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

ABSTRACT: 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 E_max 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).

SUBMITTER: Toyoshima J

PROVIDER: S-EPMC8085977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionPeficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment.MethodsWe searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity.ResultsThe network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes.ConclusionsPeficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors.

Project description:BACKGROUND:Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52?weeks' duration. However, safety and effectiveness after long-term treatment have not been assessed. METHODS:This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12?weeks) and phase 3 (RAJ3 and RAJ4; 52?weeks) peficitinib studies in Asia (mainly Japan). Eligible patients (n?=?843) received oral peficitinib once daily (100?mg, or 50?mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150?mg) or reduced (to 50?mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP). RESULTS:Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7?months and the maximum dose was 100?mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6?-?3.1), herpes zoster-related disease 6.8 (95% CI, 5.6?-?8.3), and malignancies 1.1 (95% CI, 0.7?-?1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively. CONCLUSIONS:The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6?years was well tolerated in Asian patients with RA. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

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

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