Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor

Hamaguchi, Hisao; Amano, Y.; Moritomo, Ayako; Shirakami, Shohei; Nakajima, Yutaka; Nakai, Kengo; Nomura, Noriko; Ito, Michiho; Higashi, Yasuyuki; Inoue, Takayuki

doi:10.1016/j.bmc.2018.08.005

Cited by 68 publications

(48 citation statements)

References 34 publications

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“…3 University of Tokyo, Tokyo, Japan. 4 Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 5 Seoul National University, Seoul National University Hospital, Seoul, South Korea.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…Current treatment of RA is based on disease-modifying antirheumatic drugs (DMARDs), usually starting with methotrexate (MTX), and biologic agents such as tumor necrosis factor-alpha (TNF-α) inhibitors in patients not responding to conventional DMARDs [2,3]. The Janus kinase (JAK) family of non-receptor protein tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) plays a crucial role in multiple cytokine receptor signaling pathways [4] and is a promising target for RA treatment in patients with insufficient response to DMARDs and biologic agents. JAK inhibitors available for the treatment of patients with RA include tofacitinib (a pan-JAK inhibitor approved in the USA, Europe, and Asia [5][6][7][8]), baricitinib (a JAK1 and JAK2 selective inhibitor approved in the USA, Europe and Asia [9][10][11][12]), and more recently peficitinib (ASP015K; approved in Japan).…”

Section: Introductionmentioning

confidence: 99%

“…Peficitinib is a pan-JAK inhibitor that inhibits JAK1, JAK2, JAK3, and TYK2 [13]. Compared with other JAK inhibitors, peficitinib is moderately selective for JAK3 (over JAK1, JAK2, and TYK2) [4,14]. Less potent inhibition of JAK2 may explain why reduced hemoglobin levels, potentially attributable to JAK2 inhibition, have not been observed with peficitinib [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Safety and effectiveness of peficitinib (ASP015K) in patients with rheumatoid arthritis: interim data (22.7 months mean peficitinib treatment) from a long-term, open-label extension study in Japan, Korea, and Taiwan

Takeuchi

Tanaka

et al. 2020

Arthritis Res Ther

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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).

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Section: Acknowledgementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Safety and effectiveness of peficitinib (ASP015K) in patients with rheumatoid arthritis: interim data (22.7 months mean peficitinib treatment) from a long-term, open-label extension study in Japan, Korea, and Taiwan

Takeuchi

Tanaka

et al. 2020

Arthritis Res Ther

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“…The JAK family (JAK1, JAK2, JAK3, and tyrosine kinase-2 [TYK2]) of non-receptor tyrosine kinases plays a crucial role in pro-inflammatory signaling pathways implicated in the pathogenesis of RA [7], and several JAK inhibitors with differential selectivity have been developed [7,8]. Peficitinib is a pan-JAK inhibitor that inhibits JAK1, JAK2, JAK3, and TYK2 [8,9]. Recent evidence suggests that peficitinib may suppress the proliferation and migration of RA…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

et al. 2020

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Background and Objective Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. Methods In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. Results Dose proportionality of maximum plasma drug concentration (C max ) and area under the plasma concentration-time curve extrapolated to infinity (AUC inf ) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized C max was 45.7-98.8% higher and AUC inf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. Conclusions Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Doseproportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. ClinicalTrials.gov identifier NCT01225224.

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“…Tab. 1 IC50 (= Konzentration, bei der 50 % Inhibition erreicht wird) der verschiedenen JAK(Januskinase)-Inhibitoren in vitro in nMol[73,74] …”

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Biologika und „small molecules“ bei der rheumatoiden Arthritis

Blüml

2020

Z Rheumatol

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ZusammenfassungDie Therapie der rheumatoiden Arthritis hat in den letzten Jahren gewaltige Umbrüche erfahren. Es steht mittlerweile ein großes Armamentarium an verschiedensten Medikamenten mit unterschiedlichen molekularen Angriffspunkten zur Verfügung. Zu diesen neuen Waffen zählen die Biologika (biologische DMARDs [bDMARDs; „disease modifying antirheumatic drugs“]) und die „targeted synthetic DMARDs“ (tsDMARDs). Gemeinsam ist diesen neueren Therapien für die rheumatoide Arthritis, dass man im Unterschied zu den konventionellen DMARDs die molekularen Angriffspunkte kennt. Mithilfe der neuen Medikamente kann den meisten Patienten geholfen werden, obwohl es nach wie vor Patienten gibt, die auf alle vorhandenen Therapien nicht adäquat reagieren. In diesem Review soll ein kurzer Überblick über die derzeitig verfügbaren und wirksamen Präparate für die Behandlung der rheumatoiden Arthritis gegeben werden.

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Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor

Cited by 68 publications

References 34 publications

Safety and effectiveness of peficitinib (ASP015K) in patients with rheumatoid arthritis: interim data (22.7 months mean peficitinib treatment) from a long-term, open-label extension study in Japan, Korea, and Taiwan

Safety and effectiveness of peficitinib (ASP015K) in patients with rheumatoid arthritis: interim data (22.7 months mean peficitinib treatment) from a long-term, open-label extension study in Japan, Korea, and Taiwan

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

Biologika und „small molecules“ bei der rheumatoiden Arthritis

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