Manabu Iwasaki

Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study

Objective To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA). Methods In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant disease-modifying antirheumatic drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg. The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12. Results Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy. Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response. The total incidence of treatment-emergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively). TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg). Conclusions Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile. These findings support further developments of peficitinib for RA treatment. Trial registration number NCT01649999; Results.

Long-Term Cinacalcet HCl Treatment Improved Bone Metabolism in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism

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).

Positive Outcomes of High Hemoglobin Target in Patients With Chronic Kidney Disease Not on Dialysis: A Randomized Controlled Study

Correcting anemia in patients with chronic kidney disease (CKD) to higher hemoglobin (Hb) levels may be associated with increased risk. No optimal target for Hb has been established. This controlled study examined 321 patients with CKD who were not on dialysis, had a Hb level of <10 g/dL, and a serum creatinine of 2.0 to 6.0 mg/dL. They were randomized into two target Hb groups: 161 to high Hb (11.0–13.0 g/dL) to receive darbepoetin alfa and low Hb to 160 (9.0–11.0 g/dL) to receive recombinant erythropoietin. The study lasted 48 weeks. Of 154 and 153 patients with adverse events, cardiovascular adverse events developed in 42 and 51 patients in the high and low Hb groups, respectively, with no significant difference in the incidence. All quality of life scores improved in the high Hb group and vitality improved significantly more with high Hb (P = 0.025). The left ventricular mass index (LVMI) remained stable in the low Hb group, but there was a significant decrease in LVMI in the high group (P < 0.001). There were no safety concerns with targeting a higher Hb level during the 48 weeks of this study. Patients with a higher Hb target had comparatively better outcomes with respect to quality of life and LVMI.

Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C

BACKGROUND & AIMS Assessment of the risk of hepatocellular carcinoma (HCC) development is essential for formulating personalized surveillance or antiviral treatment plan for chronic hepatitis C. We aimed to build a simple model for the identification of patients at high risk of developing HCC. METHODS Chronic hepatitis C patients followed for at least 5 years (n=1003) were analyzed by data mining to build a predictive model for HCC development. The model was externally validated using a cohort of 1072 patients (472 with sustained virological response (SVR) and 600 with nonSVR to PEG-interferon plus ribavirin therapy). RESULTS On the basis of factors such as age, platelet, albumin, and aspartate aminotransferase, the HCC risk prediction model identified subgroups with high-, intermediate-, and low-risk of HCC with a 5-year HCC development rate of 20.9%, 6.3-7.3%, and 0-1.5%, respectively. The reproducibility of the model was confirmed through external validation (r(2)=0.981). The 10-year HCC development rate was also significantly higher in the high-and intermediate-risk group than in the low-risk group (24.5% vs. 4.8%; p<0.0001). In the high-and intermediate-risk group, the incidence of HCC development was significantly reduced in patients with SVR compared to those with nonSVR (5-year rate, 9.5% vs. 4.5%; p=0.040). CONCLUSIONS The HCC risk prediction model uses simple and readily available factors and identifies patients at a high risk of HCC development. The model allows physicians to identify patients requiring HCC surveillance and those who benefit from IFN therapy to prevent HCC.

Sequences in the Interferon Sensitivity-Determining Region and Core Region of Hepatitis C Virus Impact Pretreatment Prediction of Response to PEG-Interferon Plus Ribavirin: Data Mining Analysis

The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated‐interferon (PEG‐IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity‐determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG‐IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P = 0.01) predicted sustained virological response independent of other covariates. The decision‐tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0–1) but was 83% in selected subgroups of younger patients (<60 years), wild‐type sequence at Core70, and higher level of low‐density lipoprotein cholesterol (LDL‐C) (≥120 mg/dl). Reproducibility of the model was validated (r2 = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG‐IFN plus RBV therapy. A decision‐tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response. J. Med. Virol. 83:445–452, 2011.

Dose determination of cinacalcet hydrochloride in Japanese hemodialysis patients with secondary hyperparathyroidism.

Abstract:  Cinacalcet hydrochloride is a calcimimetic agent that activates the calcium‐sensing receptor on the surface of parathyroid cells and inhibits parathyroid hormone (PTH) secretion. To manage secondary hyperparathyroidism, cinacalcet, which lowers PTH levels without increasing serum calcium, phosphorus and calcium–phosphorus product (Ca × P) levels, may provide a new potential therapy. To identify the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism, this double‐blind, placebo‐controlled, parallel, dose‐finding study was conducted. One hundred and twenty Japanese hemodialysis patients with intact PTH levels greater than or equal to 300 pg/mL were randomized into four groups: placebo, and 12.5, 25 and 50 mg of cinacalcet. The treatment period was three weeks followed by a two‐week follow‐up observation period. Cinacalcet decreased serum intact PTH levels in a dose‐dependent manner, and also decreased serum calcium, phosphorus, Ca × P, tartrate‐resistant acid phosphatase and osteocalcin levels. The treatment with cinacalcet was generally well tolerated in this study. However, the incidence of treatment‐related adverse events, such as gastrointestinal disorders and hypocalcemia, and the rate of withdrawal from the study due to treatment‐related adverse events were higher in the 50 mg dose group than in the other groups. On the basis of both efficacy and safety results, 25 mg has been identified as the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism.

Darbepoetin Alfa Effectively Maintains Hemoglobin Concentrations at Extended Dose Intervals Relative to Intravenous rHuEPO in Japanese Dialysis Patients

Abstract:  Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its three‐fold longer half‐life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. In this multicenter, open‐label study, 513 dialysis patients maintained on stable rHuEPO therapy were switched to KRN321 at extended dose intervals. Those receiving rHuEPO two (n = 144, 28.1%) or three times (n = 305, 59.5%) per week were switched to KRN321 once per week, and those receiving rHuEPO once per week (n = 64, 12.5%) were switched to KRN321 once every two weeks. The doses of KRN321 (10–120 μg) were titrated to maintain Hb concentrations at 10–13 g/dL and, if possible, within 11–12 g/dL for up to 52 weeks. If the Hb concentration remained between 10.5 and 12 g/dL, conversion of the dosing frequency from once per week to once every two weeks was allowed. Hemoglobin concentrations were maintained regardless of the dosing interval. The percentage of patients with Hb values within 11–12 g/dL was 23.6% at week 0, 41.3% at week 7, 46.1%−51.9% between weeks 11 and 22 and 45.6% at week 52. KRN321 was well tolerated and the safety profile was consistent with previous trials conducted for KRN321. KRN321, when administered at extended dose intervals, is well tolerated and effective Hb concentrations are attained in Japanese hemodialysis patients.

Darbepoetin alfa (KRN321) administered intravenously once monthly maintains hemoglobin levels in peritoneal dialysis patients.

Abstract:  Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half‐life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. This multicenter, open‐label, single‐arm study of 72 patients with end stage renal failure on peritoneal dialysis (PD) evaluated the efficacy and safety of KRN321 administered intravenously with the dosing intervals extended to monthly. PD patients that were either rHuEPO‐naïve or rHuEPO‐receiving were enrolled. In rHuEPO‐naïve patients, the initial dose of KRN321 was 40 μg weekly by intravenous administration. For rHuEPO‐receiving patients, an initial regimen of fortnightly intravenous administration was given and the initial dose was based on the dose of rHuEPO used before switching to KRN321. After starting the study medication, the Hb concentration was maintained between 10.0 g/dL and 13.0 g/dL. In those patients whose Hb concentrations showed a stable time‐course, the dosing intervals of KRN321 were extended. The results suggest that it may be feasible to reduce the frequency of treatment to a monthly schedule, with an associated adjustment of dose, in most patients. Adverse events were observed in 67 of the 72 patients (93.1%, 267 events). Most of all the adverse events were reported in patients with chronic renal failure receiving conventional rHuEPO. No safety problems specific to KRN321 were noted. These results suggest that KRN321 could reduce of frequency of hospital visits for PD patients receiving erythropoietic therapy for renal anemia.

Pranlukast dry syrup inhibits symptoms of Japanese cedar pollinosis in children using OHIO Chamber

Pranlukast (PLK) is a leukotriene receptor antagonist (LTRA) that has been approved for treatment of asthma in patients of all ages and allergic rhinitis (AR) in adults but not for AR in children in Japan. This randomized, double-blind, placebo-controlled, crossover study used an artificial exposure chamber (OHIO Chamber) to investigate the efficacy and safety of PLK in children from 10 to 15 years old with seasonal AR (SAR) due to Japanese cedar (JC) pollen. Eighty-four subjects were enrolled and randomized to the treatment arm and 74 were included in the per protocol set. Subjects received either PLK dry syrup (DS) or placebo for 1 week. They were challenged with JC pollen in the OHIO Chamber for 3 hours. Total nasal symptom scores (TNSSs) were recorded every 30 minutes during the exposure. PLK DS treatment suppressed the TNSS changes from baseline significantly when compared with placebo. The difference in the least square means in TNSS between the PLK DS-treated group and placebo group was -0.37 (95% CI, -0.54, -0.20) with a value of p < 0.0001, showing that PLK DS significantly suppressed the nasal symptoms. Regarding specific nasal symptoms, PLK DS significantly suppressed sneezing, nasal discharge, and nasal obstruction. The effect of PLK DS on nasal obstruction was most prominent, with significant improvement relative to placebo beginning 60 minutes after the start of exposure. No serious adverse events were reported during the study. In this study, PLK DS is effective and safe for treatment in children with SAR.

Age and total ribavirin dose are independent predictors of relapse after interferon therapy in chronic hepatitis C revealed by data mining analysis.

BACKGROUND This study aimed to define factors associated with relapse among responders to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy in chronic hepatitis C. METHODS A cohort of genotype 1b chronic hepatitis C patients treated with PEG-IFN plus RBV and who had an undetectable HCV RNA by week 12 (n=951) were randomly assigned to model derivation (n=636) or internal validation (n=315) groups. An independent cohort (n=598) were used for an external validation. A decision tree model for relapse was explored using data mining analysis. RESULTS The data mining analysis defined five subgroups of patients with variable rates of relapse ranging from 13% to 52%. The reproducibility of the model was confirmed by internal and external validations (r(2)=0.79 and 0.83, respectively). Patients with undetectable HCV RNA at week 4 had the lowest risk of relapse (13%), followed by patients <60 years with undetectable HCV RNA at week 5-12 who received ≥3.0 g/kg of body weight of RBV (16%). Older patients with a total RBV dose <3.0 g/kg had the highest risk of relapse (52%). Higher RBV dose beyond 3.0 g/kg was associated with further decrease of relapse rate among patients <60 years (up to 11%) but not among older patients whose relapse rate remained stable around 30%. CONCLUSIONS Data mining analysis revealed that time to HCV RNA negativity, age and total RBV dose was associated with relapse. To prevent relapse, ≥3.0 g/kg of RBV should be administered. Higher dose of RBV may be beneficial in patients <60 years.