Yuichiro Kaneko

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.

Randomized Controlled Trial of Bixalomer Versus Sevelamer Hydrochloride in Hemodialysis Patients With Hyperphosphatemia

Hyperphosphatemia is a prognostic factor for morbidity and mortality in chronic kidney disease. Bixalomer is a nonabsorbable polymer that decreases serum phosphate levels by binding phosphate in the gastrointestinal tract. This study compared the efficacy and safety of bixalomer versus sevelamer hydrochloride for controlling hyperphosphatemia in hemodialysis patients. This was a multicenter, randomized open‐label, non‐inferiority study. The primary endpoint was serum phosphate on completion of treatment. Administration of bixalomer was started at 1.5 g/day and adjusted to a maximum of 7.5 g/day depending on the serum phosphate level. Sevelamer hydrochloride was started at 3.0 or 6.0 g/day and adjusted to a maximum of 9.0 g/day. Treatment was continued for 12 weeks. Fifty‐five patients were randomized to each treatment group. After 12 weeks, the baseline adjusted mean serum phosphate level was 5.87 mg/dL in the bixalomer group and 5.55 mg/dL in the sevelamer group, with a difference of 0.31 mg/dL and 95% confidence interval (CI) of [−0.13 to 0.76]. The upper limit of the 95%CI for the difference of the mean serum phosphate level between the two groups was <1.0 mg/dL, which was the non‐inferiority margin in this study. Thus, non‐inferiority of bixalomer to sevelamer was confirmed. The incidence of adverse events was lower in the bixalomer group, and bixalomer did not promote acidosis. Bixalomer achieved a similar reduction of serum phosphate to sevelamer, while causing fewer adverse reactions. Consequently, the usefulness of bixalomer for treating hyperphosphatemia was confirmed.

Long-term treatment of hyperphosphatemia with bixalomer in Japanese hemodialysis patients.

Bixalomer is a nonabsorbable polymer that binds phosphate in the gastrointestinal tract and lowers the serum phosphate level by inhibiting phosphate absorption. The safety and efficacy of long‐term bixalomer treatment were assessed in Japanese hemodialysis patients with hyperphosphatemia. This was a multicenter open‐label study with a 48‐week treatment period. The main efficacy endpoints were the serum phosphate level and rate of achieving the target serum phosphate range (3.5–6.0 mg/dL). Bixalomer was initiated at a dose of 1.5 g/day, which was increased to a maximum of 7.5 g/day depending on the serum phosphate response. Of 248 subjects who started treatment, 179 completed the study. The mean serum phosphate level decreased over time and remained around 5.5 mg/dL from weeks 16 to 48. The target serum phosphate level was reached in >50% of subjects by week 7 and was maintained in 65.2% to 75.9% until week 48. The incidence of adverse events and adverse drug reactions was 94.4% and 29.4%, respectively. There was a potential relationship with the study drug for four serious adverse events (ischemic colitis, hemorrhagic intestinal diverticulum, esophageal ulcer, and acute cholecystitis), which occurred in one patient each. Constipation was the most common adverse drug reaction (21.0%). Most adverse events and adverse drug reactions occurred soon after starting administration, and their incidence did not increase during long‐term treatment. Bixalomer did not reduce the bicarbonate level or promote metabolic acidosis. Bixalomer is clinically useful for the long‐term treatment of hyperphosphatemia.

Dose‐Finding Study of Bixalomer in Patients With Chronic Kidney Disease on Hemodialysis With Hyperphosphatemia: A Double‐Blind, Randomized, Placebo‐Controlled and Sevelamer Hydrochloride‐Controlled Open‐Label, Parallel Group Study

Hyperphosphatemia is a prognostic factor for morbidity and mortality in chronic kidney disease. Bixalomer (Kiklin® Capsules) is a non‐absorbable polymer that decreases serum phosphate levels by binding phosphate in the gastrointestinal tract. This study was a multicenter, double‐blind, randomized, placebo‐controlled study to confirm the superiority of bixalomer to placebo for a 4‐week treatment period in patients with chronic kidney disease on hemodialysis with hyperphosphatemia. Sevelamer hydrochloride (HCl), a similar non‐absorbable polymer, was used as an active comparator for open‐label as a reference without statistical comparison for efficacy and safety. The primary endpoint was the change in serum phosphorus level from baseline. The safety profile was also investigated. The number of subjects was 32 in the placebo group and 31 in each bixalomer group (1.5, 3.0 and 4.5 g/day), respectively. The baseline serum phosphorus level was 7.95 to 8.25 mg/dL. Bixalomer showed a significant decrease in serum phosphorus level at all doses compared with placebo, and the adjusted mean change in serum phosphorus level from the baseline to the end of treatment (at Week 4 or at the time of discontinuation) was +0.24 mg/dL in the placebo group, −0.75 mg/dL in the 1.5 g/day group, −1.32 mg/dL in the 3.0 g/day group, and −1.80 mg/dL in the 4.5 g/day group, showing a dose‐dependent decrease in serum phosphorus level. The mean change in serum phosphorus level was −2.32 mg/dL in the sevelamer HCl group under the mean dose of 4.8 g/day. Major adverse events included constipation, hard feces, vomiting, etc.; however, none of the adverse events were serious or severe. Consequently, the superiority of bixalomer to placebo and its dose‐dependency for treating hyperphosphatemia were confirmed (Clinical trial registration: NCT00505037).

Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations

Epidermal growth factor receptor (EGFR)‐activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non‐small‐cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once‐daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose‐escalation/dose‐expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25‐600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M‐positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simons two‐stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9‐54.0). Median duration of progression‐free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment‐related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR‐activating and T790M mutations.

Suppression of infliximab antibody levels by azathioprine in patients with rheumatoid arthritis

In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enrolled a total of 10 Japanese adult patients with RA who were treated with infliximab concomitantly with methotrexate or azathioprine. Serum concentrations of infliximab and ATI of these patients were measured. The mean serum infliximab concentrations was 1.6±1.3 μg/ml in patients with methotrexate and 1.0±0.5 μg/ml in patients with azathioprine. Serum ATI concentrations were below the limit of quantitation in 4 of 5 patients in each group. The results from the present study suggest that azathioprine suppresses ATI production.

Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment

Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT*3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT*3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85±0.30 mg/kg/day vs. 1.2±0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA.

Proteinuria selectivity index as a prognostic biomarker in lupus nephritis.

Objectives The selectivity index has been proposed in predicting the response to immunosuppressive therapy in nephrotic syndrome and other primary kidney disorders. The aim of this study was to elucidate the predictive value of the selectivity index for the treatment response and renal outcome in patients with lupus nephritis. Methods Forty-four patients with lupus nephritis with selectivity index available at the time of renal biopsy were divided into two groups according to the cut-off value of the selectivity index determined by a receiver operating characteristics curve to differentiate treatment responders from non-responders. The baseline characteristics, overall response rate and renal functional outcome were studied retrospectively, and compared between the two groups. Prognostic factors for achieving remission were identified. Results The cut-off value of the selectivity index was 0.167. The low selectivity index (<0.167) and the high selectivity index (≥0.167) group included 24 and 20 patients, respectively. The overall response rate was significantly higher (88% vs. 50%, P = 0.007) and the rate of progression to end-stage renal disease was lower in the low selectivity index group (0% vs. 15%, P = 0.049). More patients in the high selectivity index group had chronic lesions on renal biopsy (P = 0.002). The selectivity index was the prognostic factor for achieving overall response based on a multivariate analysis (P = 0.020). Conclusions A selectivity index ≥0.167 was a strong predictor for a poor treatment response and the presence of chronic lesions on renal biopsy. Further exploration with a larger cohort and longer follow-up period is warranted.

THU0585 Distinct Clinical Features Distinguishing IGG4-Related Disease and Multicentric Castlesman's Disease

Background IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease with multiple-organ involvement characterized by infiltration of IgG4+plasma cells and elevated serum IgG4 concentrations. However, similar findings are observed in multicentric Castlemans disease (MCD)1, thereby making it difficult to differentiate one disease from the other. Objectives The aim of this study was to clarify the differences of clinical characteristics and laboratory findings in IgG4-RD and MCD for differential diagnosis. Methods All consecutive patients with IgG4-RD and MCD who visited the Rheumatology or Hematology department in our institutes from January 2000 to November 2015 were retrospectively reviewed. Patient characteristics and laboratory data at the time of diagnosis were compared. Results Forty-nine patients with IgG4-RD and 48 patients with MCD were included. Patients with IgG4-RD were older compared to MCD (57.4 vs 47.3 years, p<0.0001) and there was no difference in gender distribution. While lymph nodes were affected less frequently in IgG4-RD compared to MCD (49% vs 100%, p<0.0001), lacrimal glands, salivary glands and pancreas were affected only in IgG4-RD. The levels of serum IgG, IgA and IgM were significantly lower in patients with IgG4-RD compared to MCD (IgG: 1945.6 mg/dl vs 4317.5 mg/dl, p<0.0001, IgA: 172 mg/dl vs 669 mg/dl, p<0.0001, IgM: 83 mg/dl vs 279 mg/dl, p<0.0001), whereas no difference was observed in serum IgE levels. Although level of serum IgG4 was also equivalent between IgG4-RD and MCD (607 mg/dl vs 353 mg/dl, p=0.211), IgG4/IgG ratio was significantly higher in IgG4-RD compared to MCD (0.30 vs 0.09, p<0.0001). In addition, atopic history was more frequent (71.4% vs 16.7%, p<0.0001), and the proportion of eosinophils (6.4% vs 2.7%, p<0.0001) was significantly higher in IgG4-RD compared to MCD. The level of serum C-reactive protein (0.3 mg/dl vs 5.4 mg/dl, p<0.0001) and erythrocyte sedimentation rate (35.9 mm/hr vs 110.7 mm/hr, p<0.0001), the prevalence of anemia (10.2% vs 50.0%, p<0.0001) and thrombocytosis (2.0% vs 31.3%, p<0.0001) were significantly higher in MCD compared to IgG4-RD. Conclusions The involvement of lacrimal gland, salivary gland and pancreas was unique for IgG4-RD. While allergic reaction such as hypereosinophilia and atopic history was more frequently observed in IgG4-RD, intense inflammation was the distinct characteristics for MCD. The distribution of organ involvement and marked inflammatory reaction represented by elevated serum CRP, anemia and thrombocytosis were important features to distinguish between IgG4-RD and MCD. References Y. Sato et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castlemans disease. Mod Pathol 2009;22:589–599. Acknowledgement We sincerely thank all the physicians and others caring for the patients enrolled in this study. Disclosure of Interest None declared