Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib after Short-term Treatment of Rheumatoid Arthritis

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Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib after Short-term Treatment of Rheumatoid Arthritis
Key Take-Away: 

Janus kinases (JAKs), the intracellular tyrosine kinases illustrates a remarkable performance in rheumatoid arthritis (RA) management. Janus kinase family has four family members, JAK1, JAK2, JAK3, and TYK2. The present study focused on selective inhibition of JAK-1 and shown to exhibit higher efficacy & safety as compared to other JAK inhibitors.

Recent advancement in treating RA has been accomplished with janus kinase (JAK) inhibitors (Jakinibs), an orally available disease-modifying anti-rheumatic drug targeting the intracellular kinase JAK and with similar efficacy to biologics.

ABSTRACT: 
Background: 

Recent advancement in treating RA has been accomplished with janus kinase (JAK) inhibitors (Jakinibs), an orally available disease-modifying anti-rheumatic drug targeting the intracellular kinase JAK and with similar efficacy to biologics. 

The study was conducted to test the hypothesis that selective inhibition of JAK-1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors.

Methods: 

In two 4-week exploratory, double-blind, placebo-controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS-6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib.

The primary efficacy endpoint was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4.

Results: 

Treatment with filgotinib at 75-300 mg met the primary endpoint and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score (DAS) in 28 joints using the C-reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers.

The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK-2 inhibition related], no effects on liver transaminases, and no increase in low-density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK-1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during the therapy, and the most common such event was nausea.

Conclusion: 

Selective inhibition of JAK-1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.

 

Source:

Arthritis Rheumatol. 2017 Jun 16

Link to the source:

http://www.ncbi.nlm.nih.gov/pubmed/28622463

The original title of the article:

Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective Janus kinase 1 inhibitor, after short-term treatment of rheumatoid arthritis: Results of two randomized Phase IIA trials

Authors:

Vanhoutte F et al.

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