Regulatory Decision Summary for Rinvoq

The purpose of this Supplement to a New Drug Submission (SNDS) was to add a new indication of non-radiographic axial spondyloarthritis (nr-axSpA) to Rinvoq (upadacitinib; [UPA]) 15 mg once-daily (QD). The Sponsor proposed the following indication:

Rinvoq is indicated for the treatment of non-radiographic axial spondyloarthritis with objective signs of inflammation who have had an inadequate response to, or intolerance to, nonsteroidal anti-inflammatory drugs (NSAIDs).

Further to the review of the submission, the following indication was approved:

Rinvoq is indicated for the treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation who have had an inadequate response to a biologic Disease Modifying Anti-Rheumatic Drugs (DMARD) or when use of those therapies is inadvisable. Rinvoq may be used as monotherapy or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs).

A Supplement to a New Drug Submission (SNDS) was filed to support the approval of the 15 mg QD dose of Rinvoq (upadacitinib) for the treatment of adults with non-radiographic axial spondyloarthritis (nr-axSpA). Though similar in disease characteristics, disease burden, and response to treatment to the other axSpA subtype ankylosing spondylitis (AS), nr-axSpA differs by the absence of conventional radiography evidence of damage to affected sacroiliac (SI) joints. Treatment recommendations for nr-axSpA are largely extrapolated from evidence in AS.

The efficacy and safety of Rinvoq 15 mg QD for nr-axSpA were assessed in a single, ongoing, Phase 3 randomized, double-blinded, placebo (PBO)-controlled, multicentre study (M19-944-2) that enrolled 314 participants with active nr-axSpA. Study participants had an inadequate response (IR) to non-steroidal anti-inflammatory drugs and about one third of participants had prior exposure to biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs). Study M19-944-2 included an ongoing 52-week PBO-controlled period followed by a 52-week open-label extension wherein subjects taking PBO were switched to UPA; a planned 48-week remission-withdrawal period after Week 104 was not initiated at data cut-off. Study M19-944-2 included lower number than the recommended 300-600 patients for 6 months and 100 patients for 1 year for a drug intended for long-term treatment of a non-life-threatening condition (International Council for Harmonization-Efficacy Guideline E1 [ICH E1]). Data from the AS clinical program was considered supportive due to disease comparability; data from Studies M16-098 and M19-944-1 comprised 182 bDMARD-naïve AS patients and 414 bDMARD-IR AS patients.

The primary efficacy outcome for Study M19-944-2 was Assessment of SpondylArthritis International Society (ASAS) 40 response rates at Week 14. ASAS40 is a composite endpoint that is robust and appropriate for axSpA clinical trials; the 14-week time point for efficacy was considered acceptable for the specified efficacy outcomes. A significant increase in the ASAS40 response rate was shown in the UPA (44.9%) compared to PBO (22.5%) group. The ASAS40 response was consistent for select subgroups including bDMARD-IR patients. All components of the ASAS response were non-ranked secondary endpoints and demonstrated nominal significant improvement in the UPA compared with PBO group from Week 2 through Week 14. Twelve of 14 key secondary efficacy outcomes were met at Week 14 in Study M19-944-2; these were associated with disease activity (Ankylosing Spondylitis Disease Activity Score and categories, Bath AS Disease Index 50, ASAS20, ASAS Partial Remission), inflammation (Spondyloarthritis Research Consortium of Canada Score SI), function (Bath AS Functional Index), and other patient reported outcomes (AS Quality of Life, ASAS Health Index, Total and Nocturnal back pain). Significance was not met for measures of spinal mobility (i.e., Bath AS Metrology Index) or enthesitis (i.e., Maastricht AS enthesitis score). The step-down statistical approach that was applied to assess the multiple pre-defined secondary efficacy outcomes was considered valid. Similar endpoints and statistical approaches were applied for the AS clinical program. Efficacy data beyond Week 14 was not provided for Study M19-944-2. Long-term efficacy data relied on the 2-year data from Study M16-098: ASAS40/20/PR, ASAS components, BASDAI50, ΔASDAS (CRP), and BASFI were maintained or increased from Week 14 through Week 104 in AS patients taking UPA.

There was no dedicated dose-response study, rather UPA posology for nr-axSpA was informed by studies in rheumatoid arthritis (RA), Study M16-098 in AS patients, and the results of exposure-response analysis. Using a population pharmacokinetics model, the exposure to UPA in nr-axSpA participants was consistent with what was observed in RA and AS patients with no dose adjustments recommended in the nr-axSpA population.

The safety of UPA was supported by 187 participants (representing 116.6 Patient Years [PY]) nr-axSpA participants who received at least one dose of UPA in Study M19-944-2, including 35 (18.7%) participants exposed to UPA for ≥ 12 months. An updated Sponsor-provided Safety Update Report (SUR) comprised 230 patients exposed to UPA including 86 and 11 participants exposed for ≥ 12 months and 18 months, respectively. In Study M16-098, 182 AS patients received UPA for up to 104 weeks (representing 308.6 PY), including 149 and 79 participants exposed to UPA for ≥ 18 months and ≥ 2 years, respectively. No new or elevated risks of adverse events (AEs) were identified in the nr-axSpA population. However, the safety profile in nr-axSpA is limited in number and duration. Therefore, caution is warranted in the interpretation of data for AEs that are uncommon or have a long latency.

The wording of the proposed indication was changed to align with the AS indication, thereby limiting the indication to treatment of adults with nr-axSpA who have had an inadequate response or intolerance to bDMARDs or for whom these therapies are not appropriate.

Based on the available data, the overall benefit-harm-uncertainty profile of Rinvoq 15 mg QD is considered favorable for the treatment of nr-axSpA in adults.