AbbVie Submits Applications for Upadacitinib in Non-Radiographic Axial Spondyloarthritis to U.S. Food and Drug Administration and European Medicines Agency

ABBVie (NYSE: ABBV) today announced that it has submitted applications seeking approvals for upadacitinib (RINVOQ ® 15 mg once daily) to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs). The applications are supported by the Phase 3 SELECT-AXIS 2 (Study 2) clinical trial.

In the SELECT-AXIS 2 trial (Study 2), evaluating the efficacy and safety of upadacitinib in adult patients with nr-axSpA, upadacitinib met its primary and most ranked secondary endpoints. ¹ Treatment with upadacitinib 15 mg once daily resulted in reductions in signs and symptoms of nr-axSpA, including back pain and inflammation, as well as improvements in physical function and disease activity at week 14 versus placebo. ¹

"Axial spondyloarthritis is a chronic inflammatory disease affecting the spine and can cause patients, who tend to be younger adults living active lives, to suffer from debilitating pain and significantly decrease their quality of life," ² said Thomas Hudson , M.D., senior vice president of research and development, chief scientific officer, AbbVie. "AbbVie is committed to working with the FDA and EMA to make upadacitinib available as a treatment option for patients living with this disease."

In addition, AbbVie has requested label enhancements for upadacitinib in the European Union (EU) to include adult patients with active ankylosing spondylitis (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 (Study 1), as well as two-year results of the Phase 2/3 SELECT-AXIS 1 clinical trial. ^1,3 AbbVie also provided these data to the FDA in support of the agency's ongoing review of the supplemental New Drug Application (sNDA) for upadacitinib in AS.

The safety data observed in these patients with AS or nr-axSpA were generally consistent with the known safety profile of upadacitinib. No new safety risks were identified. ^1,3,4,5

About 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 ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). ⁶ In ankylosing spondylitis, patients have definitive structural damage of the sacroiliac joints visible on x-rays. ⁶ 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 SELECT-AXIS 1 and SELECT-AXIS 2 trial programs ^{1,4,5, 7}
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 ankylosing spondylitis 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, tolerability and efficacy of RINVOQ in subjects who completed Period 1. Primary results from SELECT-AXIS 1 were previously announced in November 2019 with 2-year results presented in November 2021 . More information on this trial can be found at www.clinicaltrials.gov (NCT03178487).

SELECT-AXIS 2 was conducted as a master study protocol that contains two standalone studies with randomization, data collection, analysis and reporting conducted independently. The Phase 3, randomized, placebo-controlled, double-blind studies are evaluating the efficacy and safety of upadacitinib compared with placebo on reduction of signs and symptoms in adult participants with active axSpA including bDMARD-IR AS ( Study 1 ) and nr-axSpA ( Study 2 ). More information on this trial can be found at www.clinicaltrials.gov (NCT04169373).

In all studies, the primary endpoint was the percentage of subjects achieving an ASAS40 response after 14 weeks of treatment.

About RINVOQ ^® (upadacitinib)
Discovered and developed by AbbVie scientists, RINVOQ is a selective JAK inhibitor that is being studied in several immune-mediated inflammatory diseases. Based on enzymatic and cellular assays, RINVOQ demonstrated greater inhibitory potency for JAK-1 vs JAK-2, JAK-3, and TYK-2. ⁸ The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness and safety is not currently known. RINVOQ 15 mg is approved by the U.S. Food and Drug Administration (FDA) for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers and adults with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. RINVOQ 15 mg is approved by the European Commission for adults with moderate to severe active rheumatoid arthritis, adults with active psoriatic arthritis and adults with active ankylosing spondylitis. RINVOQ is approved by the European Commission for adults (15 mg and 30 mg) and adolescents (15 mg) with moderate to severe atopic dermatitis. Phase 3 trials of RINVOQ in rheumatoid arthritis, atopic dermatitis, psoriatic arthritis, axial spondyloarthritis, Crohn's disease, ulcerative colitis, giant cell arteritis and Takayasu arteritis are ongoing. ^{9 -16} Use of RINVOQ in AS is not approved by FDA and its safety and efficacy remain under review. Use of RINVOQ in nr-axSpA is not approved and its safety and efficacy have not been evaluated by regulatory authorities.

RINVOQ U.S. Uses and Important Safety Information ⁷  
RINVOQ is a prescription medicine used to treat adults with:

• Moderate to severe rheumatoid arthritis when 1 or more medicines called tumor necrosis factor (TNF) blockers have been used, and did not work well or could not be tolerated.
• Active psoriatic arthritis when 1 or more medicines called TNF blockers have been used, and did not work well or could not be tolerated.

It is not known if RINVOQ is safe and effective in children under 18 years of age.

What is the most important information I should know about RINVOQ?
  RINVOQ may cause serious side effects, including:

• Serious infections. RINVOQ can lower your ability to fight infections. Serious infections have happened while taking RINVOQ, including tuberculosis (TB) and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider (HCP) should test you for TB before starting RINVOQ and check you closely for signs and symptoms of TB during treatment with RINVOQ. You should not start taking RINVOQ if you have any kind of infection unless your HCP tells you it is okay. You may be at higher risk of developing shingles (herpes zoster).
• Increased risk of death in people 50 years and older who have at least 1 heart disease (cardiovascular) risk factor.
• Cancer and immune system problems. RINVOQ may increase your risk of certain cancers. Lymphoma and other cancers, including skin cancers, can happen. Current or past smokers are at higher risk of certain cancers, including lymphoma and lung cancer.
• Increased risk of major cardiovascular (CV) events such as heart attack, stroke, or death in people 50 years and older who have at least 1 heart disease (CV) risk factor, especially if you are a current or past smoker.
• Blood Clots. Blood clots in the veins of the legs or lungs and arteries can happen with RINVOQ. This may be life-threatening and cause death. Blood clots in the veins of the legs and lungs have happened more often in people who are 50 years and older and with at least 1 heart disease (CV) risk factor.
• Tears in the stomach or intestines and changes in certain laboratory tests . Your HCP should do blood tests before you start taking RINVOQ and while you take it. Your HCP may stop your RINVOQ treatment for a period of time if needed because of changes in these blood test results.

What should I tell my HCP BEFORE starting RINVOQ?

Tell your HCP if you:

• Are being treated for an infection, have an infection that won't go away or keeps coming back, or have symptoms of an infection such as:

• Have TB or have been in close contact with someone with TB.
• Are a current or past smoker.
• Have had a heart attack, other heart problems, or stroke.
• Have had any type of cancer, hepatitis B or C, shingles (herpes zoster), blood clots in the veins of your legs or lungs, diverticulitis (inflammation in parts of the large intestine), or ulcers in your stomach or intestines.
• Have other medical conditions including liver problems, low blood cell counts, diabetes, chronic lung disease, HIV, or a weak immune system.
• Live, have lived, or have traveled to parts of the country, such as the Ohio and Mississippi River valleys and the Southwest, that increase your risk of getting certain kinds of fungal infections. If you are unsure if you've been to these areas, ask your HCP.
• Have recently received or are scheduled to receive a vaccine. People who take RINVOQ should not receive live vaccines.
• Are pregnant or plan to become pregnant. Based on animal studies, RINVOQ may harm your unborn baby. Your HCP will check whether or not you are pregnant before you start RINVOQ. You should use effective birth control (contraception) to avoid becoming pregnant while taking RINVOQ and for at least 4 weeks after your last dose.
• Are breastfeeding or plan to breastfeed. RINVOQ may pass into your breast milk. You should not breastfeed while taking RINVOQ and for at least 6 days after your last dose.

Tell your HCP about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RINVOQ and other medicines may affect each other, causing side effects.

Especially tell your HCP if you take:

• Medicines for fungal or bacterial infections
• Rifampicin or phenytoin
• Medicines that affect your immune system

If you are not sure if you are taking any of these medicines, ask your HCP or pharmacist.

What should I do or tell my HCP AFTER starting RINVOQ?

• Tell your HCP right away if you have any symptoms of an infection. RINVOQ can make you more likely to get infections or make any infections you have worse.
• Get emergency help right away if you have any symptoms of a heart attack or stroke while taking RINVOQ, including:
• Discomfort in the center of your chest that lasts for more than a few minutes or that goes away and comes back
• Severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw
• Pain or discomfort in your arms, back, neck, jaw, or stomach
• Shortness of breath with or without chest discomfort
• Breaking out in a cold sweat
• Nausea or vomiting
• Feeling lightheaded
• Weakness in one part or on one side of your body
• Slurred speech
• Tell your HCP right away if you have any signs or symptoms of blood clots during treatment with RINVOQ, including:

• Tell your HCP right away if you have a fever or stomach-area pain that does not go away, and a change in your bowel habits.

What are the common side effects of RINVOQ?
These include upper respiratory tract infections (common cold, sinus infections), shingles (herpes zoster), herpes simplex, bronchitis, nausea, cough, fever, and acne. These are not all the possible side effects of RINVOQ.

How should I take RINVOQ?
RINVOQ is taken once a day with or without food. Do not split, break, crush, or chew the tablet. Take RINVOQ exactly as your HCP tells you to use it. RINVOQ is available in 15 mg extended-release tablets.

This is the most important information to know about RINVOQ. For more information, talk to your HCP.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit   www.fda.gov/medwatch    or call 1-800-FDA-1088.

If you are having difficulty paying for your medicine, AbbVie may be able to help. Visit    AbbVie.com/myAbbVieAssist    to learn more.

Please click here for the Full Prescribing Information and Medication Guide .

EU Indications and Important Safety Information about RINVOQ™ (upadacitinib)

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.

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 9 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   . 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, including the impact of the COVID-19 pandemic on AbbVie's operations, results and financial results, 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 of the Allergan acquisition, failure to promptly and effectively integrate Allergan's businesses, significant transaction costs and/or unknown or inestimable liabilities, potential litigation associated with the Allergan acquisition, 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 2020 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission (SEC). 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.

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