AbbVie Announces European Commission Approval of RINVOQ® (upadacitinib) for the Treatment of Moderately to Severely Active Crohn's Disease

?  Seventh approved indication for RINVOQ in the European Union (EU) and the first and only oral Janus Kinase (JAK) inhibitor approved to treat adult patients with moderately to severely active Crohn's disease

?  Third gastroenterology indication approved across AbbVie's Inflammatory Bowel Disease portfolio in less than a year

?  A significantly higher proportion of patients treated with RINVOQ achieved the co-primary endpoints of endoscopic response and clinical remission and the key secondary endpoint of corticosteroid-free clinical remission at weeks 12 and 52 compared to placebo^1-4; safety results in Crohn's disease were generally consistent with the known safety profile of RINVOQ^1,5-9

?  Crohn's disease is a chronic, systemic disease that manifests as inflammation within the gastrointestinal tract and is progressive, potentially producing complications that require urgent medical care, including surgery^10,11

NORTH CHICAGO, Ill., April 17, 2023 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced the European Commission (EC) approved RINVOQ^® (upadacitinib, 45 mg [induction dose] and 15 mg and 30 mg [maintenance doses]) as the first oral Janus Kinase (JAK) inhibitor for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.^1-4

"The EC approval of RINVOQ in Crohn's disease is a significant milestone in offering patients the first and only once-daily oral treatment that can provide endoscopic improvement, and sustained symptom relief, making a difference in their daily lives," said Thomas Hudson, M.D., senior vice president, research and development, chief scientific officer, AbbVie. "With existing therapies, not all patients are able to achieve adequate disease control to meet their treatment goals, which is why we continue to embrace the challenge of expanding our IBD portfolio with new treatment options."

The EC approval is supported by data from two induction studies, U-EXCEED and U-EXCEL, and the U-ENDURE maintenance study.¹ Statistical significance was achieved for the co-primary endpoints and key secondary endpoints with RINVOQ 45 mg in the induction studies and RINVOQ 15 mg and 30 mg in the maintenance study compared to placebo.^1-4

Co-Primary Endpoint Results from the Phase 3 program include^1-4:

• Endoscopic response*: In U-EXCEED and U-EXCEL, 35% and 46% of patients treated with RINVOQ 45 mg achieved endoscopic response at week 12, respectively, compared to 4% and 13% of patients receiving placebo.¹ In U-ENDURE, 28% and 40% of patients treated with RINVOQ 15 mg and 30 mg achieved endoscopic response at week 52, respectively, compared to 7% of patients receiving placebo.¹
    
• Clinical remission^?: In U-EXCEED and U-EXCEL, 40% and 51% of patients treated with RINVOQ 45 mg achieved clinical remission at 12 weeks, respectively, compared to 14% and 22% of patients receiving placebo.¹ Additionally, in U-ENDURE, 36% and 46% patients treated with RINVOQ 15 mg and 30 mg achieved clinical remission at 52 weeks, respectively, compared to 14% of patients receiving placebo.¹

Key Secondary and Additional Endpoints include:

• Corticosteroid-free clinical remission^?: In U-EXCEED and U-EXCEL, 37% and 44% of patients treated with RINVOQ 45 mg achieved steroid-free remission at week 12, respectively, compared to 7% and 13% of patients receiving placebo. In U-ENDURE, 35% and 45% of patients treated with RINVOQ 15 mg and 30 mg achieved steroid-free remission at week 52, respectively, compared to 14% of patients receiving placebo.¹
     
• Mucosal healing^§: Additionally, in U-EXCEED and U-EXCEL, 17% and 25% of patients treated with RINVOQ 45mg achieved SES-CD ulcerated surface subscore of 0 at week 12, respectively, compared to 0% and 5% of patients receiving placebo. In U-ENDURE, 13% and 24% of patients treated with RINVOQ 15 mg and 30 mg achieved SES-CD ulcerated surface subscore of 0 at week 52 compared to 4% of patients receiving placebo (all with nominal p-value<0.001).¹

"Crohn's disease is a burden that can present patients with daily, often uncomfortable challenges," said Laurent Peyrin-Biroulet, M.D., Ph.D., professor of gastroenterology and head of the Inflammatory Bowel Disease group at the Gastroenterology Department, University Hospital of Nancy, France. "These studies demonstrated RINVOQ's ability to achieve key treatment targets, including endoscopic outcomes and symptomatic relief, that are critical for patients and beneficial for long-term care."

The safety profile of RINVOQ in Crohn's disease was generally consistent with the known safety profile of RINVOQ.^1-4 Similar rates of serious adverse events including serious infections, were observed between patients receiving RINVOQ and placebo.^1-4 The most common adverse events included nasopharyngitis, acne and COVID-19 in the RINVOQ treatment group.^1-4 Reports of malignancy, major cardiovascular events, venous thromboembolic events and gastrointestinal perforation were infrequently observed (<1.0 Events/100 Patient-Years).  

RINVOQ is approved in the EU for the treatment of adults with radiographic axial spondyloarthritis, non-radiographic axial spondyloarthritis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, adults and adolescents with atopic dermatitis and now Crohn's disease.^1,5-9

About Crohn's Disease
Crohn's disease is a chronic, systemic disease that manifests as inflammation within the gastrointestinal tract, causing persistent diarrhea and abdominal pain.^10,11It is a progressive disease, meaning it gets worse over time in a substantial proportion of patients or may develop complications that require urgent medical care, including surgery.^10,11 Because the signs and symptoms of Crohn's disease are unpredictable, it causes a significant burden on people living with the disease?not only physically, but also emotionally and economically.^10,11

About the U-EXCEED and U-EXCEL Inductions Studies, and the U-ENDURE Maintenance Study^1-4
The three Phase 3 studies are multicenter, randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of RINVOQ 45 mg as induction therapy and RINVOQ 15 mg and 30 mg as maintenance therapy in patients with moderately to severely active Crohn's disease. Topline results of the U-EXCEED and U-EXCEL induction studies were announced in December 2021 and February 2022. Topline results of the U-ENDURE maintenance study were announced in May 2022. More information can be found on www.clinicaltrials.gov (U-EXCEED: NCT03345836 , U-EXCEL: NCT03345849 , U-ENDURE: NCT03345823).

About RINVOQ^® (upadacitinib) 
Discovered and developed by AbbVie scientists, RINVOQ is a selective and reversible Janus Kinase (JAK) inhibitor.¹ In human cellular assays, RINVOQ preferentially inhibits signaling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2.¹

Phase 3 trials of upadacitinib (RINVOQ) in giant cell arteritis and Takayasu arteritis are ongoing.^1,12-14

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

Indications

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.

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.

Crohn's disease

RINVOQ is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.

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
RINVOQ should only be used if no suitable treatment alternatives are available in patients:

• 65 years of age and older;
• patients with history of atherosclerotic cardiovascular (CV) disease or other CV risk factors (such as current or past long-time smokers);
• patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use in patients 65 years of age and older
Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients ?65 years of age, as observed in a large randomised study of tofacitinib (another JAK inhibitor), RINVOQ should only be used in these patients if no suitable treatment alternatives are available. In patients ?65 years of age, there is an increased risk of adverse reactions with RINVOQ 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily.

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 RINVOQ. The most frequent serious infections reported included pneumonia and cellulitis. Cases of bacterial meningitis and sepsis have been reported with RINVOQ. Among opportunistic infections, TB, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis have been reported. RINVOQ should not be initiated in patients with an active, serious infection, including localized infections. RINVOQ should be interrupted if a patient develops a serious or opportunistic infection until the infection is controlled. A higher rate of serious infections was observed with RINVOQ 30 mg compared to 15 mg. As there is a higher incidence of infections in the elderly and patients with diabetes in general, caution should be used when treating these populations. In patients ?65 years of age, RINVOQ should only be used if no suitable treatment alternatives are available.

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 RINVOQ. Consider interruption of RINVOQ if the patient develops herpes zoster until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should occur before and during therapy. If hepatitis B virus DNA is detected, a liver specialist should be consulted.

Vaccination
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 RINVOQ, in agreement with current immunization guidelines.

Malignancy
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including RINVOQ. In a large randomised active?controlled study of tofacitinib (another JAK inhibitor) in RA patients ?50 years of age with ?1 additional CV risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma, and non-melanoma skin cancer (NMSC), was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors. A higher rate of malignancies, including NMSC, was observed with RINVOQ 30 mg compared to 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. In patients ?65 years of age, patients who are current or past long-time smokers, or patients with other malignancy risk factors (e.g., current malignancy or history of malignancy), RINVOQ should only be used if no suitable treatment alternatives are available.

Hematological abnormalities
Treatment should not be initiated, or should be temporarily interrupted, in patients with hematological abnormalities observed during routine patient management.

Gastrointestinal Perforations
Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and from post?marketing sources. RINVOQ should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or opioids. Patients with active Crohn's disease are at increased risk for developing intestinal perforation. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.

Major adverse cardiovascular events
MACE were observed in clinical studies of RINVOQ. In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in RA patients ?50 years of age with ?1 additional CV risk factor, a higher rate of MACE, defined as CV death, non-fatal myocardial infarction and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors. Therefore, in patients ?65 years of age, patients who are current or past long-time smokers, and patients with history of atherosclerotic CV disease or other CV risk factors, RINVOQ should only be used if no suitable treatment alternatives are available.

Lipids
RINVOQ 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 RINVOQ 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, RINVOQ should be interrupted until this diagnosis is excluded.

Venous thromboembolism
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinical trials for RINVOQ. In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in RA patients ?50 years of age with ?1 additional CV risk factor, a dose?dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors. In patients with CV or malignancy risk factors, RINVOQ should only be used if no suitable treatment alternatives are available. In patients with known VTE risk factors other than CV or malignancy risk factors (e.g. previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder), RINVOQ should be used with caution. Patients should be re-evaluated periodically to assess for changes in VTE risk. Promptly evaluate patients with signs and symptoms of VTE and discontinue RINVOQ in patients with suspected VTE.

Hypersensitivity reactions
Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving RINVOQ. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

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 RINVOQ 15 mg were upper respiratory tract infections, blood creatine phosphokinase (CPK) increased, ALT increased, bronchitis, nausea, neutropenia, cough, AST increased, and hypercholesterolemia. Overall, the safety profile observed in patients with psoriatic arthritis or active axial spondyloarthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with RA.

The most commonly reported adverse reactions in AD trials (?2% of patients) with RINVOQ 15 mg or 30 mg were upper respiratory tract infection, acne, herpes simplex, headache, blood CPK increased, cough, folliculitis, abdominal pain, nausea, neutropenia, pyrexia, and influenza. Dose dependent increased risks of infection and herpes zoster were observed with RINVOQ. The safety profile for RINVOQ 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 the UC and CD trials (?3% of patients) with RINVOQ 45 mg, 30 mg or 15 mg were upper respiratory tract infection, pyrexia, blood CPK increased, anemia, headache, acne, herpes zoster, neutropaenia, rash, pneumonia, hypercholesterolemia, bronchitis, aspartate transaminase increased, fatigue, folliculitis, alanine transaminase increased, herpes simplex, and influenza.

The overall safety profile observed in patients with UC was generally consistent with that observed in patients with RA.

Overall, the safety profile observed in patients with CD treated with RINVOQ was consistent with the known safety profile for RINVOQ.

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 

Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Gastroenterology
With a robust clinical trial program, AbbVie is committed to cutting-edge research to drive exciting developments in inflammatory bowel diseases (IBD), like ulcerative colitis and Crohn's disease. By innovating, learning and adapting, AbbVie aspires to eliminate the burden of IBD and make a positive long-term impact on the lives of people with IBD. For more information on AbbVie in gastroenterology, visit https://www.abbvie.com/our-science/therapeutic-focus-areas/immunology/immunology-focus-areas/gastroenterology.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 our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, LinkedIn or Instagram. 

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, uses of future or conditional verbs 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 expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. 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 2022 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, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

References:

1. RINVOQ [Summary of Product Characteristics]. AbbVie Deutschland GmbH & Co. KG; March 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf 
2. Colombel JF, Panes J, Lacerda AP, Peyrin-Biroulet L. Efficacy and safety of upadacitinib induction therapy in patients with moderately to severely active Crohn's disease who failed prior biologics: results form a randomized phase 3 U-EXCEED study. Gastroenterology. 2022;162(7):S-1394. doi:10.1016/S0016-5085(22)64061-7  
3. Loftus EV, Colombel LF, Lacerda AP, et al. Efficacy and safety of upadacitinib induction therapy in patients with moderately to severely active Crohn's disease: results from a randomized phase 3 U-EXCEL study. United European Gastroenterol J. 2022;10(8):103-104. doi: 10.1002/ueg2.12293.
4. Panes J, Loftus E, Lacerda AP, Peyrin-Biroulet L, D'Haens G, Panaccione R. Efficacy and safety of upadacitinib maintenance therapy in patients with moderately to severely active Crohn's disease: results from a randomized phase 3 U-ENDURE maintenance study. American College of Gastroenterology. 2022;1-14.
5. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2
6. Cohen SB, van Vollenhoven RF, Winthrop KL, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. [published correction appears in Ann Rheum Dis. 2021 May;80(5):e83]. Ann Rheum Dis. 2021;80(3):304-311. doi:10.1136/annrheumdis-2020-218510 
7. van der Heijde D, Song IH, Pangan AL, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019;394(10214):2108-2117. doi:10.1016/S0140-6736(19)32534-6
8. Mease PJ, Lertratanakul A, Anderson JK, et al. Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2. Ann Rheum Dis. 2021;80(3):312-320. doi:10.1136/annrheumdis-2020-218870
9. Danese, S, Vermeire, S, Zhou, W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399(10341):2113-2128. doi: 10.1016/S0140-6736(22)00581-5.
10. Crohn's disease. Symptoms and causes. Mayo Clinic. Accessed March 8, 2023. https://www.mayoclinic.org/diseases-conditions/crohns-disease/symptoms-causes/syc-20353304
11. The facts about inflammatory bowel diseases. Crohn's & Colitis Foundation of America. Accessed March 8, 2023. https://www.crohnscolitisfoundation.org/sites/default/files/2019-02/Updated%20IBD%20Factbook.pdf
12. Pipeline. AbbVie. Accessed March 3, 2023. https://www.abbvie.com/our-science/pipeline.html
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14. A study to evaluate the efficacy and safety of upadacitinib in participants with Takayasu arteritis (TAK) (SELECT-TAK). ClinicalTrials.gov. Updated November 28, 2022. Accessed March 6, 2023. https://clinicaltrials.gov/ct2/show/NCT04161898

* Endoscopic response is defined as a decrease in simple endoscopic score for Crohn's disease (SES-CD) of >50% from baseline (or at least a 2-point reduction from baseline in patients with a baseline score of 4) of the induction.    
^? Clinical remission per SF/AP is defined as average daily very soft or liquid stool frequency ?2.8 AND abdominal pain score ?1.0 and neither greater than baseline.
^? Corticosteroid-free clinical remission is defined as discontinuation of corticosteroid and achievement of clinical remission among subjects on corticosteroid at baseline in the induction studies and is defined as without corticosteroid use for 90 days and achievement of clinical remission in the maintenance study.
^§ Mucosal healing is defined as SES-CD ulcerated surface subscore of 0 in patients with SES-CD ulcerated surface subscore ? 1 at baseline. Mucosal healing was a prespecified endpoint, not controlled for multiplicity.

SOURCE AbbVie