Regulatory Decision Summary for Rinvoq

This Supplemental New Drug Submission (SNDS) was filed to obtain market authorization for a new indication for Rinvoq for the treatment of adult patients with moderately to severely active Crohn’s disease who have had either an intolerance, inadequate response or demonstrated dependence to corticosteroids, or intolerance, inadequate or loss of response to immunomodulators or to one or more biologic therapies (i.e., tumour necrosis factor-alpha [TNFα] antagonists, gut-selective anti-inflammatory biologics, interleukin 12/23 inhibitors).

Upon review, an indication for the treatment of adult patients with moderately to severely active Crohn’s disease 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.

This Supplemental New Drug Submission (SNDS) was filed to obtain market authorization for a new indication for Rinvoq (upadacitinib extended-release tablets) for the treatment of adult patients with moderately to severely active Crohn’s disease who have had either an intolerance, inadequate response or demonstrated dependence to corticosteroids, or intolerance, inadequate or loss of response to immunomodulators or to one or more biologic therapies (i.e., tumour necrosis factor-alpha [TNFα] antagonists, gut-selective anti-inflammatory biologics, interleukin 12/23 inhibitors). Additionally, in support of this new indication, this SNDS proposes a new 45 mg strength dosage form.

The proposed indication was supported by the results of two replicative pivotal Phase 3 induction studies (Study M14-431 part 1 [P1] and M14-433 P1) and one pivotal Phase 3 maintenance study (M14-430). In addition, a Phase 2 placebo controlled, dose-ranging escalation induction and maintenance study was conducted (M13-740).

The two pivotal induction studies were conducted in 1021 patients aged 18-75 years with moderately to severely active Crohn’s Disease (CD) who had demonstrated prior treatment failure (i.e., an inadequate response to, loss of response to, or intolerance to at least one conventional and/or biologic therapy). Studies M14-431 P1 and M14-433 P1 included 495 and 526 patients, respectively, who were randomized 2:1 to Rinvoq 45 mg daily (QD) or placebo for 12 weeks. The co-primary endpoints were induction of clinical remission at week 12 and induction of endoscopic response at week 12. Clinical remission was defined per Patient Reported Outcomes (PRO) for soft stool frequency and daily abdominal pain score. Endoscopic response was defined as a 50% reduction in Simple Endoscopic Score-Crohn’s Disease (SEC-CD) from baseline. Multiplicity-controlled secondary endpoints included clinical remission per the Crohn’s Disease Activity Index (CDAI), endoscopic remission, fatigue, and quality of life assessments. Additionally, the proportion of subjects who have steroid free clinical remission was also evaluated. The co-primary endpoints in the two induction studies were met. Clinical remission per PRO was achieved by 39.8% and 50.8% of patients administered Rinvoq 45 mg QD and 14% and 22.2% placebo in each respective induction study. Endoscopic response was achieved by 34.6% and 33.0% of patients administered Rinvoq 45 mg QD and 3.4% and 13% placebo in each respective induction study. The differences compared to placebo were statistically significant (p< 0.001) and clinically meaningful. Results of subgroup analyses, including patients with and without prior biologic therapy, were consistent with the overall results, with the exception of the subgroup of patients with ileal only disease at baseline in which efficacy could not be established. In addition, Rinvoq 45 mg was statistically significantly superior to placebo for the majority of multiplicity-controlled secondary endpoints.

The primary efficacy analysis for the maintenance study was conducted in the first 502 subjects from Rinvoq 45 mg treatment groups in the induction studies who had achieved clinical response at Week 12, defined as ≥ 30% decrease in soft/liquid stool frequency; and/or ≥ 30% decrease in average daily abdominal pain score. Patients were randomized to receive daily Rinvoq 15 mg, Rinvoq 30 mg, or placebo under the protocol with 52-week treatment duration in a 1:1:1 ratio. The co-primary efficacy endpoints were clinical remission at Week 52 and endoscopic response at Week 52, using the same defining criteria as in the induction studies. In addition to the multiplicity-controlled secondary endpoints investigated in the induction trials, two important multiplicity controlled secondary endpoints were maintenance of clinical remission and corticosteroid-free clinical remission. The co-primary endpoints were met as the proportion of patients achieving clinical remission and endoscopic response at Week 52 were statistically significantly higher in patients treated with Rinvoq 15 mg and Rinvoq 30 mg compared to placebo-control. Clinical remission per PRO was achieved by 35.5%, 46.4%, and 14.4% in patients administered Rinvoq 15 mg, Rinvoq 30 mg, and placebo, respectively. Endoscopic response was achieved by 27.6%, 40.1%, and 7.3% in patients administered Rinvoq 15 mg, Rinvoq 30 mg, and placebo, respectively. The clinical remission and endoscopic response rates were numerically higher in patients treated with Rinvoq 30 mg compared to Rinvoq 15 mg and did not depend on prior biologic treatment failure. Rinvoq 30 mg and Rinvoq 15 mg were statistically significantly superior to placebo for the majority of multiplicity controlled secondary endpoints, and Rinvoq 30 mg was numerically superior to Rinvoq 15 mg. Importantly, clinical remission (per CDAI) at Week 52, among subjects with clinical remission (per CDAI) at Week 0, was higher in subjects treated with Rinvoq 30 mg (65.2%) and UPA 15 mg (49.5%) compared to placebo (21.2%). Additionally, steroid free use at least 90 days prior to Week 52 and clinical remission per CDAI in subjects taking corticosteroids at baseline was higher in UPA 30 mg (39.7%) and UPA 15 mg (39.7%) treated patients compared to placebo (4.9%).

The safety of Rinvoq UPA 15 and 30 mg has been characterized in other approved indications. Safety data for the 45 mg dose is more limited since it was only assessed previously in ulcerative colitis clinical studies. In the phase 3 clinical development program for CD 833 subjects received at least 1 dose of Rinvoq 45 mg. Of these, 744 patients received at least one induction dose of Rinvoq 45 mg. Of the 521 subjects who received either Rinvoq 15 mg or Rinvoq 30 mg maintenance treatment, 52.5% and 77.3% respectively received Rinvoq for at least 52 weeks. The most commonly reported adverse reactions (>2% of patients) with induction dose of Rinvoq 45 mg were upper respiratory tract infection (12.9%), anemia (7.4%), acne (6.2%), pyrexia (4.2%), increased blood creatine phosphokinase (3.0%), influenza (3.0%), herpes simplex (2.7%), herpes zoster (2.2%) and neutropenia (2.1%). With maintenance dose of UPA 15 mg or 30 mg the most commonly reported adverse reactions were upper respiratory tract infection (14.9%), pyrexia (8.7%), headache (6.6%), herpes zoster (6.1%), acne (5.2%), increased blood creatine phosphokinase (4.1%), fatigue (3.9%), pneumonia (4.1 %), aspartate aminotransferase increased (3.9%), bronchitis (3.9%) alanine aminotransferase increased (3.5%), neutropenia (2.2%). The most common serious adverse reactions were serious infections (most frequently anal abscesses). Adverse events of special interest were identified and evaluated for Rinvoq based on safety concerns reported for other JAK inhibitor products, as well as the data from preclinical and clinical studies. The adverse events of special interest were: serious infections, opportunistic infections, tuberculosis, herpes zoster, adjudicated GI perforations, anemia, neutropenia, lymphopenia, CPK elevation, hepatic disorder, renal dysfunction, and malignancy. Adverse events of special interest did occur in the clinical trial program. There was 1 death in the clinical development program, but it occurred 4 months after the last administration of UPA 45 mg but was not considered related to the study drug. Overall, the safety profile observed in patients with CD was consistent with the safety profiles in other indications.

Overall, the proposed dosing regimen of Rinvoq 45 mg for 12 weeks for induction treatment, followed by maintenance treatment with 15 mg is appropriate. For some patients, such as those with high disease burden, a maintenance dose of Rinvoq 30 mg once daily is appropriate due to safety concerns with the use of Rinvoq and other JAK inhibitors. It is recommended to use the lowest effective dose needed to maintain response. For patients ≥ 65 years of age, the only recommended maintenance dose is 15 mg once daily. An indication for the treatment of adult patients with moderately to severely active Crohn’s disease 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 is recommended.

The anticipated benefits of Rinvoq are expected to outweigh its risks under the conditions of use recommended in the Rinvoq Product Monograph 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 Product Monograph, approved by Health Canada and available through the Drug Product Database.