Regulatory Decision Summary for Rinvoq

The efficacy and safety of upadacitinib 15 mg and 30 mg, once daily (QD), have been evaluated in three pivotal Phase 3 studies in adults and adolescents with refractory moderate and severe AD. In two of those studies (M16-045 and M18-891), upadacitinib was used as monotherapy, and in one study (M16-047) it was used in combination with topical corticosteroids (TCS). In addition, a Phase 2b dose-ranging study (M16-048), and a safety study in Japanese patients (M17-377) were submitted.

Based on the results from the dose-ranging study, 15 mg and 30 mg, once daily were used in the pivotal studies.

The design of the pivotal studies was similar, and included a 35-day screening period, a 16-week double blind (DB) period, a blinded extension (BE) period of up to week 136, and a 30-day follow-up visit. In all three studies, subjects who met eligibility criteria were randomized in a 1:1:1 ratio to receive a daily oral dose of upadacitinib 30 mg or upadacitinib 15 mg or matching placebo QD for 16 weeks. The study drug could be taken with or without food. In the combination study, patients also received concomitant TCS. Following completion of the double-blinded period, patients originally randomized to upadacitinib continued receiving the same dose until week 136. An active comparator was not included in any study. The BE period of the study has not been completed.

The statistical analysis plan for these studies was complicated and examined multiple key-secondary end-points, which were multiplicity controlled. The key-secondary end-points were different for the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA), and all end-points, as well as both statistical analyses methods were submitted to Health Canada (HC). The validity of the statistical analyses was found to be acceptable.

All subjects in the studies were between 12 and 75 years of age, and had refractory moderate to severe atopic dermatitis. Over half of the subjects had previously received systemic treatment.

Efficacy results were statistically significant and clinically relevant for both the 15 mg and 30 mg doses across all three pivotal studies. The previously validated co-primary end-points of the proportion of subjects with a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) 0 (clear) or 1 (almost clear) with at least a 2-point improvement and the proportion of subjects with Eczema Area and Severity Index (EASI) 75 (improvement of at least 75% in EASI score from baseline) at week 16, were achieved successfully. The multiple key-secondary end-points showing improvements in skin clearance, pruritus, and health-related quality of life were also achieved. The onset of effect was rapid. The 30 mg dose provided numerical benefit over the 15 mg dose. Concomitant TCS treatment did not contribute much additional efficacy; however, it supports the proposed use of upadacitinib with TCS. The effects in adolescents over 40 kilograms (kg) were similar to those in adults. Adolescents under 40 kg were excluded from the study.

The pharmacometrics exposure-efficacy analysis was acceptable and supported the results from the individual studies. 

The safety database consisted of 2893 subjects, of whom 344 were adolescent. This was considered appropriate for a safety evaluation. A small percentage of the subjects had been evaluated for long-term safety; however, the number of subjects who were exposed for over 1 year (246 for 15 mg, and 263 for 30 mg) was considered acceptable based on the recommendation of the International Council for Harmonisation (ICH) Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety for Drugs used in Long-Term Treatment (E1) guidance.

There were no new important safety findings in the AD population, including the adolescent subgroup, as compared with studies in other indications with upadacitinib. Both short-term and long-term safety issues have been previously identified and reflected in the product monograph (PM). As observed previously, the known adverse events (AEs) occurred at an overall higher frequency with the 30 mg dose compared with the 15 mg dose. The 30 mg dose of upadacitinib has been evaluated for other indications; however, AD is the first indication for which the 30 mg dose is being recommended for approval. Additional long-term safety data and post-market surveillance will enable further characterization of the safety of this dose in adults. Long-term safety for upadacitinib in other disease indications is comprised entirely of data collected from adults. Since adolescents are a new patient population recommended for treatment with upadacitinib, additional long-term safety data and post-market surveillance will enable further characterization of safety in adolescents.

Uncertainties exist regarding the characterization of key risks of upadacitinib across indications, and its use in certain populations who were underrepresented in clinical trials. This includes patients with moderate hepatic impairment, severe renal impairment, and patients aged 75 or greater. These uncertainties are reflected in the PM.

The data from the global phase 3 AD studies in subjects ≥65 years of age are limited and indicate a higher frequency of AEs, serious AEs including serious infection, and AEs leading to discontinuation, particularly of the 30 mg dose, in this population. Thus, while the benefit-risk profile of upadacitinib 15 mg dose in this population is considered favourable, the benefit-risk profile for the 30 mg dose is considered uncertain, therefore the 30 mg dose is not recommended in adults 65 years of age and older.

The benefit-risk profile of upadacitinib, 15 mg is considered favourable in subjects 12 years of age and older, over 40 kg, with refractory moderate to severe AD who are not adequately controlled with a systemic treatment (e.g. steroid or biologic) or when use of those therapies is inadvisable. 

The benefit-risk profile of upadacitinib, 30 mg is considered favourable in subjects 18 to 65 years of age with refractory moderate to severe atopic AD who are not adequately controlled with a systemic treatment (e.g. steroid or biologic) or when use of those therapies is inadvisable.

The appropriate dosing, as well as the potential risks and uncertainties are mitigated through appropriate wording in the product monograph.

A risk management plan, which includes educational material, is available for this product.

This submission is considered acceptable with respect to the safety and efficacy data reviewed.

A Notice of Compliance (NOC), pursuant to section C.08.004 of the Food and Drug Regulations, is recommended.