Regulatory Decision Summary for Xeljanz

The purpose of this Supplement to a New Drug Submission (SNDS) was to add a new indication of polyarticular course juvenile idiopathic arthritis (pcJIA) and juvenile psoriatic arthritis (jPsA) to Xeljanz 5 mg twice-a-day (BID). Upon review, the recommended indication for Xeljanz was:

Xeljanz (tofacitinib) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+] or negative [RF-], extended oligoarthritis, and systemic JIA without systemic manifestations), and juvenile psoriatic arthritis (jPsA) in children weighing ≥ 40 kg who have responded inadequately or are intolerant to tumour necrosis factor (TNF) inhibitors or when use of those therapies is inadvisable.

Juvenile idiopathic arthritis (JIA) is a chronic progressive inflammatory arthritis of unknown etiology that has an onset before 16 years of age and with manifestations lasting for ≥ 6 weeks. Based on features present in the first 6 months, JIA is categorized into 7 subtypes: rheumatoid factor (RF) positive or negative polyarthritis, systemic (s)JIA, oligoarthritis (persistent or extended), juvenile psoriatic arthritis (jPsA), enthesitis-related arthritis (ERA), and undifferentiated arthritis. Pharmacological treatment of JIA is directed at ameliorating symptoms and promoting disease remission, and includes non-steroidal anti-inflammatory drugs (NSAIDs), corticoids and disease-modifying anti-rheumatic drug (DMARDs).

An SNDS was filed to support the approval of Xeljanz (tofacitinib) for the treatment of active polyarticular (p)JIA and jPsA. The initial submission proposed dosing for patients aged 2 to < 18 year with the approved 5 mg tablet twice-daily (BID) or a new oral solution formulation (1 mg/mL) at bodyweight-based equivalent BID. Study A3921354 performed in healthy adults demonstrated bioequivalence of the 5 mg tablet formulation with an equivalent dose (i.e., 5 mL) of the 1 mg/mL solution formulation. During review, the Sponsor withdrew consideration for the solution formulation citing business reasons (not due to safety or efficacy concerns), and limited the proposed dosing to 5 mg tablets for patients weighing ≥ 40 kg.

The efficacy of tofacitinib was assessed primarily in a well-designed 44-week Phase 3 randomized withdrawal, multicentre study (A3920014) in patients aged 2 to < 18 years with active pJIA (i.e, RF+, RF-, extended oligoarthritis, sJIA without systemic manifestations) who had demonstrated an inadequate response to ≥ 1 DMARD, as well as jPsA and ERA participants with oligoarthritis with an inadequate response to NSAIDs. Study A3920014 enrolled 225 participants, who received at least one dose of tofacitinib (~38% solution and ~62% tablet formulations) in the 18-week open-label (OL) phase. There were 21 (9.3%) patients discontinued from the OL phase due to insufficient response, and 185 participants that completed the OL phase. There were 173 (76.9%) participants that achieved an American College of Rheumatology (ACR)30 response at the end of the OL phase of Study A3921104 and were eligible to enter the 26-week double-blind (DB) phase; 88 participants were randomized to tofacitinib and 85 participants were randomized to placebo.

The primary efficacy outcome of Study A3921104 was occurrence of disease flare in pJIA participants during the DB phase by Week 44/End of Study (EoS); jPsA and ERA participants were prespecified for omission from the statistical analysis. The study met the primary endpoint with a statistically lower occurrence of disease flare in the pJIA tofacitinib (n = 21; 29.2%) compared to the placebo (n = 37; 52.9%) group. Key secondary and additional efficacy endpoints were considered supportive of the efficacy of tofacitinib in pJIA patients. Interim analysis of LTE Study A3921145 (to Month 66) were generally consistent with the findings of Study A3921104. The occurrence of disease flare at Week 44 in jPsA participants was similar in the tofacitinib (n = 2; 28.3%) group but higher in the placebo group (n = 6; 75.0%) compared to pJIA results. Considering evidence from the pJIA population and the adult PsA indication, an indication for jPsA was considered acceptable. In contrast, and indication was not sought for ERA, wherein the occurrence of disease flares were numerically the same in ERA participants receiving tofacitinib (n = 4; 44.4%) or placebo (n = 4; 57.1%).

The safety of tofacitinib in JIA was derived from Studies A3921104, A3921145 and the Phase 1 multi-dose Study A3921103; these studies included 251 JIA participants, corresponding to 351 PYs of tofacitinib exposure at data cut-off. There were 104 participants continuously exposed to tofacitinib for > 12 months, corresponding to 253 PYs. The majority of participants were female (74.1%), aged 12 to < 18 (58.6%), White (88.0%), weighed ≥ 40 kg (59.4%), and had RF+/- polyarthritis (64.1%). The safety profile of tofacitinib in the JIA population was generally comparable to the profile established in RA patients receiving tofacitinib. The most common adverse events (AEs; ≥ 10%) were upper respiratory tract infections, nasopharyngitis, headache, JIA and vomiting. There were 23 (9.2%) serious (S)AEs, which were reported only once by preferred term, with the exception of JIA. Treatment-related SAEs were primarily infections and infestations but also included gastrointestinal disorders and musculoskeletal and connective tissue disorders. There were no deaths nor reports of AEs of special interest except for serious infections (2.4%) and herpes zoster (1.3%). There were 3 participants with mild/moderate hepatic events that were adjudicated as possible/probable drug-induced liver injury. There is uncertainty with respect to the risk of AEs with long latency or rare events due to the limited number and duration of exposure of JIA patients to tofacitinib.

The tofacitinib JIA clinical programme was not designed to assess the potential impacts of tofacitinib on bone growth for an appropriate duration. Ongoing pharmacovigilance will be useful in monitoring for potential developmental changes. The Risk Management Plan addressed important safety information, identified potential risks/pharmacovigilance activities, and was deemed acceptable by the Marketed Health Products Directorate.

The indication was limited to use of Xeljanz for the treatment of pJIA or jPsA patients who have had an inadequate response or intolerance to TNF inhibitors or when use of these is inadvisable. Aside from data included as part of the JIA clinical programme, the Sponsor provided data supportive of the inclusion of acne as a post-market adverse reaction and a Warnings and Precautions statement regarding the possibility of hypoglycemia in patients treated for diabetes; the Reviewer had no objections to the inclusion of these safety risks in the Xeljanz Product Monograph (PM).

Overall, the benefit-harm-uncertainty profile was favourable for Xeljanz for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Xeljanz, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.