AbbVie today announced the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended the approval of upadacitinib (RINVOQ® 15 mg, once daily) for the treatment of active non-radiographic axial spondyloarthritis (nr‑axSpA) in adult patients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs).*
Patients with axSpA often experience delayed diagnosis and once they do receive a diagnosis, there are limited therapies available to help control disease symptoms, such as inflammation, back pain and stiffness. The CHMP's recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need."
Neil Gallagher, MD, PhD, Vice President of Development, Chief Medical Officer, AbbVie
The CHMP positive opinion is a scientific recommendation for marketing authorization to the European Commission (EC), which will review it and issue a Commission decision that will be valid in all member states of the European Union (EU), as well as Iceland, Liechtenstein, Northern Ireland and Norway.
AbbVie’s application for the approval of upadacitinib in nr-axSpA is supported by results from the Phase 3 SELECT-AXIS 2 study, for which AbbVie disclosed topline results in 2021. In the Phase 3 clinical study, the SELECT-AXIS 2 nr-axSpA study met the primary endpoint of Assessment of SpondyloArthritis international Society 40 percent response criteria (ASAS40), and the first 12 of 14 ranked secondary endpoints. Safety data were previously reported with no new risks identified compared to the known safety profile of upadacitinib.
Upadacitinib is currently approved for use in the EU in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis.
The use of upadacitinib in nr-axSpA is not approved in the U.S. or EU. Its efficacy and safety remain under review.
About the SELECT-AXIS 2 program
SELECT-AXIS 2 (NCT04169373) was conducted under a master protocol and includes two separate studies (SELECT-AXIS 2 AS (bDMARD-IR) study, or Study 1 and SELECT-AXIS 2 nr-axSpA study, or Study 2).
More information on the SELECT-AXIS 2 program is available at: https://www.clinicaltrialsregister.eu/ (2019-003229-12) in the EU, and at: www.clinicaltrials.gov (NCT04169373) in the U.S.
Study 1: SELECT-AXIS 2 AS (bDMARD-IR) study6
A randomized, double-blind, placebo-controlled Phase 3 trial, which evaluated the efficacy and safety of upadacitinib compared with placebo, in 420 patients with a clinical diagnosis of AS who fulfilled the modified New York criteria, had BASDAI score ≥4 and total back pain score ≥4 (based on a numerical scale of 0-10), and had an inadequate response to bDMARD therapy.
Study 2: SELECT-AXIS 2 nr-axSpA study1
A randomized, double-blind, placebo-controlled, Phase 3 trial which evaluated the efficacy and safety of upadacitinib compared with placebo, in 314 patients with a clinical diagnosis of nr-axSpA. Patients enrolled in the study had active signs of inflammation as indicated by MRI + sacroiliac joint inflammation, and/or high sensitivity C-reactive protein (hs-CRP) >upper limit of normal (2.87 mg/L) at screening, and who had BASDAI score ≥4 and a total back pain score ≥4 (based on a numerical scale of 0-10).
About Axial Spondyloarthritis (axSpA)
Axial spondyloarthritis is a chronic inflammatory disease that affects the spine, causing back pain, limited mobility, and structural damage.4 It consists of two subsets that have been clinically defined as radiographic axial SpA (ankylosing spondylitis) and non-radiographic axial spondyloarthritis (nr-axSpA).4 In ankylosing spondylitis, patients have definitive structural damage of the sacroiliac joints visible on X-rays.4 Non-radiographic axial spondyloarthritis is clinically defined by the absence of definitive X-ray evidence of structural damage to the sacroiliac joint by plain X-ray.4
About RINVOQ® (upadacitinib)5
Discovered and developed by AbbVie scientists, RINVOQ is a selective JAK inhibitor that is being studied in several immune-mediated inflammatory diseases. In human cellular assays, RINVOQ preferentially inhibits signaling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2.5
In the EU, RINVOQ is approved for the treatment of adults with moderate to severe active rheumatoid arthritis who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs; for the treatment of active psoriatic arthritis (PsA) in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs; for the treatment of active ankylosing spondylitis (AS) in adult patients who have responded inadequately to conventional therapy; and for adults (15 mg and 30 mg) and adolescents (15 mg) with moderate to severe atopic dermatitis.5
Phase 3 trials of RINVOQ in axial spondyloarthritis, Crohn's disease, giant cell arteritis and Takayasu arteritis are ongoing.7,8,9,10 Use of RINVOQ in nr-axSpA is not approved and remains under review by regulatory authorities.
EU indications and important safety information about RINVOQ® (upadacitinib)5
Indications
Rheumatoid arthritis
RINVOQ is 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.
Psoriatic arthritis
RINVOQ is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate.
Ankylosing spondylitis
RINVOQ is indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.
Atopic dermatitis
RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.
Important safety information
Contraindications
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.
Special warnings and precautions for use
Immunosuppressive medicinal products
Use in combination with other potent immunosuppressants is not recommended.
Serious infections
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. As there is a higher incidence of infections in patients ≥65 years of age, caution should be used when treating this population.
Viral reactivation
Viral reactivation, including cases of herpes zoster, was reported in clinical studies. The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib.
Vaccinations
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.
Malignancy
The risk of malignancies, including lymphoma is increased in patients with rheumatoid arthritis (RA). 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.
Hematological abnormalities
Treatment should not be initiated, or should be temporarily interrupted, in patients with hematological abnormalities observed during routine patient management.
Diverticulitis
Upadacitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis.
Cardiovascular risk
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.
Lipids
Upadacitinib treatment was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.
Hepatic transaminase elevations
Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo.
Venous thromboembolisms
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.
Adverse reactions
The most commonly reported adverse reactions in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis clinical trials (≥2% of patients in at least one of the indications) with upadacitinib 15 mg were upper respiratory tract infections, blood creatine phosphokinase (CPK) increased, alanine transaminase (ALT) increased, bronchitis, nausea, cough, aspartate transaminase (AST) increased, and hypercholesterolemia.
The most commonly reported adverse reactions in atopic dermatitis trials (≥2% of patients) with upadacitinib 15 mg or 30 mg were upper respiratory tract infection, acne, herpes simplex, headache, CPK increased, cough, folliculitis, abdominal pain, nausea, neutropenia, pyrexia, and influenza. The most common serious adverse reactions were serious infections.
The safety profile of upadacitinib with long term treatment was generally similar to the safety profile during the placebo-controlled period across indications.
Overall, the safety profile observed in patients with psoriatic arthritis or active ankylosing spondylitis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with RA. In atopic dermatitis, dose-dependent increased risks of infection and herpes zoster were observed with upadacitinib. Based on limited data, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dose compared to the 15 mg dose in patients aged 65 years and older.
The safety profile for upadacitinib 15 mg in adolescents was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated. Dose-dependent changes in ALT increased and/or AST increased (≥ 3 x ULN), lipid parameters, CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatment were similar to what was observed in the rheumatologic disease clinical studies.
This is not a complete summary of all safety information.
See RINVOQ full summary of product characteristics (SmPC) at: www.ema.europa.eu/en.
Globally, prescribing information varies; refer to the individual country product label for complete information.
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