Regulatory Decision Summary for Xeljanz

The purpose of this Supplement to a New Drug Submission (SNDS) was to add a new indication for ankylosing spondylitis (AS) to Xeljanz (5 mg BID) Product Monograph (PM).

The sponsor proposed that Xeljanz be indicated for the treatment of adult patients with active AS who have responded inadequately to conventional therapy. In part to reflect the relative safety profile of approved AS treatments, the accepted indication for Xeljanz was for the treatment of adult patients with active AS who have responded inadequately to a biologic disease-modifying antirheumatic drug (bDMARD) or when use of those therapies is inadvisable.

A Supplement to a New Drug Submission (SNDS) was filed to support the approval of Xeljanz (tofacitinib; TOFA) 5 mg twice-daily (BID) for the treatment of adults with active ankylosing spondylitis (AS).

The efficacy and safety of TOFA 5 mg BID was supported primarily from the Phase 3, double-blinded, placebo (PBO)-controlled, multicentre Study A39211120 that included 270 randomized participants. Supportive evidence was provided from the Phase 2 double-blinded, PBO-controlled, multicentre, dose-ranging (2 mg, 5 mg, 10 mg TOFA) Study A39211119 that included 208 randomized participants. For both studies, active disease was appropriately established in adult patients meeting the modified New York criteria for AS and who had Bath AS disease activity index (BASDAI) and Back pain scores of ≥ 4. Study participants had an inadequate response (IR) to non-steroidal anti-inflammatory drugs; 23.0% of participants in Study A39211120 had prior exposure to biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs). Studies A39211120 and A39211119 included PBO-controlled periods of 16 and 12 weeks, respectively; Study A39211120 included an additional 32-week open label period during which participants that were randomized to PBO were switched to TOFA 5 mg BID.

The primary efficacy outcome was Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at Week 16 (Study A39211120) and Week 12 (Study A39211119). ASAS20 is a composite endpoint that is appropriate for AS clinical trials; a study duration of 12-24 weeks is considered sufficient to demonstration efficacy of treatment for AS.

In Study A39211119, TOFA 10 mg BID met the pre-specified statistical decisions rule for ASAS20 when analysed by an Emax model, whereas the greatest ASAS20 response rate was observed with TOFA 5 mg BID at Week 12. Together with other additional efficacy outcomes, including measures of structural change, Study A39211119 supported the use of TOFA 5 mg BID in the confirmatory trial.

Study A39211120 met the primary endpoint, demonstrating greater improvement in ASAS20 response rate at Week 16 in participants taking TOFA 5 mg BID (56.4%) compared with participants taking PBO (29.4%). The study also demonstrated Type-1 error controlled significance of the more robust key secondary efficacy outcome of ASAS40 response rate, demonstrating superiority of TOFA 5 mg BID (40.6%) compared with PBO (12.5%). Type-1 error controlled significance was demonstrated for related secondary outcomes including ASAS components and ASAS20/40 response rates at Weeks 2 and 4, respectively, and for secondary outcomes associated with disease activity (Ankylosing Spondylitis Disease Activity Score and categories, BASDAI50), inflammation (high sensitivity C-Reactive Protein), spinal mobility (Bath AS Mobility Index), and patient reported outcomes (AS quality of life). Subgroup analyses was supportive of TOFA 5 mg BID including for the treatment of bDMARD-IR AS patients, who represent a difficult to treat population with limited treatment options. Efficacy of TOFA 5 mg BID appeared to be maintained from Week 16 to Week 48 in participants randomized to TOFA in Study A39211120. Comparable improvements in the primary and secondary efficacy outcomes were shown between Week 24 through 48 in participants that switched after Week 16 from PBO to TOFA 5 mg BID.

A population pharmacokinetics model and exposure-response analysis demonstrated that the exposure to TOFA in AS participants was consistent with what was observed in RA patients; dose adjustments for patients with renal impairment, hepatic impairment or receiving CYP3A4 inhibitors were recommended in the AS population to be equivalent to those recommended in the RA population.

The safety of TOFA 5 mg BID was supported by 316 participants (representing 208.9 PY) AS participants who received at least one dose of TOFA 5 mg BID in the AS clinical programme, including 108 participants exposed to TOFA 5 mg BID for ≥ 12 months. A dose-specific safety profile of TOFA was not well established in the AS clinical programme; doses of TOFA 2 mg and 10 mg were assessed only in Study A39211119, each with 52 AS patients, and these were not analyzed separately in the integrated safety summary. No new AEs were identified in the AS population and, with the exception of a higher rate of increased transaminases in the AS population that was included in the accepted Xeljanz Product Monograph, the rates of other AEs were within those observed in the RA and PsA populations. However, the AS clinical programme was not sufficiently sensitive for the detection of AEs that are uncommon or have a long latency. With consideration for the limited data of TOFA 10 mg BID in the AS population, for the elevated risks identified with TOFA 10 mg BID in the RA population, and the recommended posology of TOFA in RA and PsA populations, a statement was included in accepted PM that Xeljanz 10 mg BID is not recommended for the treatment of AS.

Due in part to intended chronic use of TOFA for the AS population who may require decades of treatment, and to the established safety profile of bDMARDs as compared to TOFA, the AS indication was limited to patients that are bDMARD-IR, or for whom bDMARDs are not appropriate.

Based on the available data, the overall benefit-harm-uncertainty profile of Xeljanz 5 mg BID is considered favorable for the treatment of active AS in adult patients.