Background/Purpose:

The distinct role of JAK family members (JAK1, JAK2, JAK3 and TYK2) in signaling for cytokines and growth factors has established these kinases as therapeutic targets for inflammatory diseases and cancer.  JAK1 plays a dominant role in signalling for inflammatory cytokines, JAK2 signals for erythropoietin and thus is central to haematopoiesis, and JAK3 is key to the adaptive immune system. We hypothesized that inhibiting JAK1 would provide an efficacious treatment for rheumatoid arthritis (RA), while avoiding effects associated with the inhibition of other JAKs.  Filgotinib (GLPG0634) demonstrated selectivity for inhibition of JAK1 over JAK2, JAK3 and TYK2 in biochemical and cell assays.  In phase 2 clinical trials, filgotinib rapidly improved signs and symptoms of RA within 1 week with good tolerability and safety.  The data presented here bring additional evidence for its clinical JAK1 selectivity in RA patients.

Methods:

RA patients (n=91) with insufficient response to MTX were randomized to receive placebo or 30, 75, 150, or 300 mg filgotinib once-daily orally for 4 weeks as add-on to MTX in a double-blind phase 2a study.  Blood was sampled pre-dose and on the last day of treatment. CRP, Chitinase-3 L1 (CHI3L1) and VEGF plasma concentrations were measured using an ELISA assay from R&D Systems and the Myriad RBM InflammationMAP© assay. Hemoglobin concentration was measured using the Siemens Advia technology. Red blood cell (RBC) and reticulocyte counts as well as CD8⁺ and natural killer (NK: CD3^– CD16⁺ CD56⁺) cell percentages were measured by flow cytometry.

Results:

4 weeks of treatment with filgotinib decreased plasma concentrations of the inflammatory disease markers CRP, CHI3L1/YKL-40 and VEGF, whose expressions are controlled by STAT factors. The mean blood concentration of haemoglobin increased by up to 0.4 g/dL at 300 mg (from 12.5 g/dL to 12.9 g/dL), while reticulocyte and RBC counts, which are all directly controlled by erythropoietin, were not impacted by treatment, indicating that JAK2 activity was not inhibited at these doses and regimen. Similarly, no effects were observed on blood CD8⁺and NK cell percentages, suggesting that the gamma chain signalling, mostly dependent on JAK3 signalling, was not inhibited by filgotinib.

Conclusion:

In patients with active RA, 4 weeks of treatment with filgotinib, a selective inhibitor of JAK1, reduced plasma concentrations of inflammatory markers. This correlates well with the previously reported improvement in signs and symptoms of RA. Treatment did not adversely influence erythrocytes and reticulocytescounts and showed a mean improvement in haemoglobin, supporting the hypothesis that JAK2 signalling was not inhibited. There were no effects on CD8+ or NK cell counts, which are regulated by JAK3 signalling. Thus, these data provide further evidence for the JAK1 selectivity of filgotinib in RA patients. Future studies will need to establish potential clinical correlates of the observed increase in haemoglobin, such as an improvement in fatigue or lower rates of infections with less decrease in immune cells.

Refrence:

O’Shea J, Schwartz D, Villarino A, Gadina M, McInnes I and Laurence A. Annu. Rev. Med. 2015.66:311-328

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/absence-of-effects-of-filgotinib-on-erythrocytes-cd8-and-nk-cells-in-rheumatoid-arthritis-patients-brings-further-evidence-for-the-jak1-selectivity-of-filgotinib/