Selective JAK1 inhibition shows promise in RA patients
medwireNews: The highly selective janus kinase (JAK)1 inhibitor filgotinib shows efficacy and has an encouraging safety profile in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate, say researchers who investigated the agent in two short phase IIa trials.
They explain that although less selective JAK inhibitors have “an early onset of action and long-term efficacy in RA,” they are associated with side effects such as infections and infestations, and decreases in neutrophil count.
The research team focused on targeting JAK1 “based on the hypothesis that JAK1 is the predominant JAK family member in inflammatory pathways and autoimmune pathology, while a cleaner safety profile may be achieved by avoiding inhibition of other JAK types.”
In study 1, designed to show proof-of-concept, 36 patients with active RA were randomly assigned to receive filgotinib 200 mg/day, either given in a single or twice-daily 100 mg dose, or placebo, while in the dose-ranging study 2, 91 participants were randomly allocated to receive daily filgotinib at doses of 30, 75, 150, or 300 mg, or placebo. Participants in both studies were treated for a 4-week period against a background of a stable methotrexate regimen.
The primary endpoint of a 20% improvement in ACR criteria (ACR20) at week 4 was achieved by 83% of 24 filgotinib-treated patients in study 1 – this compared with a rate of 33% among the 12 patients in the placebo group.
And in study 2, the majority (65%) of 20 patients given the 300 mg dose of filgotinib had an ACR20 response after 4 weeks, as did 41% of 17 placebo-treated participants.
The proportion of patients with an ACR20 response tended to rise progressively from week 1 to week 4 for all treatment groups in both studies. And among those treated with the 75 mg or higher doses of filgotinib, this was accompanied by a progressive dose-dependent improvement in the disease activity score at 28 joints using C-reactive protein (DAS28-CRP) relative to baseline.
“Filgotinib was generally well tolerated,” say Frédéric Vanhoutte (Galápagos NV, Mechelen, Belgium) and colleagues, with treatment-related adverse events observed in 25.0% of patients in study 1 and in 12.1% of those in study 2. Side effects tended to be “mild or moderate and transient on therapy,” they continue.
There was only one report of an infection during the course of both studies – one case of cystitis in a patient in the 300 mg group, which resolved while on-study.
Decreases in neutrophil counts of around 14% to 24% relative to baseline were observed for participants who received filgotinib at doses of 75 mg or higher, but these did not develop into neutropenia.
Filgotinib-treated patients in both studies were more likely to experience dose-dependent elevations in high-density lipoprotein (HDL) levels than their counterparts given placebo, but these increases were not accompanied by increases in either low-density lipoprotein (LDL) or total cholesterol levels.
“Larger and longer-term studies are needed to identify if these are transient or long-term filgotinib effects on the HDL and LDL levels, respectively,” the researchers write in Arthritis & Rheumatology.
And they conclude: “The observed safety and efficacy in RA patients provide initial evidence that selective inhibition of JAK1 may represent a future way to treat RA.”
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