Regulatory Decision Summary for Rinvoq

This Supplemental New Drug Submission (SNDS) was filed to obtain market authorization for a new indication for Rinvoq (Upadacitinib), a Janus kinase (JAK) inhibitor, for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, loss of response to, or were intolerant to either conventional therapy or a biologic agent (i.e., tumour necrosis factor-alpha [TNFα] antagonists, integrin receptor antagonists or interleukin 12/23 inhibitors). Upon review, an indication for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have demonstrated prior treatment failure, i.e., an inadequate response to, loss of response to, or intolerance to at least one of conventional, and/or biologic therapy was approved. Additionally, in support of this new indication, this SNDS includes Chemistry and Manufacturing information on a new Rinvoq 45 mg extended-release tablet strength.

This SNDS was filed to obtain market authorization for a new indication for Rinvoq for the treatment of adult patients with moderately to severely active UC who have had an inadequate response, loss of response to, or were intolerant to either conventional therapy or a biologic agent (i.e., tumour necrosis factor-alpha [TNFα] antagonists, integrin receptor antagonists or interleukin 12/23 inhibitors). Additionally, in support of this new indication, this SNDS includes Chemistry and Manufacturing information on a new Rinvoq 45 mg extended-release tablet strength.

The proposed indication was supported by the results of two replicate pivotal Phase 3 induction studies (M14-234 sub-study 2 [SS2] and M14-675) and one pivotal Phase 3 maintenance study (M14-234 SS3). Additional studies were also included in support of the indication, including a Phase 2b dose-range finding study (M14-234 SS1) and a Phase 3 long-term extension (LTE) study (M14-533).

The two pivotal induction studies were conducted in 988 patients aged 18-75 years of age with moderately to severely active UC who had demonstrated prior treatment failure (i.e., an inadequate response to, loss of response to, or intolerance to at least one of conventional (non-bio-IR), and/or biologic (bio-IR) therapy). Study M14-234 SS2 and M14-675 included 473 and 515 patients, respectively, who were randomized 2:1 to Rinvoq 45 mg daily (QD) or placebo for 8 weeks. The primary efficacy endpoint was induction of clinical remission at week 8. Clinical remission was defined per a modified Mayo Score (mMS; defined as stool frequency subscore (SFS) ≤1 and not greater than baseline, rectal bleeding subscore (RBS) of 0, and endoscopic subscore of ≤1). The modified Mayo score is based on the Mayo scoring system for UC disease activity, excluding the Physician’s Global Assessment, and provides an assessment of disease severity. Multiplicity-controlled secondary endpoints included clinical response, endoscopic and histologic endpoints, and quality of life assessments. Additionally, two newly proposed endpoints of abdominal pain and bowel urgency were evaluated. Clinical remission at week 8 was achieved by 26.1% and 33.5% of patients administered Rinvoq 45 mg QD and 4.8% and 4.1% placebo in each respective induction study. The differences compared to placebo were statistically significant (p<0.001) and clinically meaningful. In addition, all secondary endpoints were in favor of Rinvoq (p<0.001). The results in subgroups, including bio-IR and bio naïve patients were consistent with the overall results.

The maintenance study, M14-234 SS3, was conducted on the first 451 randomized subjects in the induction studies who had achieved clinical response at week 8 (defined as decrease ≥2 points and ≥30% from baseline and a decrease in RBS ≥1 from baseline or an absolute RBS ≤1). Patients were randomized to receive daily Rinvoq 15 mg, Rinvoq 30 mg, or placebo under the protocol with 52-week treatment duration. The primary endpoint was the proportion of patients who achieved clinical remission at week 52, using the same defining criteria as in the induction studies. A statistically significant (<0.001) and clinically meaningful treatment difference between Rinvoq 15 mg and 30 mg QD and placebo were observed for the primary and all key secondary endpoints at week 52. Clinical remission was achieved by 42%, 52%, and 12% in patients treated with Rinvoq 15 mg, Rinvoq 30 mg, and placebo, respectively. The differences compared to placebo were statistically significant (p<0.001) and clinically meaningful. In addition, the outcomes of the key secondary endpoints were in favor of the treatment arms.

The safety of Rinvoq 15 mg and 30 mg has been characterized in previous studies in other approved indications; however, safety data for the 45 mg induction dose is more limited since it is currently not approved for any indication and data are limited to the 719 treated patients in the UC induction studies. Across the UC global phase 2b and phase 3 studies, 1,304 subjects received at least 1 dose of Rinvoq. Of these, 987 subjects received at least 1 induction dose of Rinvoq 45 mg. Of the 576 subjects who received either Rinvoq 15 mg or 30 mg maintenance treatment, 242 and 237 had at least 26 weeks exposure to Rinvoq 15 mg or 30 mg, respectively, and 131 and 137 had at least 52 weeks exposure to Rinvoq 15 mg or 30 mg treatment, respectively.

The most commonly reported adverse drug reactions (ADR) with the induction dose of Rinvoq 45 mg QD were upper respiratory tract infection, acne, blood creatine phosphokinase (CPK) increased, neutropenia, rash, lymphopenia, pyrexia, folliculitis and herpes simplex. With the maintenance doses of Rinvoq 15 mg or 30 mg, the most commonly reported ADRs were upper respiratory tract infection, blood CPK increased, neutropenia, rash, herpes zoster, hypercholesterolemia, AST increased, folliculitis, influenza, and herpes simplex, ALT increased and hyperlipidemia. The most common serious ADRs were serious infections. The safety profile of Rinvoq during the long-term extension study was generally consistent with the safety profile during the placebo-controlled periods. Overall, the safety profile observed in patients with UC was consistent with the safety profiles in other indications, with the exception of rash and lymphopenia that were identified as new ADRs. There were 2 deaths in the clinical development program, both occurred in the long-term extension study and were not considered related to study drug.

Adverse events of special interest (AESI) were identified and evaluated for Rinvoq based on safety concerns reported for other JAK inhibitors, as well as data from preclinical and clinical studies. The AESIs included serious infection, opportunistic infection (excluding tuberculosis [TB] and herpes zoster), herpes zoster, active TB, hepatic disorders, anemia, neutropenia, lymphopenia, CPK elevation, renal dysfunction, adjudicated gastrointestinal (GI) perforation, and adjudicated major adverse cardiovascular events (MACE).

Safety risks have been mitigated through labelling in the Product Monograph (PM) and through revisions to the Risk Management Plan (RMP).

Overall, the proposed dosing regimen of Rinvoq 45 mg QD for 8 weeks for induction of clinical remission, followed by maintenance treatment with Rinvoq 15 mg is appropriate. For some patients, such as those with refractory, severe, or extensive disease, a maintenance dose of 30 mg QD may be appropriate. It is recommended to use the lowest effective dose needed to maintain response and to discontinue treatment if response is not maintained with the 30 mg dose. For patients ≥65 years of age, the only recommended maintenance dose is 15 mg once daily. In patients who have responded to treatment with Rinvoq, corticosteroids may be reduced and/or discontinued.

The anticipated benefits of Rinvoq are expected to outweigh its risks under the conditions of use recommended in the Rinvoq PM at this time. A Notice of Compliance (NOC) is recommended for this submission from a clinical perspective.

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