Neutralizing-antibody-independent SARS-CoV-2 control correlated with intranasal-vaccine-induced CD8+ T cell responses.

Effective vaccines are essential for the control of the coronavirus disease 2019 (COVID-19) pandemic. Currently developed vaccines inducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-antigen-specific neutralizing antibodies (NAbs) are effective, but the appearance of NAb-resistant S variant viruses is of great concern. A vaccine inducing S-independent or NAb-independent SARS-CoV-2 control may contribute to containment of these variants. Here, we investigate the efficacy of an intranasal vaccine expressing viral non-S antigens against intranasal SARS-CoV-2 challenge in cynomolgus macaques. Seven vaccinated macaques exhibit significantly reduced viral load in nasopharyngeal swabs on day 2 post-challenge compared with nine unvaccinated controls. The viral control in the absence of SARS-CoV-2-specific NAbs is significantly correlated with vaccine-induced, viral-antigen-specific CD8+ T cell responses. Our results indicate that CD8+ T cell induction by intranasal vaccination can result in NAb-independent control of SARS-CoV-2 infection, highlighting a potential of vaccine-induced CD8+ T cell responses to contribute to COVID-19 containment.

Correction to: Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients.

The article "Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients.

Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a serious and common complication in patients receiving peritoneal dialysis (PD). Cinacalcet is currently the recommended therapy for SHPT; however, gastrointestinal (GI)-related symptoms can result in low adherence and high discontinuation rates. Evocalcet is a novel calcimimetic agent that has non-inferior efficacy while providing a more tolerable safety profile. METHODS: This was a multicenter, intra-subject dose-adjustment treatment study evaluating the efficacy and safety of 1-8 mg evocalcet orally administered once daily for 32 weeks for the treatment of SHPT in PD patients. Patients then entered a 20-week extension period (dose range 1-12 mg). The primary endpoint was the proportion of patients who achieved a mean intact parathyroid hormone (iPTH) level of 60-240 pg/mL during the evaluation period (weeks 30-32). Secondary efficacy endpoints included the proportion of patients achieving ≥ 30% decrease in iPTH levels. RESULTS: A total of 39 Japanese PD patients with SHPT received evocalcet. The target mean iPTH level of 60-240 pg/mL was achieved by 71.8% (28/39) of patients during the evaluation period and 83.3% (20/24) of patients at week 52. The proportion of patients who achieved ≥ 30% decrease in iPTH levels from baseline was 74.4% (29/39) during the evaluation period and 87.5% (21/24) at week 52. Adverse drug reactions occurred in 46.2% (18/39) of patients, with most being of mild-to-moderate severity including GI-related events. CONCLUSION: This study shows the long-term efficacy and safety of evocalcet when orally administered to PD patients with SHPT once daily. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02549417, https://clinicaltrials.gov/ct2/show/NCT02549417 ; JAPIC: JapicCTI-153016, http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-153016 .

Long-Term Efficacy and Safety of Evocalcet in Japanese Patients with Secondary Hyperparathyroidism Receiving Hemodialysis.

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), and as the disease progresses SHPT is associated with systemic consequences, termed CKD-mineral and bone disorder. Currently, cinacalcet is indicated for the treatment of SHPT; however, cinacalcet is associated with upper gastrointestinal adverse events. Evocalcet has been developed to address these issues, but the long-term safety and efficacy of evocalcet need to be evaluated. To more accurately reflect clinical practice, this phase 3, multicenter, open-label study was specifically designed without a cinacalcet washout period, and focused on those patients who switched from cinacalcet to evocalcet. A total of 137 SHPT patients undergoing hemodialysis were enrolled, of whom 113 switched from cinacalcet to evocalcet. The most frequent type of adverse drug reaction was decreased adjusted calcium. The incidence of gastrointestinal-related adverse events did not increase in a dose-dependent manner as the dose of evocalcet was increased. The percentage of patients achieving the target intact parathyroid hormone concentration increased from 40.9% to 72.3% with 52-week treatment. The corrected serum calcium and phosphorus levels remained largely unchanged throughout the study. The long-term safety and efficacy of evocalcet was confirmed using a clinically relevant intra-subject dose-adjustment strategy in SHPT patients undergoing hemodialysis.

First-in-Asian Phase I Study of the Anti-Fibroblast Growth Factor 23 Monoclonal Antibody, Burosumab: Safety and Pharmacodynamics in Adults With X-linked Hypophosphatemia.

X-linked hypophosphatemia (XLH) is a disease caused by abnormally elevated FGF23 levels, which cause persistent hypophosphatemia accompanied by subsequent reduction in bone mineralization that presents as rickets or osteomalacia. Burosumab is a fully human monoclonal antibody targeting FGF23 that is under development for the treatment of FGF23-related hypophosphatemia including XLH. The safety, tolerability, and proof of concept of burosumab have been evaluated in patients with XLH in previous studies conducted in countries outside of Asia. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and expression of anti-drug antibodies in Japanese and Korean adults with XLH. This was a multicenter, sequential dose-escalation, open-label, single-dose study. This study began with cohort 1 (s.c. dose of burosumab 0.3 mg/kg), after which the dose was escalated sequentially in cohort 2 (s.c. dose of burosumab 0.6 mg/kg) and cohort 3 (s.c. dose of burosumab 1.0 mg/kg). The PK of burosumab were linear within the dose range of 0.3 to 1.0 mg/kg. The PD effects such as serum phosphorus concentration, serum 1,25[OH]2D3 concentration, and ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) were elevated after a single s.c. administration. The area under the receiver-operating characteristic curve from 0 to t (AUC0-t) values calculated using the change from baseline values of serum phosphorus, serum 1,25(OH)2D3, and TmP/GFR were correlated with the AUC0-t of burosumab. Furthermore, no serious adverse events (AEs), deaths, remarkable increase or decrease in the corrected calcium or intact PTH levels, or signs of nephrocalcinosis or its worsening were observed after treatment. Some AEs and drug-related AEs were observed; however, there were no clinically meaningful tendencies. The positive effects and acceptable safety profile seen in this study are encouraging for Japanese and Korean patients with XLH.

Assessment of CYP-Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans.

Evocalcet is a novel calcimimetic agent for the treatment of secondary hyperparathyroidism (SHPT). This study evaluated the effects of evocalcet on inhibition and induction of cytochrome P450 (CYP) isozymes. Although drug interactions arising from reversible inhibition of CYP isozymes by evocalcet were considered unlikely based on the results of in vitro studies and static model analyses, the potential for evocalcet to cause time-dependent inhibition of CYP3A or induction of several CYP isozymes could not be ruled out. Therefore, a clinical drug-drug interaction (DDI) study to evaluate the effects of evocalcet on the pharmacokinetics (PKs) of probe substrates for CYP isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A) was conducted in healthy male volunteers using a novel cocktail combination. Evocalcet did not significantly affect the PKs of the probe substrates, confirming that CYP-mediated interactions were unlikely.

Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

BACKGROUND: This study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis. METHODS: In this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events. RESULTS: Plasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE 'blood calcium decreased' occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased). CONCLUSION: Multiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

An open-label, randomized, phase 3 study of the efficacy and safety of antithrombin gamma in patients with sepsis-induced disseminated intravascular coagulation syndrome.

BACKGROUND: A recombinant form of antithrombin (AT), called AT gamma, is being developed as an alternative to AT derived from human plasma. To compare the efficacy and safety of AT gamma to plasma-derived AT (pAT), we conducted a randomized, open-label, multicenter trial in patients with sepsis-induced disseminated intravascular coagulation (DIC). METHODS: Eligible patients, recruited at 30 clinical sites, had been diagnosed with sepsis-induced DIC (by the Japanese Association for Acute Medicine [JAAM] DIC criteria) and AT activity at 70% or below. Patients were randomized 1:1 to either 36 IU/kg/day AT gamma (n = 110) or 30 IU/kg/day pAT (n = 112), both administered intravenously for 5 days. The primary endpoint was recovery from DIC at day 6 or early study withdrawal. DIC recovery was defined as a DIC score of less than four. Secondary endpoints were DIC score, outcome on day 28, sequential organ failure assessment score, acute physiology and chronic health evaluation II score (APACHE II), and plasma AT activity. Adverse events and adverse drug reactions were recorded using MedDRA/J version 16.0. RESULTS: Baseline patient demographics and clinical features were similar in the two treatment groups. On day 6 (or at withdrawal), DIC recovery had occurred in 62 of 110 (56.4%; 95% confidence interval, 46.6-65.8%) patients in the AT gamma group and 59 of 112 (52.7%; 95% confidence interval, 43.0-62.2%) patients in the pAT group. In both treatment groups, DIC recovery rate values tended to be higher when stratified by baseline AT activity rates. All changes in other secondary endpoints were similar in both treatment groups. Safety was also similar in the two treatment groups. Adverse events occurred in 89 of 108 (82.4%) patients in the AT gamma group and 99 of 113 (87.6%) patients in the pAT group. CONCLUSIONS: Safety and efficacy were similar for 36 IU/kg/day AT gamma and 30 IU/kg/day pAT. These results confirm that AT gamma is an excellent alternative to pAT for improving outcomes for patients with DIC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01384903; June 2011.

Phase 2b study of evocalcet (KHK7580), a novel calcimimetic, in Japanese patients with secondary hyperparathyroidism undergoing hemodialysis: A randomized, double-blind, placebo-controlled, dose-finding study.

BACKGROUND: Evocalcet has been developed as a new calcimimetic agent for hemodialysis (HD) patients with secondary hyperparathyroidism (HDSHPT), eliciting fewer gastrointestinal symptoms and drug interactions. We evaluated the efficacy, safety, and optimal starting dose of evocalcet in HDSHPT. METHODS: In this 3-week, Phase 2b, randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-finding study, Japanese HDSHPT with intact parathyroid hormone (iPTH) ≥240 pg/mL and serum calcium level corrected for albumin ≥8.4 mg/dL were randomized to evocalcet 0.5, 1, 2 mg/day administered orally or placebo under double-blind conditions, and cinacalcet 25 mg/day (open-label conditions). RESULTS: In total, 152 HDSHPT were randomized. The mean ± standard deviation (median, interquartile range) of percent changes in iPTH from baseline to end of treatment were -8.40±25.43% (-12.16, 39.60), -10.56±22.86% (-14.24, 27.85), and -20.16±34.23% (-23.83, 39.05) in the evocalcet 0.5, 1, and 2 mg/day groups and 5.44±25.85% (3.52, 35.39) and -25.86±27.76% (-29.79, 34.15) in the placebo and cinacalcet groups, respectively. The dose-response profile for each evocalcet group vs placebo showed statistically significant differences for all contrast patterns. Whole PTH, corrected calcium, ionized calcium, phosphorus, and intact fibroblast growth factor 23 decreased after treatment initiation in the evocalcet and cinacalcet groups. Adverse events were observed in 30%-50% of patients (all groups). Incidence of adverse events was similar among all groups except for decreased calcium, which occurred more frequently in the evocalcet 2 mg and cinacalcet groups. CONCLUSIONS: The dose response and safety of all administered doses of evocalcet were confirmed, as well as the efficacy of evocalcet ≥1 mg in a strictly Japanese sample of HDSHPT. Therefore, evocalcet 1 mg was considered appropriate as an initial dose for HDSHPT.

Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study.

BACKGROUND AND OBJECTIVES: Evocalcet is a novel calcimimetic agent with potential to improve the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. This study aimed to determine the pharmacokinetics, pharmacodynamics, and safety of evocalcet in healthy Japanese subjects. METHODS: This was a single-blind, placebo-controlled, single-dose study and an 8-day multiple-dose study of evocalcet (MT-4580/KHK7580) in 66 healthy Japanese subjects. RESULTS: After a single dose of evocalcet 1-20 mg, the time to maximum plasma concentration was attained in 1.5-2 h (median), and the elimination half-life was 12.98-19.77 h (mean). Within this dose range, the maximum plasma concentration and area under plasma concentration-time curve increased dose proportionally, confirming linearity. The trough plasma concentrations were relatively unchanged after multiple administration of evocalcet 6 and 12 mg. Evocalcet decreased intact parathyroid hormone and corrected calcium and phosphorus levels in a dose-proportional manner. Regarding its safety, no upper gastrointestinal adverse event occurred after the single and multiple administration of evocalcet at doses up to 12 mg. Tetany was detected in 1 subject (17%) after multiple administration of evocalcet 12 mg. In healthy subjects, the tolerability and safety of evocalcet were observed for a single dose of evocalcet at doses up to 20 mg, and for multiple doses up to 12 mg. CONCLUSIONS: These results suggest that evocalcet may have a comparable efficacy and better safety profile than that of cinacalcet, one of the current treatments for secondary hyperparathyroidism in patients with chronic kidney disease.

Nrf2 activator for the treatment of kidney diseases.

Kidney diseases are highly prevalent worldwide, and significantly reduce the quality of life of patients, creating an urgent need for effective therapeutic modalities. Despite this significant unmet medical need, none of the drugs launched to date have demonstrated promising potential to cure kidney diseases. This is likely due to the structural complexity of the kidney as well as difficulties in setting appropriate endpoints for clinical trials and identifying appropriate therapeutic targets. Recently, an alternative endpoint for clinical trials (i.e., a 30% or 40% reduction in estimated glomerular filtration rate [eGFR] from baseline following 2-3 years of observation) has been considered in the United States, European Union, and Japan, and is expected to contribute to the progress of drug development for kidney diseases. Further, oxidative stress and inflammation are currently thought to be key factors in the progression of kidney diseases, prompting more research on drugs targeting the mechanisms related to these factors for treatment. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system has drawn much attention in recent years for its anti-oxidative and anti-inflammatory properties, and its pharmacological potential for treatment of kidney diseases is being widely investigated in both clinical and non-clinical studies. This review summarizes the current issues in the treatment of kidney diseases, including clinical endpoints, Nrf2 activators as treatment options, and perspectives on pharmaceutical applications of Nrf2 activators.

Pharmacokinetics of evocalcet in secondary hyperparathyroidism patients receiving hemodialysis: first-in-patient clinical trial in Japan.

PURPOSE: Cinacalcet is a positive allosteric modulator of calcium-sensing receptors in the parathyroid gland and an effective treatment for secondary hyperparathyroidism. However, this agent has considerable side effects and dosage limitations, which impair effective treatment. Therefore, we investigated the pharmacokinetics, pharmacodynamics, and safety of the novel calcimimetic, evocalcet. PATIENTS AND METHODS: This was a multicenter, open-label study of single oral doses of 1, 4, and 12 mg evocalcet using an intrapatient dose escalation protocol in 29 Japanese secondary hyperparathyroidism patients receiving hemodialysis. Pharmacokinetics was assessed by plasma evocalcet concentrations. Pharmacodynamic evaluations consisted of measuring intact parathyroid hormone, serum corrected calcium, and fibroblast growth factor 23 concentrations. Safety and tolerability were evaluated by the analysis of adverse events (AEs). RESULTS: After a single 1-, 4-, or 12-mg dose, plasma evocalcet levels increased dose proportionally in a linear manner. Pharmacodynamic analyses showed that evocalcet effectively reduced intact parathyroid hormone and serum corrected calcium levels in a dose-dependent manner. AEs occurred in 31.0%, 28.6%, and 38.5% of patients receiving a single dose of 1, 4, or 12 mg, respectively. Most AEs were mild in severity. CONCLUSION: Evocalcet is effective in the short term, has linear pharmacokinetics, and is well tolerated as observed by the low incidence of AEs.

Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, -15%, per protocol set analyses). In the evocalcet and cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: -4.0% [95% confidence interval -11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: -14.2% [-20.9%, -7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT.

Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension.

BACKGROUND: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint. RESULTS: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups. CONCLUSIONS: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.

Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

Risk of end-stage renal disease in Japanese patients with chronic kidney disease increases proportionately to decline in estimated glomerular filtration rate.

Predominantly based on North American and European studies, 30% to 40% declines in estimated glomerular filtration rate (eGFR) over a few years are strongly associated with the risk of end-stage renal disease (ESRD) and have been proposed as surrogate endpoints of ESRD for clinical research. However, this association has not been systematically quantified in Asian populations. To do this we studied adult Japanese patients with baseline eGFR 10-59 ml/min/1.73m2. Changes in eGFR from baseline measured by centrally assessed serum creatinine were linked to subsequent ESRD in 2410 patients after one year and in 2079 patients after year 2. After year 1, 1.4% experienced a 53% decrease in eGFR (equivalent to doubling of serum creatinine), whereas 4.3% and 9.7% had eGFR decrease of 40% or 30% or more, respectively. The corresponding numbers after 2 years were 4.2%, 10.9%, and 19.3%, respectively. After year 1 baseline period, 498 patients developed ESRD over a median follow-up of 2.9 years (365 ESRD cases over a median follow-up of 2 years after year 2). In year 1, after accounting for potential confounders, a strong linear association was found between eGFR declines and subsequent ESRD, with adjusted hazard ratios of 20.7 (95% confidence interval 14.3-30.1) for a 53% decrease, 9.6 (7.4-12.5) for a 40% decrease, and 5.3 (4.1-6.9) for a 30% decrease compared to no change. Corresponding hazard ratios for year two analysis were 17.3 (11.8-25.3), 6.5 (4.7-9.1), and 3.1 (2.2-4.4), respectively. The associations were consistent across demographics and kidney diseases. Thus, 30% to 40% declines in eGFR are strongly associated with the risk of ESRD in Japanese patients with reduced eGFR, broadening global implications as a surrogate endpoint in clinical research.

A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma.

Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.

A randomized controlled trial comparing darbepoetin alfa doses in red blood cell transfusion-dependent patients with low- or intermediate-1 risk myelodysplastic syndromes.

Darbepoetin alfa (DA) is a standard treatment for anemia in lower-risk MDS. However, to date there has been no comparative study to investigate the initial dosage. We, thus, conducted a randomized controlled trial to elucidate the optimal initial dosage of DA. International Prognostic Scoring System low or intermediate-1 risk MDS patients with hemoglobin levels ≤9.0 g/dL, serum erythropoietin levels ≤500 mIU/mL, and red blood cell transfusion dependency were enrolled. Patients were randomized to receive DA either at 60, 120, or 240 µg/week for 16 weeks followed by continuous administration with dose adjustment up to 48 weeks. Of 17, 18, and 15 patients in the 60, 120, and 240 µg DA groups included in the efficacy analysis, 64.7, 44.4, and 66.7 %, respectively, achieved the primary endpoint (major or minor erythroid response), while 17.6, 16.7, and 33.3 % achieved major erythroid responses in the initial 16-week period. No clinically significant safety concerns were identified. DA reduced the transfusion requirements effectively and safely in transfusion-dependent, lower-risk MDS patients. Given the highest achievement rate of the major erythroid response in the 240 µg group and the absence of dose-dependent adverse events, 240 µg weekly is the optimal initial dosage.

High Hemoglobin Levels Maintained by an Erythropoiesis-Stimulating Agent Improve Renal Survival in Patients with Severe Renal Impairment.

Our goal was to investigate the effect modification of maintaining a high Hb target range through erythropoiesis-stimulating agent therapy on the renal outcome with respect to chronic kidney disease (CKD) stage and concurrent diabetes condition in patients with CKD. We used data from a previously reported randomized controlled trial involving 321 CKD patients not on dialysis, with Hb levels of <10 g/dL, and serum creatinine (Cr) of 2.0 to 6.0 mg/dL, and in which maintaining Hb levels at 11.0-13.0 g/dL with darbepoetin-α (High Hb group) resulted in a greater renal protective effect than maintaining Hb levels at 9.0-11.0 g/dL with epoetin-α (Low Hb group). We conducted a post-hoc analysis of the effects of baseline CKD stage and concurrent diabetic condition on the renal composite endpoint, consisting of death, initiation of renal replacement therapy, and doubling of the serum Cr level. Both groups with stage 4 CKD had a 3-year cumulative renal survival rate of 53.8%, whereas in patients with stage 5 CKD, the rate in the High Hb group (31.0%) was significantly (P = 0.012) higher than that in the Low Hb group (19.1%). The observations made in patients with stage 5 CKD were maintained on further analysis of non-diabetic patients, but were not seen in those with diabetes or stage 4 CKD. These results suggest that in patients with stage 5 CKD, especially those without diabetes, achieving a higher target Hb level with erythropoiesis-stimulating agents is associated with a greater renoprotective effect.