Summary Basis of Decision for Rinvoq

Clinical Pharmacology

Upadacitinib, the medicinal ingredient in Rinvoq, is a Janus kinase (JAK) inhibitor. Janus kinases are intracellular enzymes involved in cell signalling processes which regulate inflammatory responses, hematopoiesis, and immune surveillance. Upadacitinib inhibits JAKs with a high degree of selectivity relative to other kinases. The inhibition of JAKs by upadacitinib prevents JAKs from activating signal transducers and activators of transcription (STATs), which modulate intracellular activities including gene expression.

Both immediate-release and extended-release formulations were used in clinical pharmacology studies. The two formulations were found to have similar efficacy in a dedicated relative bioavailability study.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of upadacitinib have been well characterized in rheumatoid arthritis (RA) patients and healthy volunteers. Following multiple once daily doses of 15 mg in RA patients, upadacitinib was absorbed rapidly. The median time to maximum observed plasma concentration (tmax) was 2 to 3 hours under fasting conditions, and 4 hours under non-fasting conditions. Steady state concentrations were achieved within four days, with minimal accumulation. Plasma exposure to upadacitinib was dose-proportional over the range of 7.5 mg to 45 mg using the extended-release formulation under fasting conditions. The mean terminal elimination half-life (t½) was 9 to 14 hours, and the oral clearance (CL/F) rate was estimated as 40.5 L/h. Upadacitinib was predominantly eliminated as the unchanged parent substance in the urine and feces. Results additionally indicated that with the 15 mg once daily dose, oral clearance of upadacitinib is approximately 38% lower in RA patients than in healthy volunteers.

Upadacitinib was shown to be a selective and reversible inhibitor of JAKs through tests conducted in whole blood from healthy volunteers. A dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation was observed. Maximal inhibition occurred one hour after dosing, and returned to baseline levels by the end of the dosing interval (within 24 hours).

Upadacitinib was not shown to prolong the corrected QT (QTc) interval in RA patients following repeated once-daily doses of the 15 mg extended-release formulation.

Renal function was not found to have any clinically relevant effects on the pharmacokinetics of upadacitinib. Additionally, mild or moderate hepatic impairment were not found to have any clinically relevant effects on upadacitinib exposure. However, upadacitinib is not recommended for patients with severe hepatic impairment, as it has not been assessed in this population.

Rinvoq should be used with caution in patients who are also treated with strong cytochrome P450 (CYP) 3A4 inhibitors, as a 75% increase in exposure to upadacitinib was observed in patients following co-administration.

Additionally, co-administration of Rinvoq with strong CYP 3A4 inducers is not recommended, as this was found to decrease exposure to upadacitinib by 61%.

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

Clinical Efficacy

The clinical efficacy of Rinvoq was demonstrated primarily through five pivotal, Phase III clinical studies. The individual study designs are described below, followed by the analysis of their collective results.

The primary efficacy endpoint in each of the pivotal studies is the proportion of patients who achieved a response as measured by the American College of Rheumatology (ACR) criteria at a pre-determined point during the study. In these pivotal studies, the ACR20 response was defined as at least a 20% improvement in both the number of tender and the number of swollen joints, along with at least a 20% improvement in three or more (≥ 3) of the following criteria: patient global assessment of disease activity, physician global assessment of disease activity, functional ability measure (assessed using the Health Assessment Questionnaire - Disability Index [HAQ-DI]), patient's assessment of pain (visual analog pain scale), and C reactive protein (CRP). The ACR50 and ACR70 responses use the same criteria, with improvement levels of 50% and 70%, respectively.

Study I

Study I was a 48-week study evaluating the efficacy of Rinvoq in 947 patients with moderate to severe active RA who were naïve to methotrexate. Patients were randomized to receive one of three treatments administered once daily as a monotherapy: 15 mg Rinvoq, 30 mg Rinvoq, or methotrexate. At Week 26, non-responding patients receiving Rinvoq were rescued through additional blinded treatment with methotrexate. Non-responding patients receiving methotrexate were also rescued through additional blinded treatment with either 15 mg or 30 mg Rinvoq. The primary efficacy endpoint was the proportion of patients who achieved an ACR50 response at Week 12.

Study II

Study II was a 14-week study evaluating the efficacy of Rinvoq in 648 patients with moderate to severe active RA who had an inadequate response to methotrexate. Patients were randomized to receive one of three treatments administered once daily as a monotherapy for 14 weeks: 15 mg Rinvoq, 30 mg Rinvoq, or continued their stable dose of methotrexate. At Week 14, patients receiving methotrexate were advanced to treatment with 15 mg or 30 mg Rinvoq once daily. The transition to treatment with Rinvoq occurred in a blinded manner, and the dosage strength was based on a pre-determined assignment at baseline. The primary efficacy endpoint was the proportion of patients who achieved an ACR20 response at Week 14.

Study III

Study III was a 12-week study evaluating the efficacy of Rinvoq in 661 patients with moderate to severe active RA, who had an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Patients were randomized to receive one of three treatments administered once daily in addition to background csDMARD therapy: 15 mg Rinvoq, 30 mg Rinvoq, or placebo. At Week 12, patients receiving placebo were advanced to treatment with 15 mg or 30 mg Rinvoq once daily. The transition to treatment with Rinvoq occurred in a blinded manner, and the dosage strength was based on a pre-determined assignment at baseline. The primary efficacy endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Study IV

Study IV was a 48-week study evaluating the efficacy of Rinvoq in 1,629 patients with moderate to severe active RA, who had an inadequate response to methotrexate. Patients were randomized to receive one of three treatments administered once daily in addition to background treatment with methotrexate: 15 mg Rinvoq, adalimumab (an active comparator), or placebo. Starting from Week 14 (at Weeks 14, 18 and 22), non-responding patients receiving Rinvoq were switched to receive treatment with adalimumab in a blinded manner. Similarly, non-responding patients receiving placebo or adalimumab were switched to receive treatment with Rinvoq in a blinded manner. At Week 26, all patients receiving placebo were switched to receive treatment with Rinvoq in a blinded manner. The primary efficacy endpoint was the proportion of patients who achieved an ACR20 response at Week 12, relative to patients in the placebo group.

Although an active comparator group was included, this study was not properly designed to assess whether Rinvoq is superior to adalimumab. Due to the cross over element at Week 14 and other features of its design, this study is not considered adequate to enable a robust benefit-harm-uncertainty assessment comparing Rinvoq to adalimumab. Therefore, no conclusions can be drawn with respect to superiority.

Study V

Study V was a 12-week study evaluating the efficacy of Rinvoq in 499 patients with moderate to severe active RA, who had an inadequate response or intolerance to biologic DMARDs. Patients were randomized to receive one of three treatments administered once daily for 12 weeks in addition to background csDMARD therapy: 15 mg Rinvoq, 30 mg Rinvoq, or placebo. At Week 12, patients receiving the placebo were switched to the 15 mg or 30 mg Rinvoq treatment groups in a blinded manner, based on pre-determined assignment at baseline. The primary efficacy endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Results

Statistically significant increases were observed in all five pivotal studies with respect to the proportion of patients who achieved a positive ACR20 (ACR50 for Study I) response with the daily 15 mg dose of Rinvoq, relative to methotrexate (Studies I and II) or placebo (Studies III, IV, and V). Statistically significant improvements were also observed across several other efficacy measures, relative to their respective controls.

The outcomes of the five pivotal studies clearly demonstrated that treatment with Rinvoq produces a clinically meaningful benefit in patients with moderately to severely active RA. Rinvoq was found to be effective when used either as monotherapy, or in combination with methotrexate or csDMARDs in patients naïve to methotrexate or who had inadequate responses to methotrexate, csDMARDs, and/or biologic DMARDs.

Only the 15 mg dose of Rinvoq was proposed for authorization. Although the pivotal studies also assessed the efficacy of the 30 mg dose, it was associated with an increased safety risk and no clear additional benefit was observed relative to the 15 mg dose.

The inhibition of progression of structural joint damage was evaluated as a secondary endpoint using the modified Total Sharp Score (mTSS) at Week 24 in Study I and at Week 26 in Study IV. Treatment with Rinvoq resulted in significantly greater inhibition of the progression of structural joint damage relative to methotrexate monotherapy (Study I) and relative to placebo plus methotrexate (Study IV).

Indication

For more information, refer to the Rinvoq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The data reviewed for the clinical safety evaluation were derived primarily from 4,443 patients exposed to Rinvoq over the course of the Phase II and III studies. Of these patients, 2,972 (67%) were exposed to Rinvoq for at least 48 weeks, which provided sufficient data to conduct an initial overall benefit-risk assessment.

Safety data from these studies must be interpreted with caution. Upadacitinib, the medicinal ingredient in Rinvoq, is a member of the Janus kinase (JAK) inhibitor class of drugs, which have immunosuppressive effects. Certain types of adverse events may present more frequently with longer durations of exposure to upadacitinib (e.g., malignancies or venous thromboembolic events [VTEs]).

Adverse events and serious adverse events were reported at a higher percentage in patients treated with 15 mg Rinvoq than in those who received the placebo. An increased incidence of adverse events and serious adverse events was reported in patients treated with 15 mg Rinvoq in both the controlled and long term periods of the Phase III studies. The types of adverse events and serious adverse events observed were similar between treatment arms, and were consistent with events reported in other studies of RA involving immunosuppressants and JAK inhibitors.

The most frequently reported adverse events were upper respiratory tract infection, nasopharyngitis, urinary tract infection, nausea, bronchitis, increased blood creatine phosphokinase (CPK), cough, and back pain. Each of these adverse events were reported in ≥2% of patients treated with 15 mg Rinvoq, and was reported at a higher rate in this patient group than in patients receiving the placebo.

The most frequently reported serious adverse events in patients treated with Rinvoq (incidence rate ≥0.5/100 patient-years) included pneumonia, osteoarthritis, and pulmonary embolism. The most frequently reported adverse drug reactions (ADRs) (in ≥1% of patients treated with 15 mg Rinvoq) were upper respiratory tract infections, nausea, increased CPK, cough, neutropenia, pyrexia, and hypercholesterolemia. In addition to these ADRs, urinary tract infection, herpes zoster, nasopharyngitis, bronchitis, sinusitis, and headache were also reported in patients treated with 15 mg Rinvoq (incidence rate ≥1/100 patient-years). The adverse events which most often led to treatment discontinuation were infections including pneumonia and herpes zoster (incidence rate ≥0.5/100 patient-years).

Several adverse events observed during treatment with Rinvoq (upadacitinib) are consistent with those associated with other JAK inhibitors. These include neutropenia, elevated lipid concentrations, elevated CPK levels, and viral reactivation.

Grade 2 and Grade 3 neutropenia were observed at higher frequencies in patients treated with Rinvoq than in patients who received the placebo. However, adverse events of neutropenia were observed at similar rates in the groups receiving 15 mg Rinvoq, adalimumab, and methotrexate.

Treatment with Rinvoq was also associated with a dose-dependent increase in lipid concentrations, including triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. However, the increased lipid concentrations did not affect the overall atherogenic indices, and were responsive to statin therapy. Additionally, there was no relationship identified between elevated lipid levels and major adverse cardiovascular events in the Phase III studies.

As with other JAK inhibitors, Rinvoq was associated with elevated CPK levels. The elevation of CPK levels was higher in patients treated with Rinvoq than in patients who received adalimumab, methotrexate, or a placebo. The elevation of CPK levels appeared to be dose-dependent, but the majority of cases were asymptomatic.

Viral reactivation (e.g., herpes zoster) has been reported in patients treated with potent immunosuppressants including members of the JAK inhibitor class of drugs. In the safety analysis for this submission, a higher rate of herpes zoster infection was observed in patients treated with upadacitinib relative to patients receiving a placebo, methotrexate, or adalimumab. A dose-dependent effect was observed, with higher rates of herpes zoster infections in patients treated with 30 mg upadacitinib compared to those treated with 15 mg upadacitinib. Additionally, two definitive cases of hepatitis B virus (HBV) reactivation were identified in patients treated with upadacitinib during the Phase II and Phase III programs.

Events of gastrointestinal perforation have been reported in clinical studies with Rinvoq, although the role of JAK inhibition in these events is not known. Six plausible upadacitinib-related cases of gastrointestinal perforation were reported in the Phase III studies. No cases were identified in patients who received a placebo, methotrexate, or adalimumab.

A Serious Warnings and Precautions box in the Rinvoq Product Monograph highlights the risks of serious infection, malignancies, and thrombosis. Patients treated with Rinvoq are at an increased risk for developing serious infections which may lead to hospitalization or death. In the clinical studies, most patients who developed serious infections were taking immunosuppressants such as methotrexate or corticosteroids concomitantly. Lymphoma and other malignancies have also been reported in patients treated with Rinvoq. Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with JAK inhibitors, including Rinvoq, for inflammatory conditions. Many of these cases were serious, and some resulted in death. Comprehensive guidelines and recommendations are included in the Rinvoq Product Monograph to promote the safe and effective use of Rinvoq.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Rinvoq. For more information, refer to the Rinvoq Product Monograph, approved by Health Canada and available through the Drug Product Database.