Ixekizumab Efficacy in Patients with Severe Peripheral Psoriatic Arthritis: A Post Hoc Analysis of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (SPIRIT-P1).

INTRODUCTION: The efficacy and safety of ixekizumab, an anti-interleukin-17A antibody, in patients with severe symptoms of psoriatic arthritis are largely unexplored. We report the efficacy and safety of ixekizumab in a post hoc analysis of the SPIRIT-P1 trial. METHODS: Patients were treated with placebo, ixekizumab 80 mg every 2 weeks (Q2W) or 4 weeks (Q4W), or adalimumab 40 mg Q2W for 24 weeks. In this subgroup analysis of SPIRIT-P1, the population with severe psoriatic arthritis was defined using the modified composite psoriatic activity index total score > 7 and peripheral arthritis score = 3 (> 4 tender or swollen joint count and ≥ 0.5 Health Assessment Questionnaire-Disability Index). Efficacy was measured by joint and skin endpoints including disease progression. RESULTS: In the severe population, significantly more patients (p ≤ 0.001) treated with ixekizumab than placebo achieved 20% improvement according to the American College of Rheumatology criteria (ACR 20): 63.3% for ixekizumab Q4W, 60.4% for ixekizumab Q2W, and 24.5% for placebo. Statistically greater responses compared with placebo were observed in the severe population for ACR 50, ACR 70, ACR core set, disease activity index for psoriatic arthritis (DAPSA) low disease activity and DAPSA remission, and 28-joint disease activity score using C-reactive protein, as well as Psoriasis Area and Severity Index (PASI) 75, PASI 90, and PASI 100 (p ≤ 0.001). Efficacy findings and the safety profile of ixekizumab in the severe population were consistent with those of the overall population, with no new safety concerns identified. CONCLUSIONS: In patients with severe psoriatic arthritis, 24 weeks of treatment with ixekizumab resulted in improvements in both joint and skin symptoms. The safety profile in the severe population was consistent with the established safety profile of ixekizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01695239.

Ixekizumab 80 mg Every 2 Weeks Treatment Beyond Week 12 for Japanese Patients with Generalized Pustular Psoriasis and Erythrodermic Psoriasis.

INTRODUCTION: In 2018, ixekizumab (80 mg every 2 weeks [Q2W] beyond Week 12) received approval in Japan for patients with generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). This open-label study evaluated the efficacy and safety of ixekizumab (80 mg Q2W from Week 12 to Week 20) in Japanese patients with GPP and EP. METHODS: Seven patients with GPP and five patients with EP were enrolled. An initial dose of 160 mg (subcutaneous [SC] injection) was followed by 80 mg Q2W SC until Week 12. Primary endpoint assessed global improvement score (GIS) by comparing psoriatic findings, Static Physician Global Assessment, Psoriasis Area and Severity Index score, and other evaluations with those at the baseline and were graded as 1 = resolved, 2= improved, 3 = unchanged, and 4 = worsened. Patients who showed GIS = 1 (resolved) at Week 12 completed the study. Patients with GIS ≥ 2 continued to receive ixekizumab 80 mg Q2W until Week 20. RESULTS: At Week 12, four of seven patients with GPP showed "resolved," two showed "improved," and one showed "worsened." Of five patients with EP, one showed "resolved" and four showed "improved." Two patients with GPP and four patients with EP continued ixekizumab treatment until Week 20. At Week 20, one of the two patients with GPP showed "resolved" and one patient showed "improved." All four patients with EP showed "improved." One non-drug related serious adverse event was reported by one patient with EP at Week 12. From Week 12 to Week 20, no adverse events (AEs) were reported in patients with GPP, but two mild AEs were reported in one of the four patients with EP. CONCLUSIONS: This study indicates that ixekizumab continuous Q2W dosing is efficacious and safe for patients with GPP and EP. CLINICAL TRIAL REGISTRATION: NCT03942042.

Ixekizumab is an anti-interleukin-17 treatment for a skin condition with thick and scaly patches called psoriasis. Ixekizumab (initial dose of 160 mg followed by 80 mg administered every 2 weeks [Q2W] from Week 2 through Week 12 and thereafter 80 mg every 4 weeks [Q4W]) has been approved in Japan; people who have not achieved 100% clear skin after taking ixekizumab for 12 weeks can continue to receive ixekizumab Q2W rather than monthly. However, this approval partially lacked data from people with rare types of psoriasis, generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). The aim of this study was to look at the effectiveness and safety of continuous Q2W dosing of ixekizumab in Japanese people with GPP and EP beyond Week 12. Researchers aimed to find out whether psoriasis symptoms in this population improved if they continued Q2W treatment for > 12 weeks. Seven people with GPP and 5 with EP participated in the study (12 in total). Participants initially received 160 mg under-the-skin injection of ixekizumab, followed by 80 mg injections Q2W. Two GPP and four EP participants continued to receive ixekizumab after 12 weeks up to Week 20. One GPP participant achieved 100% clear skin, and another GPP participant and all 4 EP participants showed improvement. No participants died, and safety findings were similar to previous ixekizumab studies from both Japanese and non-Japanese people. This study suggests that people with GPP and EP who continue to take ixekizumab Q2W after 12 weeks may show improvements in their psoriasis with a well-tolerated safety profile.

Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J).

Psoriasis, a chronic, immune-mediated skin disease characterized by red, scaly plaques, affects approximately 0.3% of the population in Japan. The aim of this open-label study was to evaluate the long-term efficacy and safety of ixekizumab, a humanized, anti-interleukin-17A monoclonal antibody, in Japanese patients with plaque psoriasis (n = 78, including 11 psoriatic arthritis), erythrodermic psoriasis (n = 8) and generalized pustular psoriasis (n = 5). Ixekizumab was administrated s.c. at baseline (week 0, 160 mg), from weeks 2 to 12 (80 mg every 2 weeks), and from weeks 16 to 52 (80 mg every 4 weeks). At week 52, 92.3% of patients with plaque psoriasis achieved Psoriasis Area and Severity Index (PASI) 75, 80.8% achieved PASI 90, 48.7% achieved PASI 100, and 52.6% had remission of plaques (by static Physician Global Assessment, sPGA [0]). Difficult to treat areas of psoriasis (nail or scalp) also responded to ixekizumab. All patients with psoriatic arthritis who were assessed (5/5) achieved an American College of Rheumatology 20 response. Most patients with erythrodermic psoriasis or generalized pustular psoriasis responded to ixekizumab and the clinical outcome was maintained over 52 weeks (75% and 60% of patients achieved sPGA [0, 1] at week 52, respectively). Mostly mild or moderate treatment-emergent adverse events were reported by 79 of 91 patients; the most common were nasopharyngitis, eczema, seborrheic dermatitis, urticaria and injection site reactions. In conclusion, 52-week ixekizumab treatment was efficacious and well tolerated in Japanese patients with plaque psoriasis. Efficacy was also observed in patients with erythrodermic psoriasis, generalized pustular psoriasis and psoriatic arthritis.

Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies.

OBJECTIVES: Assess the efficacy and safety of tadalafil 5 mg once-daily in Asian men with lower urinary tract symptoms by pooling data from three clinical studies. METHODS: Data on 1199 Japanese, Korean, and Taiwanese men given tadalafil 5 mg (n = 601) or placebo (n = 598) were pooled from three double-blind, placebo-controlled, 12-week studies. Efficacy measures included International Prostate Symptom Score, and Patient and Clinician Global Impressions of Improvement. These measures were also assessed for patient subgroups (age categories, baseline disease severity and/or prostate volume, prior alpha-blocker treatment). Safety measures included adverse events, including those in selected body systems. Efficacy measure changes throughout treatment were assessed by mixed-effect model repeated-measures analysis; baseline to end-point changes for the total population and subgroups were evaluated by analysis of covariance. RESULTS: Tadalafil 5 mg led to significant improvement (vs placebo) in all International Prostate Symptom Scores at all time-points (week 4 P ≤ 0.013 for all measures; week 8 P ≤ 0.005, week 12 P < 0.001). End-point results for both global impressions scales also favored tadalafil (both P < 0.001 vs placebo). Tadalafil efficacy was similar between patient subgroups of varied disease severity (interaction P = 0.097), prior alpha-blocker use (P = 0.580), and prostate volume (P = 0.921). The drug was slightly less effective in older men (interaction P = 0.042). No unexpected adverse events were reported, and no meaningful adverse effects were observed in visual, auditory, or cardiovascular systems. CONCLUSIONS: Tadalafil 5 mg once-daily for 12 weeks is efficacious and safe in Asian men with lower urinary tract symptoms. Tadalafil is also effective in men of different ages, disease severity, prior alpha-blocker exposure, and prostate volumes.

The Efficacy and Safety of Tadalafil 5 mg Once Daily in Korean Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: An Integrated Analysis.

PURPOSE: This post hoc integrated analysis assessed the efficacy and safety of tadalafil 5 mg once daily in a large Korean population with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS). MATERIALS AND METHODS: Individual Korean participant data were integrated from three 12-week, randomized, double-blind, placebo-controlled studies in Asian men with BPH-LUTS, wherein 177 Korean men received placebo and 177 received tadalafil 5 mg once daily. The primary objective was to compare the change from baseline to week 12 in total International Prostate Symptom Score (IPSS) after treatment with tadalafil versus placebo. RESULTS: A significantly greater improvement (p<0.001) in total IPSS from baseline to week 12 was observed for tadalafil compared to placebo (least squares mean: tadalafil=-5.97; placebo=-3.94 ). Total IPSS at weeks 4 and 12, IPSS voiding and storage subscores at weeks 4, 8, and 12, and IPSS quality of life index at weeks 8 and 12 were also significantly improved (p<0.05) for tadalafil compared to placebo. There was significant improvement (p<0.001) in the patient global Impression of improvement responses and numerical improvement in the clinician global impression of improvement responses with tadalafil compared to placebo. There were no significant treatment differences for peak urine flow rate or postvoid residual volume. Few participants had treatment-emergent adverse events and there were no unexpected safety findings. CONCLUSIONS: This integrated analysis of three randomized, placebo-controlled Asian studies confirmed tadalafil 5 mg once daily as an efficacious and well-tolerated treatment for Korean men with BPH-LUTS.

Efficacy, safety, tolerability, and pharmacokinetic profile of evacetrapib administered as monotherapy or in combination with atorvastatin in Japanese patients with dyslipidemia.

The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL-C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL-C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia.

Tadalafil 5 mg once-daily therapy for men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results from a randomized, double-blind, placebo-controlled trial carried out in Japan and Korea.

OBJECTIVES: To gain further evidence on the efficacy, safety and tolerability of tadalafil 5 mg once-daily in Asian men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. METHODS: Japanese and Korean men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia were randomized to once-daily tadalafil 5 mg (n = 306) or placebo (n = 304) for 12 weeks. RESULTS: A significantly greater improvement (P < 0.001) in total International Prostate Symptom Score for the change from baseline (week 0) to study end-point (week 12) was observed for tadalafil (-6.0) versus placebo (-4.5). Significantly greater improvements (P < 0.01) in total International Prostate Symptom Score for the change from baseline to weeks 4 and 8 were observed for tadalafil versus placebo. Significantly greater improvements (P < 0.05) in International Prostate Symptom Score voiding and storage subscores, and International Prostate Symptom Score Quality of Life Index were observed for the change from baseline to end-point for tadalafil versus placebo. Significantly greater improvements (P < 0.001) in urinary symptoms were observed for tadalafil versus placebo for both Patient and Clinician Global Impressions of Improvement. No new safety concerns were identified. CONCLUSIONS: These findings confirm the efficacy and safety profile of tadalafil 5 mg once-daily in Asian men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a randomized placebo- and tamsulosin-controlled 12-week study in Asian men.

OBJECTIVES: To examine the efficacy and safety of tadalafil in Asian men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. METHODS: Asian men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia were randomized to once-daily placebo (n=154), tadalafil 2.5 mg (n=151), tadalafil 5.0 mg (n=155) or tamsulosin 0.2 mg (active control, n=152) for 12 weeks. RESULTS: Total International Prostate Symptom Score least-squares mean changes from baseline to end-point significantly improved with tadalafil 2.5 mg (-4.8, P=0.003) and 5 mg (-4.7, P=0.004) versus placebo (-3.0). Significant improvement in the International Prostate Symptom Score versus placebo was observed earlier (week 2) for tadalafil 5.0 mg than for tadalafil 2.5 mg (week 8). Significant improvements (P<0.05) in both tadalafil groups versus placebo were observed for the International Prostate Symptom Score voiding subscore, International Prostate Symptom Score Quality of Life, and for Patient and Clinician Global Impressions of Improvement. Significant improvements versus placebo were observed in the International Prostate Symptom Score storage subscore for tadalafil 5.0 mg (-1.7, P=0.021), but not tadalafil 2.5 mg (-1.5, P=0.072). No significant improvements in benign prostatic hyperplasia Impact Index or improvements in peak urinary flow rates were observed with tadalafil 2.5 mg or 5.0 mg versus placebo. Tamsulosin treatment resulted in significant improvements versus placebo across all efficacy parameters, except for peak urinary flow rates. Safety results were consistent with the known tadalafil and tamsulosin safety profiles. CONCLUSIONS: Tadalafil once daily represents an effective and well tolerated medical treatment for Asian men presenting with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

Japanese growth prediction model for prepubertal children with growth hormone deficiency.

BACKGROUND: Individual responses to growth hormone (GH) treatment are variable, and efficacy should be judged in each individual patient. OBJECTIVE: The aim of this study was to develop a prediction model for the growth response of GH treatment in Japanese prepubertal children with GH deficiency. PATIENTS AND METHODS: Pediatric patients with GH deficiency were enrolled. Auxological measurements, markers of GH status, and markers of bone metabolism were measured at baseline and at 3 and 6 months after the start of GH treatment. Correlations with height velocity (HV) at 36 months of GH treatment were calculated. Prediction models were evaluated by multiple regression analysis. RESULTS: The model, which combined the parameters of HV at 3 months, insulin-like growth factor-binding protein 3, standard deviation score, and pyridinoline at 3 months, best predicted HV at 36 months. CONCLUSIONS: This model can accurately predict the first 3 years of growth response after 3 months of GH replacement therapy in prepubertal Japanese children.

Tadalafil for the Treatment of Lower Urinary Tract Symptoms in Japanese Men with Benign Prostatic Hyperplasia: Results from a 12-week Placebo-controlled Dose-finding Study with a 42-week Open-label Extension.

OBJECTIVES: To examine the efficacy, safety, and dose response of tadalafil once daily in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS). METHODS: Men ≥45 years with moderate-to-severe BPH-LUTS were randomized to once-daily placebo (N = 140), tadalafil 2.5 mg (N = 142), or tadalafil 5.0 mg (N = 140), in a 12-week double-blind phase, followed by a 42-week, tadalafil 5.0 mg open-label extension (OLE) phase (N = 394). The primary outcome was total International Prostate Symptom Score (IPSS) change from baseline to last available observation in the double-blind phase. RESULTS: The least squares (LS) mean difference between placebo and tadalafil in total IPSS change from baseline was -0.7 (P = 0.201) and -1.1 (P = 0.062) for tadalafil 2.5 and 5 mg, respectively (ANCOVA; a dose-dependent improvement in placebo-adjusted total IPSS for tadalafil 5 mg versus 2.5 mg of 57%). Repeated-measures analyses identified a significant total IPSS change for tadalafil 5 mg (LS mean difference between placebo and tadalafil 5 mg: -1.2; P = 0.035), but not tadalafil 2.5 mg, at week 12. Significant improvements for tadalafil 5 mg were demonstrated (ANCOVA) for IPSS obstructive subscore (P = 0.033) and IPSS quality of life index (P = 0.022). Numerical improvements in IPSS scores were maintained over the OLE phase. Tadalafil was well tolerated with no unexpected adverse events. CONCLUSION: Tadalafil (5.0 mg) had a favorable benefit-to-risk profile, supporting further investigation of tadalafil (5.0 mg) in Japanese men with BPH-LUTS.

Evaluation of Quality of Life in Children with GH Deficiency and Idiopathic Short Stature Using the Child Behavior Checklist.

The quality of life (QoL) of short children is an important issue that has been studied in Western countries, but not fully in Japan. We assessed the psychosocial profiles of Japanese children with short stature using the Japanese version of the Child Behavior Checklist (CBCL). A higher score in the CBCL means a lower QoL. A total of 116 children with idiopathic short stature (ISS) and 127 children with GH deficiency (GHD), aged 4 to 15 yr, were enrolled in the study. The total CBCL scores of the children in the GHD/ISS group were found to be higher than those of the normal children group. The QoL subscales for social problems and attention problems of the young (4-11 yr) children in the GHD/ISS group were significantly higher than those of the group of children of normal height. The proportion of children with GHD/ISS classified into the borderline/abnormal range was significantly higher than that of normal children. Children with ISS tended to have higher total scores and more subscale problems, and a greater proportion of these children was classified in the borderline/abnormal range than the children with GHD, although the difference was not significant. These results suggest that QoL is impaired in Japanese children due to short stature.