RINVOQ is an oral selective and reversible JAK inhibitor indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.
SELECT-NEXT: Study design
A Phase 3 study investigating the efficacy and safety of RINVOQ + csDMARDs compared to placebo + csDMARDs in patients with moderate to severe RA and an inadequate response to csDMARDs1
Permitted background csDMARDs were oral and parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine, and leflunomide; up to 2 concomitant background csDMARDs were allowed, with the exception of the combination of MTX and leflunomide.
*From Week 12 onward, patients initially randomized to placebo at baseline were switched to RINVOQ 15 mg or upadacitinib 30 mg per prespecified randomization assignment. Patients assigned to RINVOQ 15 mg or upadacitinib 30 mg continued their assigned dose.
Primary
RINVOQ 15 mg + csDMARD(s) and upadacitinib 30 mg + csDMARD(s) vs placebo + csDMARD(s) at Week 12 for DAS28 (CRP) <3.2 (EMA) or ACR20 (FDA)
Safety
Adverse events, serious adverse events, adverse events of special interest (e.g., serious infections, opportunistic infections, MACEs, VTEs, malignancies)
- Patients ≥18 years of age were eligible to participate.
- Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (at least 6 swollen joints out of 66, at least 6 tender joints out of 68, and hsCRP of 3 mg/L or more).
- Received csDMARDs for ≥3 months and on a stable dose for ≥4 weeks before study entry.
- Patients must have had an inadequate response to at least 1 prior csDMARD (MTX, sulfasalazine, or leflunomide).
- Patients with prior exposure to at most 1 bDMARD were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3 months) or had to discontinue the bDMARD due to intolerability.
- No prior exposure to a JAK inhibitor or prior inadequate response to bDMARDs.
The approved dose of RINVOQ is 15 mg once daily. Upadacitinib 30 mg QD is not an approved dose.
ACR: American College of Rheumatology; ACR20: improvement of at least 20% in the American College of Rheumatology core criteria; bDMARD: biological disease-modifying antirheumatic drug; csDMARD: conventional synthetic disease-modifying antirheumatic drug; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EMA: European Medicines Agency; EULAR: European League Against Rheumatism; FDA: Food and Drug Administration; hsCRP : high-sensitivity C-reactive protein; JAK: Janus kinase; MACE: major adverse cardiovascular event; MTX: methotrexate; QD: once daily; SF-36: Short-Form 36; VTE: venous thromboembolic event.
RINVOQ: Efficacy with csDMARDS after inadequate response to csDMARDS
SELECT-NEXT: Low disease activity and remission at Week 12 in patients with an inadequate response to csDMARDs (NRI)1,2
*P≤0.001 vs placebo + csDMARD(s)
csDMARD: conventional synthetic disease-modifying anti-rheumatic drug; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); NRI: nonresponder imputation.
SELECT-NEXT: Adverse events through 12 weeks of treatment1
*One case of congestive cardiac failure, one cardiovascular procedure.
Safety Information2
RINVOQ is contraindicated in patients hypersensitive to the active substance or to any of the excipients, in patients with active tuberculosis (TB) or active serious infections, in patients with severe hepatic impairment, and during pregnancy.
Use in combination with other potent immunosuppressants is not recommended.
Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The most frequent serious infections reported included pneumonia and cellulitis. Cases of bacterial meningitis have been reported. Among opportunistic infections, TB, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis have been reported with upadacitinib. Prior to initiating upadacitinib, consider the risks and benefits of treatment in patients with chronic or recurrent infection or with a history of a serious or opportunistic infection, in patients who have been exposed to TB or have resided or traveled in areas of endemic TB or endemic mycoses, and in patients with underlying conditions that may predispose them to infection. Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection. As there is a higher incidence of infections in patients ≥75 years of age, caution should be used when treating this population.
Patients should be screened for TB before starting upadacitinib therapy. Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection.
Viral reactivation, including cases of herpes zoster, were reported in clinical studies. Consider interruption of therapy if a patient develops herpes zoster until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib.
The use of live, attenuated vaccines during or immediately prior to therapy is not recommended. It is recommended that patients be brought up to date with all immunizations, including prophylactic zoster vaccinations, prior to initiating upadacitinib, in agreement with current immunization guidelines.
The risk of malignancies, including lymphoma is increased in patients with rheumatoid arthritis (RA). Immunomodulatory medicinal products may increase the risk of malignancies, including lymphoma. The clinical data are currently limited and long-term studies are ongoing. Malignancies, including nonmelanoma skin cancer (NMSC), have been reported in patients treated with upadacitinib. Consider the risks and benefits of upadacitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated NMSC or when considering continuing upadacitinib therapy in patients who develop a malignancy. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Absolute neutrophil count <1000 cells/mm3, absolute lymphocyte count <500 cells/mm3, or hemoglobin levels <8 g/dL were reported in ≤1% of patients in clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with these hematological abnormalities observed during routine patient management.
RA patients have an increased risk for cardiovascular disorders. Patients treated with upadacitinib should have risk factors (e.g., hypertension, hyperlipidemia) managed as part of usual standard of care.
Upadacitinib treatment was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, upadacitinib therapy should be interrupted until this diagnosis is excluded.
Events of deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors, including upadacitinib. Upadacitinib should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient’s risk for DVT/PE include older age, obesity, a medical history of DVT/PE, patients undergoing major surgery, and prolonged immobilization. If clinical features of DVT/PE occur, upadacitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
The most commonly reported adverse drug reactions are upper respiratory tract infections (13.5%), nausea (3.5%), increased blood creatine phosphokinase (2.5%), and cough (2.2%). The most common serious adverse reactions were serious infections.
Please see the RINVOQ Summary of Product Characteristics for complete Prescribing Information.
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References
- Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10139):2503-2512. doi:10.1016/S0140-6736(18)31115-2
- RINVOQ [Summary of Product Characteristics]. AbbVie Deutschland GmbH & Co. KG; [MM,YYYY].