Regulatory Decision Summary for Rinvoq

This submission was filed as a Response to Notice of Non-compliance for a Supplement to a New Drug Submission (SNDS), the Notice of Non-compliance for which was issued in November 2021. The purpose of this SNDS was to add a new indication of ankylosing spondylitis to Rinvoq (upadacitinib) 15 mg once daily.

In addition to the currently approved indications for Rinvoq, the following additional indication was proposed by the sponsor: Rinvoq is indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

Further to the review of the submission, the following additional indication was recommended: Rinvoq is indicated for the treatment of active ankylosing spondylitis in adult patients who have had an inadequate response to a biologic disease-modifying antirheumatic drug, or when use of those therapies is inadvisable. Rinvoq may be used as monotherapy or in combination with non-steroidal anti-inflammatory drugs.

Rinvoq 15 mg tablet received Canadian marketing authorization in December 2019 for the treatment of rheumatoid arthritis in adults with an inadequate response or intolerance to methotrexate. Additional indications of Rinvoq 15 mg tablet for the treatment of active psoriatic arthritis in adults and for adults and adolescents 12 years of age and older with atopic dermatitis were approved in June 2021 and October 2021, respectively. Rinvoq 30 mg tablets for adults 18 to 65 with atopic dermatitis were approved in October 2021. Upadacitinib is on the Prescription Drugs List.

This Supplement to a New Drug Submission was filed to support the approval of the 15 mg once-daily dose of Rinvoq (upadacitinib) for the treatment of adult patients with active ankylosing spondylitis. The current review assessed data that was submitted as part of a Response to Notice of Non-compliance. In the initial submission, pivotal data was limited to interim findings from a single Phase 2/3 study (M16-098) that enrolled participants with intolerance or an inadequate response to two or more non-steroidal anti-inflammatory drugs; Study M16-098 excluded participants with biologic disease-modifying antirheumatic drug experience, despite biologic disease-modifying antirheumatic drugs being the standard-of-care second-line treatment for ankylosing spondylitis. Further, the safety evaluation of upadacitinib for patients with active ankylosing spondylitis was limited in scope due to the relatively small number of subjects enrolled in the study (n = 187). In the Response to Notice of Non-compliance, the sponsor provided interim data from a Phase 3 Study M19-944-1, which enrolled 420 biologic disease-modifying antirheumatic drug-inadequate response participants, therefore expanding the patient population and the overall number of ankylosing spondylitis patients exposed to upadacitinib. The sponsor also updated the safety data for Study M16-098 from Week 64 to Week 104.

Therefore, the efficacy and safety of Rinvoq 15 mg once daily was assessed in two randomized, double-blind, multicentre studies that enrolled 607 subjects with active ankylosing spondylitis and whose baseline demographics and disease characteristics were representative of the target ankylosing spondylitis patient population. Each study included a 14-week double-blinded, parallel-group, placebo-controlled treatment period followed by a long-term extension of 90 weeks (totalling two years) with all participants taking upadacitinib; the extension is ongoing for Study M19-944-1. The study duration was appropriate for the evaluation of efficacy. Select background therapy was permitted throughout the studies, and predominantly included non-steroidal anti-inflammatory drugs, with rescue therapy permitted after Week 16.

Formal dose-ranging studies for this indication were not conducted. Based on findings from rheumatoid arthritis and psoriatic arthritis clinical programmes, a single strength of upadacitinib (15 mg once daily) was assessed in the ankylosing spondylitis clinical programme. Using a population pharmacokinetic model for ankylosing spondylitis using data obtained in Study M16-098, the exposure to upadacitinib in ankylosing spondylitis participants was consistent with what was observed in rheumatoid arthritis and psoriatic arthritis patients with no dose adjustments recommended in the ankylosing spondylitis population. Following consultation with biostatistics, the model was considered validated and this approach was considered acceptable.

The primary endpoint was the proportion of ankylosing spondylitis patients achieving Assessment of SpondyloArthritis International Society 40 response at Week 14. The Assessment of SpondyloArthritis International Society 40 corresponds to improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of the four Assessment of SpondyloArthritis International Society domains (i.e., Patient’s Global Assessment, Patient's Assessment of Total Back Pain, Bath Ankylosing Spondylitis Functional Index, mean of Bath Ankylosing Spondylitis Disease Activity Index Questions 5 and 6) and no deterioration in the remaining domain. In both studies, Rinvoq 15 mg once daily showed a statistically significant increase in the proportion of patients exhibiting a positive Assessment of SpondyloArthritis International Society 40 response when compared to placebo. All components of the Assessment of SpondyloArthritis International Society response were non-ranked secondary endpoints, and demonstrated nominal significant improvements in the upadacitinib group compared with placebo from Week 2 through Week 14. In Study M16-098, the key secondary assessments of efficacy showed promising yet inconclusive evidence in support of upadacitinib in the treatment of ankylosing spondylitis; multiplicity-adjusted significance was met for five of ten measures of efficacy that had partial or complete overlap with the Assessment of SpondyloArthritis International Society components. However, all 14 key secondary assessments of efficacy in Study M19-944-1 met multiplicity-adjusted significance for upadacitinib compared with placebo. Consultation with biostatistics confirmed the statistical approaches applied to assess multiple secondary efficacy outcomes to be valid. Though efficacy was not evaluated beyond Week 14 in Study M19-944-1, interim analysis from Study M16-098 demonstrated that efficacy of 15 mg upadacitinib was generally maintained through Week 104.

The safety of upadacitinib was supported by 596 ankylosing spondylitis participants who received at least one dose of upadacitinib in the two clinical studies, including 438 and 228 exposed to Rinvoq 15 mg once daily for at least six months and 12 months, respectively. This met the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E1 recommendation of exposure to study drug by 300–600 patients for six months and 100 patients for one year. At two years, participants exposed to upadacitinib 15 mg (n = 79; 13.2%) were limited to those in Study M16-098; though supplemental safety data from participants exposed to 15 mg once daily and 30 mg once daily upadacitinib was provided from clinical programmes for psoriatic arthritis (comprising 1639.2 patient-years) and rheumatoid arthritis (comprising 11,201 patient-years), thus caution is warranted in the interpretation of the long-term safety profile of upadacitinib in an ankylosing spondylitis population, given the chronicity of the disease and the potential for lifetime exposure in the younger ankylosing spondylitis population compared with rheumatoid arthritis and psoriatic arthritis patients. As in the rheumatoid arthritis and psoriatic arthritis programmes, the most commonly reported adverse events were infections. No new additional serious or severe safety issues were identified in the ankylosing spondylitis population. In Study M16-098, blood creatine phosphokinase increased was among the highly reported adverse events; this was not monitored in Study M19-944-1. Hyperuricemia was reported at an increased rate in the upadacitinib group in Study M19-944-1 when compared with placebo counterparts, and compared to rates reported in M16-098 or in previous clinical programmes. Both increased creatine phosphokinase and hyperuricemia were added to the Rinvoq Product Monograph in Section 8.2 Clinical Trial Adverse Reactions for ankylosing spondylitis. With the exception of creatine phosphokinase increased, there was no evidence of an increased rate of any adverse event of special interest in the ankylosing spondylitis clinical programme compared to the rheumatoid arthritis clinical programme.

Based on the available data, the overall benefit-harm-uncertainty profile of Rinvoq 15 mg was considered favourable for the treatment of ankylosing spondylitis in adults.

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