Post hoc analysis of patients with rheumatoid arthritis under clinical remission in two Japanese Phase 3 trials of peficitinib treatment (RAJ3 and RAJ4).

OBJECTIVE: We evaluated remission rates and their relationship with baseline characteristics in patients with rheumatoid arthritis treated with the oral Janus kinase inhibitor peficitinib. METHODS: This post hoc analysis of data from two Phase 3 studies (RAJ3 and RAJ4) of peficitinib (100 and 150 mg/day) in Asian rheumatoid arthritis patients investigated clinical disease activity index (CDAI) remission and low disease activity rates from baseline to Week 52. CDAI, Health Assessment Questionnaire-Disability Index, and van der Heijde-modified total Sharp score remission/low disease activity rates at Week 52 were evaluated among patients achieving CDAI remission at Weeks 12/28. Logistic regression analyses explored the relationship between baseline characteristics and CDAI remission/low disease activity rates. RESULTS: CDAI remission rates increased over time in a dose-dependent manner in both peficitinib-treated groups. Most patients achieving CDAI remission at Weeks 12/28 also achieved remission at Week 52. Following the multivariate analysis of demographic and baseline characteristics, factors associated with the achievement of CDAI remission at Week 28 included male sex, low baseline prednisone dose (RAJ3 only), and low baseline Disease Activity Score 28-C-reactive protein (RAJ4 only). CONCLUSIONS: Peficitinib demonstrated persistent efficacy in clinical remission to Week 52. Baseline characteristics associated with CDAI remission were mostly consistent with previous studies using other disease-modifying antirheumatic drugs.

Determining the late effect parameter in the Fleming-Harrington test using asymptotic relative efficiency in cancer immunotherapy clinical trials.

The delayed treatment effect, which manifests as a separation of survival curves after a change point, has often been observed in immunotherapy clinical trials. A late effect of this kind may violate the proportional hazards assumption, resulting in the non-negligible loss of statistical power of an ordinary log-rank test when comparing survival curves. The Fleming-Harrington (FH) test, a weighted log-rank test, is configured to mitigate the loss of power by incorporating a weight function with two parameters, one each for early and late treatment effects. The two parameters need to be appropriately determined, but no helpful guides have been fully established. Since the late effect is expected in immunotherapy trials, we focus on the late effect parameter in this study. We consider parameterizing the late effect in a readily interpretable fashion and determining the optimal late effect parameter in the FH test to maintain statistical power in reference to the asymptotic relative efficiency (ARE). The optimization is carried out under three lag models (i.e. linear, threshold, and generalized linear lag), where the optimal weights are proportional to the lag functions characterized by the change points. Extensive simulation studies showed that the FH test with the selected late parameter reliably provided sufficient power even when the change points in the lag models were misspecified. This finding suggests that the FH test with the ARE-guided late parameter may be a reasonable and practical choice for the primary analysis in immunotherapy clinical trials.

Safety and effectiveness of peficitinib 100 mg/day in patients achieving clinical remission from a long-term open-label extension study in Japan, Korea, and Taiwan (RAJ2).

OBJECTIVES: This post hoc analysis of the RAJ2 study assessed long-term safety and effectiveness of peficitinib 100 mg/day for treatment of rheumatoid arthritis. METHODS: Eligible patients previously completed two Phase 3 (RAJ3 and RAJ4) studies of peficitinib in Asia. All patients received peficitinib 100 mg/day at RAJ2 Week (W)0; dose change to 50 mg/day or 150 mg/day was permitted. Safety endpoints included treatment-emergent adverse events and laboratory test results. Effectiveness endpoints included peficitinib exposure pattern, achievement of Clinical Disease Activity Index (CDAI) remission by peficitinib exposure pattern at W0 and W48, and association of demographics/characteristics with CDAI remission at W0 and W48. RESULTS: Overall, no new safety findings were reported at W48, and renal function was unaffected. Of patients included in effectiveness analyses at W48, 70.9% (451/636) had maintained peficitinib 100 mg/day since W0. Of patients who achieved CDAI remission at W0 and maintained peficitinib 100 mg/day to W48, 50.3% (79/157) maintained CDAI remission to W48. Low disease activity and a lower number of prior disease-modifying antirheumatic drugs were significantly associated with CDAI remission at W48. CONCLUSIONS: Long-term peficitinib treatment at a dose of 100 mg/day was generally well tolerated and, following induction therapy, maintained effectiveness through to W48.

Post hoc analysis of clinical characteristics of patients with radiographic progression in a Japanese phase 3 trial of peficitinib and methotrexate treatment (RAJ4).

OBJECTIVE: To determine the efficacy of peficitinib in reducing joint damage and predictive factors affecting treatment response in Japanese patients with rheumatoid arthritis. METHODS: This post hoc analysis used data from a placebo-controlled, phase 3 trial (RAJ4) of peficitinib in patients with rheumatoid arthritis and inadequate response to methotrexate. Erosion and joint space narrowing (JSN) were assessed at baseline and at Week 28/early termination of treatment using the van der Heijde-modified Sharp method. A univariate logistic regression analysis of change from baseline in a modified total Sharp score identified predictive factors with significant treatment interaction; the effects of these factors on treatment response were further evaluated using a multivariate model. RESULTS: The analyses included 481 patients. For most joint groups, peficitinib demonstrated a reduced change from baseline at Week 28/early termination in erosion and JSN scores versus placebo; a numerically greater effect was observed with peficitinib 150 mg versus 100 mg. Baseline C-reactive protein (CRP) and prednisolone dose were identified as clinically significant negative predictive factors: the treatment effect decreased as CRP or prednisolone dose increased for both peficitinib doses. CONCLUSIONS: Peficitinib 100 mg and 150 mg reduced joint damage versus placebo, across almost all joint groups. Higher baseline CRP and/or prednisolone dose were associated with reduced peficitinib efficacy. CLINICALTRIALS.GOV IDENTIFIER: NCT02305849.

Impact of age on the efficacy and safety of peficitinib (ASP015K) for the treatment of rheumatoid arthritis.

OBJECTIVES: To evaluate peficitinib efficacy and safety in Asian patients with rheumatoid arthritis (RA), stratified by age (≥20-<50, ≥50-<65, and ≥65 years). METHODS: Efficacy data from two Phase 3 studies were analysed. Safety data from one Phase 2, two Phase 3, and one open-label extension study were pooled. Incidence rates per 100 patient-years of adverse events of special interest were calculated, and Cox proportional hazard analysis was conducted. RESULTS: 1052 patients received peficitinib for 2 years (median). Peficitinib demonstrated efficacy improvements versus placebo across all age categories. Incidence rates (95% confidence interval) per 100 patient-years for ≥20-<50, ≥50-<65, and ≥65 years were 0.8 (0.4, 1.9), 2.6 (1.8, 3.7), and 4.7 (3.1, 7.0) for serious infections and 3.7 (2.5, 5.4), 6.4 (5.0, 8.2), and 11.2 (8.5, 14.7) for herpes zoster-related disease, respectively. Twenty patients reported malignancies in pooled Phase 2/3 studies. Incidences of serious infections and herpes zoster-related disease increased significantly with age, but there was no association with baseline estimated glomerular filtration rate. CONCLUSIONS: Peficitinib was efficacious in adult Asian RA patients of all ages. Age, but not estimated glomerular filtration rate, was associated with serious infections and herpes zoster-related disease, demonstrating the importance of an appropriate RA treatment strategy in older patients.

A pooled analysis of serious infections and herpes zoster-related disease in Asian patients with rheumatoid arthritis treated with peficitinib (ASP015K) over a median of 3 years.

OBJECTIVE: To analyse serious infection (SI) and herpes zoster-related disease (HZD) during long-term treatment of rheumatoid arthritis with the oral Janus kinase inhibitor, peficitinib (ASP015K). METHODS: This was a post hoc analysis of pooled data from one Phase 2b study and two Phase 3 studies and final data from a long-term extension study of peficitinib in Asian rheumatoid arthritis patients. Two pooled datasets were analysed (Phase 3 studies and Phase 2/3 studies). Univariate and multivariate Cox regression analyses explored relationships between exposure-adjusted incidence rate of SI and HZD, peficitinib dose, and baseline factors. RESULTS: Total peficitinib exposure for 1052 patients receiving once-daily peficitinib in the pooled Phase 2/3 Asian studies was 2998.9 patient-years. Exposure-adjusted incidence rates (95% confidence interval) of SI and HZD were 2.7 (2.2, 3.4) and 6.9 (6.0, 8.0) per 100 patient-years, respectively, in pooled Phase 2/3 studies. Advanced age was prognostic for SI and HZD, while baseline prednisolone dose was prognostic for SI. There was no temporal relationship between either adverse event and prolonged peficitinib administration. CONCLUSIONS: As expected in this peficitinib-treated population, older patients had increased risk of SI and HZD, and those receiving higher prednisolone doses had increased risk of SI.

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis.

AIMS: To analyse the population pharmacokinetics (PK) of peficitinib in patients with rheumatoid arthritis (RA) and assess the potential PK covariates to identify the requirement for dose adjustment in RA patients. METHODS: The analysis incorporated 2464 observations from 98 healthy volunteers and 4919 observations from 989 RA patients. A population PK model for peficitinib in RA patients was constructed by a nonlinear mixed effect model using NONMEM with prior information from a healthy volunteer model. RESULTS: A 2-compartment model with sequential zero- and first-order absorption and lag time was constructed for RA patients. Covariate exploration in the RA patient model revealed that estimated glomerular filtration rate (eGFR) and lymphocyte count had a significant effect on apparent total systemic clearance (CL), which was 91.7 L/h (2.3% relative standard error). Compared with the mean population CL, the model predicted mean changes in CL of 12.3 and -10.7% in patients with observed minimum and maximum lymphocyte count of 500 and 4600 106 /L, respectively, and mean changes in CL of -17.8 and 16.7% in patients with minimum and maximum eGFR of 36.4 and 188 mL/min/1.73m2 , respectively. The simulated population mean area under plasma concentration-time curve for 24 hours after dosing showed a 1.35-fold increase in patients with severe renal impairment (eGFR 22.5 mL/min/1.73m2 ) compared with patients with reference eGFR (91.5 mL/min/1.73m2 ). CONCLUSION: The population PK model identified eGFR and lymphocyte count as covariates for CL. The magnitude of changes was not considered clinically relevant, indicating no requirement for dose adjustment.

A pooled safety analysis of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis treated over a median of 2 years.

OBJECTIVE: To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients. METHODS: Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated. RESULTS: Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies). CONCLUSION: Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.

A drug-drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers.

PURPOSE: Peficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K. This study investigated the effect of peficitinib on metformin pharmacokinetics in vitro and in healthy volunteers. METHODS: Inhibitory effects of peficitinib and its metabolite H2 on metformin uptake into human OCT1/2- and MATE1/2-K-expressing cells were assessed in vitro. In an open-label, drug-drug interaction study, 24 healthy volunteers received a single dose of metformin 750 mg on Days 1 and 10, and a single dose of peficitinib 150 mg on Days 3 and 5-11. Blood and urine samples were collected pre-dose on Days 1 and 10, and at intervals ≤ 48 h post-dose. Metformin concentration was determined by liquid chromatography-tandem mass spectrometry and its pharmacokinetic parameters calculated. RESULTS: Peficitinib, but not H2, inhibited metformin uptake into OCT1- and MATE1/2-K-expressing cells. Repeated-dose administration of peficitinib reduced metformin area under the concentration-time curve from 0 h extrapolated to infinity (AUCinf) by 17.4%, maximum plasma concentration (Cmax) by 17.0%, and renal clearance (CLR) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated. CONCLUSION: Slight changes in AUCinf, Cmax and CLR of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant.

Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan.

OBJECTIVE: To evaluate the efficacy and safety of the oral Janus kinase (JAK) inhibitor peficitinib versus placebo in Japanese patients with rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind, parallel-group, placebo-controlled phase III study, patients with RA and inadequate response to methotrexate (MTX) were randomised 1:1:1 to placebo, peficitinib 100 mg once daily or peficitinib 150 mg once daily with MTX for 52 weeks. Based on baseline randomisation, at week 12, non-responders receiving placebo were switched to peficitinib until the end of treatment; the remaining patients were switched to peficitinib at week 28. Primary efficacy variables were American College of Rheumatology (ACR)20 response rate at week 12/early termination (ET) and change from baseline in van der Heijde-modified total Sharp score (mTSS) at week 28/ET. RESULTS: 519 patients were randomised and treated. Significantly more (p<0.001) peficitinib (58.6%, 100 mg; 64.4%, 150 mg) than placebo (21.8%) recipients achieved ACR20 response at week 12/ET. Significantly lower (p<0.001) mean changes from baseline in mTSS at week 28/ET occurred in peficitinib (1.62, 100 mg; 1.03, 150 mg) than placebo (3.37) recipients. Peficitinib was associated with haematological and biochemical parameter changes, and increased incidence of serious infections and herpes zoster-related disease. One death from suicide occurred in a patient in the placebo group after switching to peficitinib 100 mg. CONCLUSIONS: In Japanese patients with RA and inadequate response to MTX, peficitinib demonstrated significant superiority versus placebo in reducing RA symptoms and suppressing joint destruction. Peficitinib had an acceptable safety and tolerability profile, with no new safety signals compared with other JAK inhibitors. TRIAL REGISTRATION NUMBER: NCT02305849.

Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3).

OBJECTIVES: To investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA). METHODS: In this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks' treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements. RESULTS: In total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase. CONCLUSIONS: In patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo. TRIAL REGISTRATION NUMBER: NCT02308163.

FIVE-YEAR OUTCOMES OF INTRAVITREAL RANIBIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN PATIENTS WITH PATHOLOGIC MYOPIA.

PURPOSE: To determine the 5-year outcome of intravitreal ranibizumab (IVR) for myopic choroidal neovascularization (CNV). METHOD: We retrospectively analyzed the medical records of 51 eyes of 51 consecutive patients with myopic CNV who had been treated with IVR with a minimum follow-up period of 5 years after the initial IVR injection. The factors that predicted the best-corrected visual acuity (BCVA) at 5 years after IVR were determined by multiple regression analysis. RESULTS: The mean age of the subjects was 63.6 years, and the mean axial length was 29.4 mm. The mean number of IVR was 1.6, and 34 eyes (66.7%) had only a single IVR. At the baseline and at the 1-year, 2-year, 4-year, and 5-year period, the mean BCVAs were 20/49, 20/37, 20/41, 20/45, and 20/42, respectively. Stepwise multiple regression analysis showed that the BCVA at 5-year period was significantly correlated with the baseline BCVA, the number of IVR injections, and the size of the CNV-related macular atrophy. CONCLUSION: Intravitreal ranibizumab provide a 5-year visual benefit in eyes with myopic CNV compared with the natural course. A lack of enlargement of the CNV-related macular atrophy, a better baseline BCVA, and a minimum number of IVR injections were associated with better visual outcomes.

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 Simon's two-stage design (threshold response = 30%, expected response = 50%, α = 0.05, ß = 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.

SIX-YEAR OUTCOMES OF INTRAVITREAL BEVACIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN PATIENTS WITH PATHOLOGIC MYOPIA.

PURPOSE: To investigate the 6-year outcome of intravitreal bevacizumab (IVB) to treat eyes with active choroidal neovascularization (CNV) due to pathologic myopia. METHODS: Medical records of 36 eyes of 35 consecutive patients with high myopia (refractive error ≥8 D or axial length ≥26.5 mm) and active CNV, who had been treated with IVB and followed for ≥6 years were analyzed. The factors that predicted the best-corrected visual acuity (BCVA) at 6 years after IVB were determined by multiple regression analyses. RESULTS: The mean age of the subjects was 58 years, and the mean axial length was 29 mm. Twenty-one eyes had subfoveal CNV and 15 eyes had nonsubfoveal CNV. During the 6-year follow-up, the mean number of IVB was 1.78. The mean BCVA logMAR (equivalent Snellen visual acuity) was 0.50 (20/63), 0.31 (20/40), 0.39 (20/50), and 0.45 (20/63) at the baseline, and at 2, 4, and 6 years after the IVB. The BCVA was significantly improved at 2 and 4 years compared with baseline values but not at 6 years. Stepwise multiple regression analyses showed that the BVCA at 6 years was significantly correlated with the size of the CNV-related macular atrophy, and the baseline BCVA and CNV size. CONCLUSION: The significant correlation between the BCVA at 6 years and the size of the macular atrophy indicates that treatments to prevent the development of macular atrophy are important for the long-term visual outcome in eyes with active CNV.

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.

Pharmacokinetics and Safety of Single and Multiple Doses of Peficitinib (ASP015K) in Healthy Chinese Subjects.

Objective: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses. Methods: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated. Results: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0-1.5h and mean t1/2 was 7.4-13.0h for all doses. In the multiple-dose period, median tmax was 1.5-2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of >150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death. Conclusion: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses. Clinicaltrialsgov Identifier: NCT04143477.

Validation of Soft Labels in Developing Deep Learning Algorithms for Detecting Lesions of Myopic Maculopathy From Optical Coherence Tomographic Images.

PURPOSE: It is common for physicians to be uncertain when examining some images. Models trained with human uncertainty could be a help for physicians in diagnosing pathologic myopia. DESIGN: This is a hospital-based study that included 9176 images from 1327 patients that were collected between October 2015 and March 2019. METHODS: All collected images were graded by 21 myopia specialists according to the presence of myopic neovascularization (MNV), myopic traction maculopathy (MTM), and dome-shaped macula (DSM). Hard labels were made by the rule of major wins, while soft labels were possibilities calculated by whole grading results from the different graders. The area under the curve (AUC) of the receiver operating characteristics curve, the area under precision-recall (AUPR) curve, F-score, and least square errors were used to evaluate the performance of the models. RESULTS: The AUC values of models trained by soft labels in MNV, MTM, and DSM models were 0.985, 0.946, and 0.978; and the AUPR values were 0.908, 0.876, and 0.653 respectively. However, 0.56% of MNV "negative" cases were answered as "positive" with high certainty by the hard label model, whereas no case was graded with extreme errors by the soft label model. The same results were found for the MTM (0.95% vs none) and DSM (0.43% vs 0.09%) models. CONCLUSIONS: The predicted possibilities from the models trained by soft labels were close to the results made by myopia specialists. These findings could inspire the novel use of deep learning models in the medical field.

Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis.

The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION: NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.