Rheumatology Xagena

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Filgotinib, a JAK1 inhibitor, in Methotrexate-unresponsive patients with rheumatoid arthritis

Filgotinib is JAK-1 selective catalytic inhibitor. Due to its target selectivity, Filgotinib is estimated to have a good efficacy and a better safety profile than unselective JAK inhibitors ( JAKi ).
In particular, as JAK1 is not involved in the signaling pathway of erythropoietin, colony-stimulating factor, and thrombopoietin, Filgotinib should not increase the risk of anemia and thrombocytopenia.

The efficacy and safety of Filgotinib in Methotrexate-unresponsive patients with rheumatoid arthritis ( RA ) were tested in two exploratory phase IIa trials, including a monocentric four-week proof of concept study and a multicentric four-week preliminary study.

In the first trial, patients were randomized to receive Filgotinib 200 mg daily or placebo, whereas in the second one, they were randomly assigned to different doses of Filgotinib ( 30 mg, 75 mg, 150 mg, or 300 mg once daily ) or placebo.
Both the studies evidenced a satisfactory efficacy profile of the drug.
In the proof of concept study, a statistically significant number of patients achieved an ACR20 response compared to placebo.
Furthermore, a reduction in serum CRP levels and in DAS28-CRP scores was also reported in the Filgotinib-assigned arm.
Conversely, the treatment with Filgotinib was not associated with a significant improvement in the ACR20 response rate in the four-week preliminary study, although a trend was observed for the 300 mg dose.
No safety issues were reported.

These initial data together with those obtained from healthy volunteers paved the way for the development of a population’s pharmacokinetic / pharmacodynamic model to be used for dose selection in phase IIb studies.
The pharmacodynamic effect of Filgotinib is, in fact, given by the parent drug and its active metabolite. The latter derives from the loss of the cyclopropyl carboxylic acid group following the action of carboxylesterases.
Despite having a lower target selectivity for JAK1 compared to Filgotinib ( IC50 = 11.9 µmol/ml ), the active metabolite has an elimination half-life of 23 h, allowing the administration of the compound in a single daily dose.

A wide dose range and different dosing regimens, with or without Methotrexate, were investigated in 24-week dose finding phase IIb studies in patients with active rheumatoid arthritis despite the concomitant use of Metotrexate ( DARWIN 1 and DARWIN 2 ).
Results showed that Filgotinib at a dose of 100 or 200 mg once daily, given either as mono- or combo-therapy, was efficacious and well tolerated.

Recently, the published results of the 24 week FINCH2 phase III study confirmed the efficacy of Filgotinib 100 mg and 200 mg once daily in RA patients refractory to one or more bDMARD.
No opportunistic infections, malignancies, or fatalities were recorded during the observational period. ( Xagena )

Angelini J et al, Biomolecules 2020; 10(7):1002