Regulatory Decision Summary for Rinvoq

A New Drug Submission (NDS) was filed to support approval of the 15 mg once-daily (QD) dose of Rinvoq (upadacitinib) for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA).

The efficacy and safety of Rinvoq were assessed in five randomized and well-controlled Phase 3 randomized, double-blind, multicenter studies that enrolled 4,381 subjects with active RA diagnosed according to the American College of Rheumatology (ACR) criteria and whose baseline demographics and disease characteristics were representative of the target RA patient population. One of the studies enrolled subjects who were naïve to methotrexate (MTX), while other studies enrolled subjects who had an inadequate response to MTX and/or conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), or were refractory/intolerant to biologic (bDMARDs), thus, representing a more difficult to treat patient population as they had already failed generally accepted first-line and/or second line-therapy.

The primary endpoint assessed the proportion of subjects achieving an ACR20 response (>20 percent improvement) at Week 12 or 14, except for the study including patients who were MTX-naïve which utilized the ACR50. These endpoints were appropriate and consistent with guidelines to assess the clinical effectiveness of upadacitinib to improve signs and symptoms of RA patients. Secondary endpoints were chosen to support the primary endpoint and to assess other potential treatment benefits to patients with RA. These endpoints were the change from baseline for the improvement of physical function (HAQ-DI), inhibition of radiographic progression (mTSS), achievement of low disease activity (ACR 50/70 and DAS28-CRP<2.6), improvement in fatigue (FACIT-F) and general health status (SF-36).

All five studies showed a statistically significant increase in the proportion of patients exhibiting a positive ACR20 response for the Rinvoq 15 mg QD dose when compared to placebo or an active comparator, as well as a statistically significant improvement across several other efficacy measures compared to their respective controls. Rinvoq clearly demonstrated a clinically meaningful benefit in subjects with moderately to severely active RA either as monotherapy or in combination with MTX or csDMARDs in subjects who were MTX-naïve, or who had an inadequate response to MTX, csDMARDs and/or bDMARDs. There was not a clear additional benefit observed with the upadacitinib 30 mg dose in these studies and given the increased safety risk with the higher dose, only the 15 mg dose was proposed for marketing. Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score, and joint space narrowing score in two studies. The proportion of patients with no radiographic progression (mTSS change from baseline ≤0) was also assessed. Treatment with Rinvoq resulted in significantly greater inhibition of the progression of structural joint damage compared to placebo plus MTX at Week 26 and compared to MTX monotherapy at Week 24.

In terms of safety, a total of 4,443 subjects were exposed to upadacitinib in the combined Phase 2 and Phase 3 trials and formed the primary source of evidence for the safety review. The data showed a greater percentage of subjects experiencing adverse events (AEs), serious AEs and AEs of special interest in Rinvoq 15 mg compared to placebo-treated patients. The most common SAEs in patients treated with Rinvoq included pneumonia, osteoarthritis, and pulmonary embolism, but were consistent with events reported in other RA studies of immunosuppressants and JAK inhibitors. The most commonly reported AEs occurring in ≥2% of patients treated with Rinvoq 15 mg and reported at a higher incidence versus placebo were upper respiratory tract infection, nasopharyngitis, urinary tract infection, nausea, bronchitis, blood creatine phosphokinase (CPK) increased, cough, and back pain. The most common AEs leading to discontinuation from treatment were infections such as pneumonia and herpes zoster.

More patients on Rinvoq 15 mg experienced AEs of special interest including serious/opportunistic infections, reactivation of herpes zoster and hepatitis B virus, gastrointestinal perforations, anemia, neutropenia, elevated CPK, and elevated lipids compared to placebo. Malignancies and Venous thromboembolism events (VTE) were of concern with other JAK inhibitors, but the safety data of Rinvoq indicated that malignancies (other than nonmelanoma skin cancer) and adjudicated VTEs were reported at comparable rates in Rinvoq-treated subjects and subjects treated with placebo on background MTX. These data should be interpreted with caution due to the majority of subjects having been exposed for one-year or less.

The Product Monograph was revised to address uncertainties and provide information about all the safety concerns, particularly serious infections, thrombosis and malignancy risk. Further, the wording of the indication was modified to limit the indication to second line use for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

The Risk Management Plan addresses important information, identified/potential risks, and pharmacovigilance activities and was deemed acceptable by the Marketed Health Products Directorate. Based on the available data, the overall benefit-harm-uncertainty profile of Rinvoq is considered favorable.