Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease‐Modifying Antirheumatic Drugs in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis

Genovese, Mark C.; Greenwald, Maria; Codding, C.; Zubrzycka-Sienkiewicz, Anna; Kivitz, Alan; Wang, Annie; Shay, Kathyjo; Wang, Xuegong; Garg, Jay; Cardiel, Mario H.

doi:10.1002/art.40054

Cited by 84 publications

(81 citation statements)

References 20 publications

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“…In contrast to the 2 previous phase IIb studies with peficitinib (13,15), no dose-dependent ACR20 response was observed, although analysis of the DAS28 and the inflammatory markers, CRP and ESR, did suggest a dose-dependent response in the overall population. In contrast to the 2 previous phase IIb studies with peficitinib (13,15), no dose-dependent ACR20 response was observed, although analysis of the DAS28 and the inflammatory markers, CRP and ESR, did suggest a dose-dependent response in the overall population.…”

Section: Discussioncontrasting

confidence: 95%

“…Only in Europe, where the placebo response rate was in the expected range, was there a statistically significant difference between any peficitinib group and placebo in the ACR20 response rate, which is consistent with previous peficitinib phase IIb studies (13,15). This response ALT rate was considerably higher than the assumed placebo response rate of 30% in the sample size calculation.…”

Section: Discussionsupporting

confidence: 88%

“…Peficitinib in combination with MTX was well tolerated at all dose levels, with a safety profile similar to that observed in previous phase IIb trials of peficitinib (13,15). …”

Section: Discussionsupporting

confidence: 78%

“…In conclusion, peficitinib has been shown in 2 phase IIb studies to be effective in reducing the symptoms of RA in patients with a prior inadequate response to DMARDs (13,15), demonstrating a dose-dependent response in the ACR20 and ACR50 response rates as well as a change from baseline in the DAS28-CRP. Although in this study a dose response was not observed for ACR20 responses, efficacy across multiple secondary end points was demonstrated with higher peficitinib doses.…”

Section: Discussionmentioning

confidence: 86%

“…The efficacy and safety profile of peficitinib for the treatment of RA has been investigated in 2 other phase II trials. In the other phase IIb randomized study assessing the use of peficitinib without concomitant methotrexate (MTX) for the treatment of RA, the peficitinib 100 mg and 150 mg groups demonstrated a significantly higher ACR20 response at week 12 compared with placebo, which was achieved as early as week 2 (15). In the other phase IIb randomized study assessing the use of peficitinib without concomitant methotrexate (MTX) for the treatment of RA, the peficitinib 100 mg and 150 mg groups demonstrated a significantly higher ACR20 response at week 12 compared with placebo, which was achieved as early as week 2 (15).…”

mentioning

confidence: 99%

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Peficitinib, a JAK Inhibitor, in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate

Kivitz

Gutiérrez‐Ureña

Poiley³

et al. 2017

Arthritis & Rheumatology

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Section: Discussioncontrasting

confidence: 95%

Section: Discussionsupporting

confidence: 88%

“…Peficitinib in combination with MTX was well tolerated at all dose levels, with a safety profile similar to that observed in previous phase IIb trials of peficitinib (13,15). …”

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

See 3 more Smart Citations

Peficitinib, a JAK Inhibitor, in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate

Kivitz

Gutiérrez‐Ureña

Poiley³

et al. 2017

Arthritis & Rheumatology

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JAK Family Inhibitors for Autoimmune Diseases

Borzilleri

Hart

Moslin

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The JAK family of non‐receptor tyrosine kinases mediates the signaling of proinflammatory cytokines that contribute to the pathogenesis of numerous autoimmune diseases. While cytokine‐directed therapies are available to treat immune‐driven diseases, oral small‐molecule inhibitors of the JAK family (Jakinibs) have been approved as viable alternatives for the treatment of RA, PsA, and IBD. These first‐generation pan‐JAK inhibitors target the highly conserved catalytically active kinase domains in a reversible, ATP‐competitive manner, albeit in a nonselective fashion. Novel approaches to target alternative binding modes through, for example irreversible or allosteric kinase inhibition, have led to the identification of the next generation of agents, which demonstrate improved JAK family selectivity. This improved selectivity offers the potential for greater and perhaps broader efficacy by allowing for higher dosing, while avoiding undesired side effects. This article provides an overview of the JAK‐STAT signaling pathway and outlines the challenges associated with the discovery of selective JAK inhibitors while highlighting a unique allosteric TYK2 inhibitor. For each of the agents discussed, a synopsis of the medicinal chemistry efforts leading to a particular molecule is provided along with a brief summary of available preclinical and clinical efficacy and safety data.

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Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

Miyatake

Shibata

Toyoshima

et al. 2019

Clinical Pharm in Drug Dev

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Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUC inf) and maximum observed concentration (C max) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUC inf and C max , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

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Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease‐Modifying Antirheumatic Drugs in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis

Abstract: In patients with moderate-to-severe RA, orally administered once-daily peficitinib in combination with limited csDMARDs resulted in a dose-dependent ACR20 response rate over 12 weeks with satisfactory tolerability.

Cited by 84 publications

References 20 publications

Peficitinib, a JAK Inhibitor, in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate

Peficitinib, a JAK Inhibitor, in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate

JAK Family Inhibitors for Autoimmune Diseases

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

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