RINVOQ® Approved by European Commission as an Oral Treatment for Adults with Active Non-Radiographic Axial Spondyloarthritis

• With this approval, RINVOQ ^® (upadacitinib 15 mg, once daily) is the first and only Janus Kinase (JAK) inhibitor approved to treat patients across the spectrum of axial spondyloarthritis (nr-axSpA and ankylosing spondylitis) in the European Union (EU) ¹
• Approval is supported by data from the Phase 3 SELECT-AXIS 2 pivotal clinical trial in which RINVOQ delivered meaningful disease control with nearly half of nr-axSpA patients achieving ASAS40 at week 14 (45 percent versus 23 percent; p ²

ABBVie (NYSE: ABBV) today announced that the European Commission (EC) has approved RINVOQ ® (upadacitinib 15 mg, once daily), an oral therapy, 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) andor magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs). *1

"For years, healthcare providers and patients have had limited treatment options to manage axial spondyloarthritis, which can cause back pain, stiffness, and irreversible damage to the spine," said Thomas Hudson , M.D., senior vice president of research and development, chief scientific officer, AbbVie. "AbbVie is proud to offer RINVOQ as a first-in-class treatment option now approved in the European Union for adults living with nr-axSpA with objective signs of inflammation and inadequate response to NSAIDs. RINVOQ is the first and only JAK inhibitor approved to treat patients across the spectrum of axial spondyloarthritis, which includes nr-axSpA and ankylosing spondylitis."

Axial spondyloarthritis (axSpA) is a chronic, progressive and disabling inflammatory rheumatic disease that causes joint inflammation, leading to back pain and stiffness. ^3,4,5 AxSpA consists of two subsets that have been clinically defined as ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (r-axSpA), and non-radiographic axial spondyloarthritis (nr-axSpA). ⁶ Approximately 10-40 percent of patients eventually progress from nr-axSpA to r-axSpA over a 2- to 10-year period. ⁷

"The European Commission's approval of RINVOQ for the treatment of nr-axSpA offers physicians in the European Union an important new therapeutic option with proven efficacy in both nr-axSpA and AS patient populations," said Filip Van den Bosch , M.D.,** SELECT-AXIS 2 investigator and professor in the Department of Rheumatology at the University Hospital of Ghent University. "Living with nr-axSpA can pose many challenges and significantly impact a patient's quality of life. Early and effective disease management of patients with active nr-axSpA is key to improving health outcomes."

AbbVie previously disclosed topline results from the Phase 3 SELECT-AXIS 2 nr-axSpA clinical trial and the full results have been published in The Lancet . Study results show a significantly greater proportion of patients receiving RINVOQ 15 mg achieved an Assessment of SpondyloArthritis international Society 40 percent (ASAS40) response at week 14 (45 percent versus 23 percent; p 2 Statistical significance was also achieved in 12 of the 14 multiplicity-controlled secondary endpoints compared to placebo at week 14. ² Safety data were previously reported with no new risks identified compared to the known safety profile of RINVOQ. ² Through week 14, the proportion of patients who experienced an adverse event (AE) was similar between treatment groups (RINVOQ at 48 percent and placebo at 46 percent). ²

The EC Marketing Authorization for nr-axSpA means that RINVOQ is approved in all member states of the European Union, as well as Iceland , Liechtenstein , Northern Ireland and Norway .

RINVOQ also recently received a label enhancement in the EU for the already approved indication of AS to include data on patients with active AS who had an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs) based on the results of the Phase 3 SELECT-AXIS 2 clinical trial in this population, as well as two-year results of the Phase 2/3 SELECT-AXIS 1 clinical trial that evaluated AS bDMARD-naïve patients. ^8,9

AbbVie previously disclosed topline results from the Phase 3 SELECT-AXIS 2 AS bDMARD-IR study, in which a significantly greater proportion of patients receiving RINVOQ 15 mg achieved an ASAS40 response at week 14 (45 percent versus 18 percent) compared to placebo. ⁸ All 14 ranked secondary endpoints were met including those evaluating improvements from baseline in disease activity, pain (total and nocturnal back pain), function, MRI SPARCC score (spine), spinal mobility, enthesitis, and health-related quality of life. ⁸ Safety data were previously reported with no new risks identified compared to the known safety profile of RINVOQ. ⁸ Through week 14, the proportion of patients who experienced an AE was similar between treatment groups (RINVOQ at 41 percent and placebo at 37 percent). ⁸

About the SELECT-AXIS 1 and SELECT-AXIS 2 trial programs ^{2,   8   ,   9}

SELECT-AXIS 1 is a Phase 2/3, multicenter, randomized, double-blind, parallel-group, placebo-controlled study designed to evaluate the safety and efficacy of RINVOQ in adult patients with active AS who are bDMARD-naïve and had inadequate response to at least two NSAIDs or intolerance to/contraindication for NSAIDs. Period 2 is an open-label extension period to evaluate the long-term safety and efficacy of RINVOQ in subjects who completed Period 1. More information on this trial can be found at www.clinicaltrialsregister.eu/ (2017-000431-14) in the EU, and at www.clinicaltrials.gov (NCT03178487) in the U.S.

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).

Study 1: SELECT-AXIS 2 AS (bDMARD-IR) study ⁸

A randomized, double-blind, placebo-controlled Phase 3 trial, which evaluated the efficacy and safety of RINVOQ 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 study ²

A randomized, double-blind, placebo-controlled, Phase 3 trial which evaluated the efficacy and safety of RINVOQ 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).

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.

About Axial Spondyloarthritis (axSpA)

Axial spondyloarthritis is a chronic inflammatory disease that affects the spine, causing back pain, limited mobility, and structural damage. ⁶ It consists of two subsets that have been clinically defined as radiographic axial SpA (ankylosing spondylitis) and non-radiographic axial spondyloarthritis (nr-axSpA). ⁶ In ankylosing spondylitis, patients have definitive structural damage of the sacroiliac joints visible on X-rays. Non-radiographic axial spondyloarthritis is clinically defined by the absence of definitive X-ray evidence of structural damage to the sacroiliac (SI) joint by plain X-ray. ⁶

About RINVOQ   ^®   (upadacitinib)   ¹  
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.

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 non-radiographic axial spondyloarthritis in adult patients with objective signs of inflammation as indicated by elevated CRP and/or MRI, who have responded inadequately to NSAIDs; for the treatment of active ankylosing spondylitis (AS) in adult patients who have responded inadequately to conventional therapy; for adults (15 mg and 30 mg) and adolescents (15 mg) with moderate to severe atopic dermatitis; and for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent. ¹

Phase 3 trials of RINVOQ in atopic dermatitis, axial spondyloarthritis, Crohn's disease, giant cell arteritis and Takayasu arteritis are ongoing. ^{10,11,12,13,14,15}

EU Indications and Important Safety Information about RINVOQ ^® (upadacitinib) ¹

Indications

Ulcerative colitis

RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.

Rheumatoid arthritis

RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) 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 (PsA) 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.

Axial spondyloarthritis

Non-radiographic axial spondyloarthritis (nr-axSpA)
RINVOQ is indicated for the treatment of active non-radiographic axial spondyloarthritis 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).

Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)
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 (AD) 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. Upadacitinib should be interrupted if a patient develops a serious or opportunistic infection.

Tuberculosis

Patients should be screened for TB before starting RINVOQ. RINVOQ should not be given to patients with active TB. Anti-TB therapy may be appropriate for select patients in consultation with a physician with expertise in the treatment of TB. Patients should be monitored for the development of signs and symptoms of TB.

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. Consider interruption of upadacitinib if patient develops herpes zoster.

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. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

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. If alanine transaminase (ALT) or aspartate transaminase (AST) increases are observed and drug-induced liver injury is suspected, upadacitinib should be interrupted until this diagnosis is excluded.

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. If clinical features of DVT/PE occur, upadacitinib should be discontinued and patients should be evaluated and treated appropriately.

Elderly

There is an increased risk of adverse reactions with the upadacitinib dose of 30 mg once daily in patients aged 65 years and older. The recommended dose for long-term use is 15 mg once daily for this patient population.

Adverse reactions

The most commonly reported adverse reactions in RA, PsA, and axSpA 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, ALT increased, bronchitis, nausea, cough, AST increased, and hypercholesterolemia. Overall, the safety profile observed in patients with psoriatic arthritis or active axial spondyloarthritis treated with upadacitinib 15 mg was consistent with the safety profile observed in patients with RA.

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. Dose-dependent increased risks of infection and herpes zoster were observed with upadacitinib. 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.

The most commonly reported adverse reactions in UC trials (≥3% of patients) with upadacitinib 45 mg, 30 mg or 15 mg were upper respiratory tract infection, blood CPK increased, acne, neutropaenia, rash, herpes zoster, hypercholesterolemia, folliculitis, herpes simplex, and influenza. The overall safety profile observed in patients with ulcerative colitis was generally consistent with that observed in patients with RA.

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.

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.

About AbbVie in Rheumatology
For more than 20 years, AbbVie has been dedicated to improving care for people living with rheumatic diseases. Our longstanding commitment to discovering and delivering transformative therapies is underscored by our pursuit of cutting-edge science that improves our understanding of promising new pathways and targets in order to help more people living with rheumatic diseases reach their treatment goals. For more information on AbbVie in rheumatology, visit https://www.abbvie.com/our-science/therapeutic-focus-areas/immunology/immunology-focus-areas/rheumatology.html .

About AbbVie
AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across its Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com . Follow @abbvie on Twitter , Facebook , Instagram , YouTube and LinkedIn .

Forward-Looking Statements
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, failure to realize the expected benefits from AbbVie's acquisition of Allergan plc ("Allergan"), failure to promptly and effectively integrate Allergan's businesses, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, changes to laws and regulations applicable to our industry and the impact of public health outbreaks, epidemics or pandemics, such as COVID-19. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2021 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

*This recommendation is without prejudice to the final conclusions of the ongoing referral procedure under Article 20 of Regulation (EC) No 726/2004 resulting from pharmacovigilance data.

**Dr. Van den Bosch is a consultant and advisor for AbbVie.

References:

¹ AbbVie, Ltd. RINVOQ (upadacitinib) [summary of product characteristics]. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf . Accessed July 28, 2022 .

² Deodhar, A, et al. Efficacy and Safety of Upadacitinib in Patients with Active Non-Radiographic Axial Spondyloarthritis: a Double-Blind, Randomized, Placebo-Controlled Phase 3 Trial. EULAR 2022 Congress; 2534.

³ Crossfield SSR, Marzo-Ortega H, Kingsbury SR, et al. Changes in ankylosing spondylitis incidence, prevalence and time to diagnosis over two decades.  RMD Open 2021;7:e001888. doi: 10.1136/rmdopen-2021-001888.

⁴ Mayo Clinic. Ankylosing Spondylitis. 2019. Available at: https://www.mayoclinic.org/diseases-conditions/ankylosing-spondylitis/symptoms-causes/syc-20354808 . Accessed June 2022 .

⁵ Dean, LE, et al. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014 Apr;53(4):650-7. doi: 10.1093/rheumatology/ket387. Epub 2013

⁶ Deodhar AA, Understanding Axial Spondyloarthritis: A Primer for Managed Care. Am J Manag Care. 2019;25:S319-S330.

⁷ Protopopov M, Poddubnyy D. Radiographic progression in non-radiographic axial spondyloarthritis. Expert Rev Clin Immunol . 2018;14(6):525-533.

⁸ Van der Heijde , D, et al. Efficacy and Safety of Upadacitinib in Patients With Active Ankylosing Spondylitis Refractory to Biologic Therapy: a Double-Blind, Randomized, Placebo-Controlled Phase 3 Trial. EULAR 2022 Congress; 2518.

⁹ Van der Heijde D, et al. Efficacy and Safety of Upadacitinib in Patients with Active Ankylosing Spondylitis: 2-Year Results from a Randomized, Double-Blind, Placebo-Controlled Study with Open-Label Extension [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 10).

¹⁰ Evaluation of Upadacitinib in Adolescent and Adult Patients With Moderate to Severe Atopic Dermatitis (Eczema) (Measure Up 1). ClinicalTrials.gov. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03569293 . Accessed June 2022 .

¹¹ A Study to Evaluate Efficacy and Safety of Upadacitinib in Adult Participants With Axial Spondyloarthritis (SELECT-AXIS 2). ClinicalTrials.gov. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04169373 . Accessed June 2022 .

¹² A Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Participants With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Biologic Therapy. ClinicalTrials.gov. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03345836 . Accessed June 2022 .

¹³ A Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis (UC). ClinicalTrials.gov. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT02819635 . Accessed June 2022 .

¹⁴ A Study to Evaluate the Safety and Efficacy of Upadacitinib in Participants With Giant Cell Arteritis (SELECT-GCA). ClinicalTrials.gov. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03725202 . Accessed June 2022 .

¹⁵ A Study to Evaluate the Efficacy and Safety of Upadacitinib in Subjects With Takayasu Arteritis (TAK) (SELECT-TAK). ClinicalTrials.gov. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04161898 . Accessed June 2022 .

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