdominal ultrasound, chest x-ray, physical examination and clinical laboratory tests. Blood, urine and feces samples were collected at predetermined time points for pharmacokinetic analysis of jaktinib, the metabolites ZG0244 and ZG0245, which are formed by oxidation or hydrolysis metabolic pathway, respectively. Results: Jaktinib was absorbed with a median time to peak plasma concentration of 1.25–3.5 h and was eliminated with a half-life of 2.952–9.040 h. Linear pharmacokinetic characteristic was presented over the dose range from 25 to 400 mg. No obvious accumulation was observed after multiple doses for 10 days. Administration after a high-fat breakfast significantly increased the absorption of jaktinib. The accumulated fraction of jaktinib and the determined metabolites excreted in urine and feces was 19.478%. Jaktinib was well tolerated in all single dose cohorts. In multiple dose cohorts, 200 mg q24 h method was evaluated as maximally tolerated dose. Neutropenia, diarrhea, dizziness and headache were the most frequently reported treatment related adverse events. No deaths, serious or Grade ≥4 adverse events was developed. Conclusion: Jaktinib was well tolerated when single dose ranging from 25 to 400 mg and multiple dose up to 200 mg q24 h. The safety and pharmacokinetic characteristics support the next trial in myelofibrosis patients.

SIRTUIN 1 Gene Polymorphisms are Associated With Cholesterol Metabolism and Coronary Artery Calcification in Japanese Hemodialysis Patients

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BackgroundDonanemab (LY3002813) is an IgG1 antibody directed at an N-terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques.ObjectivesTo assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity.DesignPhase 1b, investigator- and patient-blind, randomized, placebo-controlled study.SettingPatients recruited at clinical research sites in the United States and Japan.Participants61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer’s disease and mild-to-moderate Alzheimer’s disease dementia.InterventionSix cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15).MeasurementsBrain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity.ResultsTreatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: −16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and −49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; −50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and −58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-halflife following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients).ConclusionsSingle and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

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Background/Aims: Few clinical trials conducted with cinacalcet have thoroughly addressed its effects of on bone metabolism. We assessed the effects of cinacalcet on bone markers in Japanese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). Methods: 200 Japanese HD patients with intact PTH (iPTH) levels ≥300 pg/ml were enrolled. The dose of cinacalcet was titrated from 25 up to 100 mg/day to achieve iPTH levels ≤250 pg/ml for 52 weeks. Results: At the end of the study visit, 57.8% of patients (115/199) had achieved iPTH levels ≤250 pg/ml. Serum Ca, phosphorus (P) and Ca × P levels decreased rapidly and were maintained throughout the study. At week 52, all bone metabolic markers levels had decreased significantly from baseline. Although bone resorption markers gradually decreased throughout the study period, bone alkaline phosphatase significantly increased during the first 4 weeks and then gradually decreased. Conclusions: The time courses of changes in bone markers after cinacalcet treatment resembled those observed after surgical parathyroidectomy (PTx), sometimes described as the hungry bone syndrome, indicating that cinacalcet treatment induces a rapid recovery in bone response to calcium. In addition, long-term efficacy and safety of cinacalcet were also observed in Japanese patients undertaking long-term hemodialysis (167.0 ± 81.4 months).