Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T).

OBJECTIVE: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. METHODS: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. CONCLUSION: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study.

OBJECTIVE: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs. METHODS: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints). RESULTS: A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p < .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p = .024; 100 mg q2w: 0.0, p = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52. CONCLUSION: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120.

OBJECTIVE: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. METHODS: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. RESULTS: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. CONCLUSION: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

Early-Phase Partial Mayo Score following Golimumab Treatment Is Associated with Endoscopic Improvement at 1 Year in Ulcerative Colitis: A post hoc Analysis of PURSUIT-J Randomized Controlled Trial.

Introduction: Golimumab (GLM) is an anti-tumor necrosis factor-alpha antibody therapy for moderately to severely active ulcerative colitis (UC). Endoscopic improvement is considered one of UC treatment's main goals, and earlier prediction of future endoscopic improvement has clinical implications. We retrospectively analyzed data from the PURSUIT-J, a phase III randomized controlled trial evaluating the efficacy of GLM in the maintenance phase, to find predictors for endoscopic improvement after 60 weeks of GLM treatment. Methods: Ninety-two patients who had completed the maintenance phase of the PURSUIT-J were divided into two groups: those with mucosal healing (MH: Mayo endoscopic subscore of 0 or 1) and those without MH at week 60 (non-MHs). Multivariate logistic regression analysis was conducted using baseline data in the induction phase to determine predictive factors for MHs compared to non-MHs. Results: Twenty-nine patients were classified as MHs and 63 as non-MHs. The multivariate logistic regression analysis showed that the odds ratio for partial Mayo (pMayo) score was highest in MHs (1.87 [95% CI: 1.18-2.98]) at baseline in the induction phase. The receiver operating characteristic analysis to determine the timing of predictions of MHs using pMayo showed that an area under the curve reached 0.8 at week 14 after the first GLM administration. Discussion/Conclusion: pMayo scores at week 14 of GLM treatment are associated with MH at week 60. These results suggest the timing when a clinical decision to continue GLM based on the patient-reported outcomes and the physician's general assessment could be considered.

Results of Macitentan in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension　- A Prospective, Multicenter, Open-Label, Single-Arm, Phase 3 Study.

Background: Macitentan, an endothelin-receptor antagonist, is approved in Japan for the treatment of pulmonary arterial hypertension (PAH). This study evaluated the use of macitentan for chronic thromboembolic pulmonary hypertension (CTEPH) in Japanese patients. Methods and Results: This open-label single-arm Phase 3 study evaluated the efficacy and safety of oral macitentan 10 mg (once daily) in Japanese CTEPH patients. The study was prematurely discontinued due to the sponsor's decision to not develop macitentan 10 mg further for the indication of CTEPH (unrelated to safety concerns). Of the 9 patients enrolled in the study, 4 completed 24 weeks of treatment. The mean (±SD) ratio of pulmonary vascular resistance (PVR) at Week 16 to baseline was 71.9±34.3%. The mean (±SD) decreases in PVR and the PVR index (PVRI) from baseline to Week 16 were 181.4±243.9 dyn·s/cm5 and 280.6±366.0 dyn·s·m2/cm5, respectively. The mean (±SD) increase in the 6-min walk distance from baseline to Week 24 was 44.3±46.8 m. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, except for 1 serious TEAE of angioplasty reported in 1/9 patients that was severe in intensity. Conclusions: Definite conclusions regarding the efficacy of macitentan 10 mg in Japanese patients with CTEPH cannot be drawn because of premature study discontinuation. No safety concerns were observed, and the safety profile was consistent with previously reported studies in CTEPH and PAH patients.

Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate: a randomized phase 3 safety and efficacy study in Japanese patients.

BACKGROUND: Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. METHODS: In this phase 3, double-blind study, 122 patients (age ≥ 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti-rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS: Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. CONCLUSIONS: Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine. TRIAL REGISTRATION: NCT01689532 . Registered 18 September 2012.

Efficacy and safety of golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study-(PURSUIT-J study).

BACKGROUND: The global phase 3 studies of golimumab [PURSUIT-SC and PURSUIT-maintenance (M)], an anti-tumor necrosis factor-α (anti-TNFα) antibody, have demonstrated clinical efficacy and safety as induction and maintenance therapies in patients with moderate to severely active ulcerative colitis (UC). This study aimed to evaluate the efficacy and safety of golimumab as maintenance therapy in the Japanese population. METHODS: In this phase 3, double-blind (DB), placebo-controlled, parallel group, randomized withdrawal study, 144 Japanese patients with moderately to severely active UC received golimumab doses of 200 mg (at week 0) and 100 mg (at week 2) subcutaneously during the 6-week open-label induction phase. Patients who responded to golimumab induction therapy entered the DB maintenance (M) phase and were randomized (1:1) to receive 100 mg of golimumab subcutaneous injection (SC) or placebo every 4 weeks for 52 weeks. The primary endpoint was clinical response through M-week 54; secondary endpoints included clinical remission and mucosal healing at M-week 30 and 54. RESULTS: Among induction responders, more patients on golimumab treatment (56.3%) maintained clinical response through M-week 54 versus the placebo group (19.4%). At both M-week 30 and 54, 50% golimumab-treated patients achieved clinical remission versus the placebo group (6.5%) and a higher proportion of patients on golimumab (59.4%) experienced mucosal healing than the placebo group (16.1%). Incidence of treatment-emergent adverse events was 96.9% in the golimumab group and 71% in the placebo group. Overall, the efficacy and safety results in this study were comparable with those observed in global studies. CONCLUSIONS: Golimumab SC treatment maintained clinical efficacy through week 54 among induction responders, and no new safety signals were observed in the patients with moderate to severely active UC. CLINICAL TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov NCT01863771.

Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.

OBJECTIVE: To evaluate the efficacy and safety of fentanyl 1 day patch in opioid-naïve patients with non-cancer chronic pain insufficiently relieved by non-opioid analgesics. RESEARCH DESIGN AND METHODS: Two phase III placebo-controlled, double-blind, group-comparison, randomized withdrawal studies were conducted in patients with osteoarthritis and/or low back pain (N01 study) and post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain (N02) in Japan. Both studies consisted of period I (10-29 days of titration, fentanyl 12.5-50.0 µg/h) and period II (12 weeks double-blind). CLINICAL TRIAL REGISTRATION: N01, NCT01008618; N02, NCT01008553 MAIN OUTCOME MEASURES: The primary endpoint was the number of days until study discontinuation due to insufficient pain relief in period II, and secondary endpoints included pain scored on visual analog scale (VAS), subject's overall assessment, the number of rescue dose, brief pain inventory short form score, score on short-form 36-item health survey version 2.0, physician's overall assessment, and assessment of adverse events. RESULTS: Of the 218 (N01) and 258 (N02) subjects who entered period I, 150 and 163 subjects entered period II, respectively. In the N01 study, the between-group difference was significant in the VAS score (95% CI: 7.3 [1.1, 13.5] mm, P = 0.0215) but not in the primary endpoint (P = 0.0846, log-rank test). In the N02 study, both primary efficacy (P = 0.0003) and VAS (8.7 [2.4, 15.0] mm, P = 0.0071) results showed that fentanyl was more effective than placebo. The major adverse events were nervous system and gastrointestinal disorders typically associated with opioid analgesic use. The incidence of adverse events in the fentanyl group was 68.5% to 85.7%. CONCLUSIONS: Although the primary efficacy results showed significant effects of fentanyl in the N02 but not the N01 study, overall results showed that fentanyl 1 day patch is effective and well tolerated.

The ClpXP ATP-dependent protease regulates flagellum synthesis in Salmonella enterica serovar typhimurium.

The ClpXP protease is a member of the ATP-dependent protease family and plays a dynamic role in the control of availability of regulatory proteins and the breakdown of abnormal and misfolded proteins. The proteolytic activity is rendered by the ClpP component, while the substrate specificity is determined by the ClpX component that has ATPase activity. We describe here a new role of the ClpXP protease in Salmonella enterica serovar Typhimurium in which ClpXP is involved in the regulation of flagellum synthesis. Cells deleted for ClpXP show "hyperflagellate phenotype," exhibit overproduction of the flagellar protein, and show a fourfold increase in the rate of transcription of the fliC encoding flagellar filament. The assay for promoter activity of the genes responsible for expression of the fliC showed that the depletion of ClpXP results in dramatic enhancement of the expression of the fliA encoding sigma factor final sigma(28), leaving the expression level of the flhD master operon lying at the top of the transcription hierarchy of flagellar regulon almost normal. These results suggest that the ClpXP may be responsible for repressing the expression of flagellar regulon through the control of the FlhD/FlhC master regulators at the posttranscriptional and/or posttranslational levels. Proteome analysis of proteins secreted from the mutant cells deficient for flhDC and clpXP genes demonstrated that the DeltaflhD mutation abolished the enhanced effect by DeltaclpXP mutation on the production of flagellar proteins, suggesting that the ClpXP possibly defines a regulatory pathway affecting the expression of flagellar regulon that is dependent on FlhD/FlhC master regulators.