Pfizer's XELJANZ (Tofacitinib) Receives FDA Approval as First JAK Inhibitor for Active Polyarticular Juvenile Idiopathic Arthritis in Patients Aged 2 and Older

Compiled by Keke

On September 28, Pfizer announced that the U.S. FDA had approved XELJANZ® (tofacitinib) for the treatment of pediatric patients aged 2 years and older with polyarticular course juvenile idiopathic arthritis (pcJIA). The approval covers two formulations: tablets and an oral solution, with dosing based on patient weight. Pfizer stated that the oral solution formulation of XELJANZ is expected to become available by the end of the first quarter of 2021, while the 5 mg tablets will be immediately available. This approval makes XELJANZ the first and only Janus kinase (JAK) inhibitor approved in the United States for the treatment of pcJIA.

This approval is based on data from the Phase 3 study A3921104, which comprised two stages: an 18-week open-label run-in phase involving 225 patients, followed by a 26-week double-blind, placebo-controlled, randomized withdrawal phase involving 173 patients, for a total duration of 44 weeks. The study aimed to evaluate the efficacy and safety of two formulations of tofacitinib (5 mg tablets or 1 mg/mL oral solution), with treatment assignment based on subject body weight (<40 kg receiving the oral solution) and/or patient characteristics.

The results showed that the trial met its primary endpoint, namely that patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tofacitinib achieved the American College of Rheumatology (ACR) 30 response for JIA (improvement of more than 30%) at the end of the 18-week open-label phase. At week 44, the disease flare rate among patients treated with tofacitinib was 31% (27/88), significantly lower than that in the placebo group (55%, 47/85; p=0.0007). A disease flare was defined as a worsening of 30% or more in at least three of the six variables in the JIA ACR core set, with no more than one of the remaining JIA core response variables improving by 30% or more after randomization (outcome measures used in JIA clinical trials).

Furthermore, in clinical studies, the profile of adverse drug reactions (ADRs) in patients with polyarticular juvenile idiopathic arthritis (pcJIA) treated with tofacitinib was consistent with that observed in adult patients with rheumatoid arthritis (RA). Common ADRs included diarrhea, headache, and hypertension; serious ADRs may include infections, malignancies, and pulmonary embolism. In 2019, the Safety Committee of the European Medicines Agency (EMA) initiated a review of tofacitinib and recommended that physicians temporarily refrain from prescribing the 10 mg twice-daily dosage to patients at high risk for pulmonary embolism. The U.S. Food and Drug Administration (FDA) has also issued warnings regarding the risk of thrombosis associated with this medication.

XELJANZ® is an inhibitor of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), meaning it interferes with the JAK-STAT signaling pathway, which transmits extracellular signals to the nucleus and affects DNA transcription. In established murine models of arthritis, tofacitinib rapidly improves inflammatory disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissues. Researchers believe that the efficacy observed in this disease model is associated with the inhibition of JAK1 and JAK3 signaling pathways, suggesting that tofacitinib may exert its therapeutic effects through mechanisms beyond the sole inhibition of JAK3. Over the past seven years, XELJANZ has undergone more than 50 clinical studies worldwide, including over 20 trials in rheumatoid arthritis (RA).

XELJANZ® had previously been approved for three indications in the United States: for the treatment of patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to methotrexate; for adult patients with active psoriatic arthritis (PsA) who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs); and for adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to tumor necrosis factor inhibitors (TNFi).

Reference Source:

1. Wikipedia

2.U.S. FDA Approves Pfizer’s XELJANZ® (tofacitinib) for the Treatment of Active Polyarticular Course Juvenile Idiopathic Arthritis