Upadacitinib Achieved Primary and Key Secondary Endpoints in First Phase 3 Induction Study in Patients with Crohn's Disease

ABBVie (NYSE: ABBV) today announced positive top-line results from U-EXCEED, a Phase 3 induction study, showing upadacitinib (45 mg once daily) achieved both primary endpoints of clinical remission a,b and endoscopic response c at week 12. 1 The U-EXCEED study enrolled patients with moderate to severe Crohn's disease who had an inadequate response or were intolerant to biologic therapy, with over 60 percent having previously failed two or more biologics. 1 U-EXCEED is the first of two Phase 3 induction studies to evaluate the safety and efficacy of upadacitinib in adults with moderate to severe Crohn's disease. 1

"The data from this first Phase 3 induction study in Crohn's disease suggest upadacitinib may help address the needs of patients suffering from this disease, as demonstrated in stringent endpoints such as endoscopic response," said Michael Severino , M.D., vice chairman and president, AbbVie. "We continue to leverage our expertise in IBD by driving research and development that help shape the IBD landscape and elevate standards of care for patients."

In U-EXCEED, clinical remission was measured by the Crohn's Disease Activity Index (CDAI) and by the patient-reported symptoms of stool frequency/abdominal pain (SF/AP). ¹ A significantly greater proportion of patients treated with a 12-week induction regimen of upadacitinib 45 mg daily achieved clinical remission per CDAI at week 12 compared to placebo (39 percent, versus 21 percent; p 1 Similar results were seen with clinical remission per SF/AP (40 percent in upadacitinib-treated patients versus 14 percent in placebo-treated patients; p 1 In this study, all patients were also evaluated for improvement in the intestinal mucosa by endoscopy. ¹ At week 12, a significantly greater proportion of patients treated with upadacitinib 45 mg achieved endoscopic response compared to the placebo group (35 percent versus 4 percent; p 1

Among patients taking corticosteroids at baseline, a significantly higher proportion of patients receiving upadacitinib 45 mg achieved steroid-free clinical remission ^d per CDAI and per SF/AP compared to placebo at week 12. ¹ A significantly higher proportion of patients receiving upadacitinib compared to placebo also achieved early symptom improvement measured by CR-100 (defined as reduction of CDAI ≥100 points from baseline) at week 2 as well as clinical remission at week 4. ¹

"I am thrilled to see the results of this first Phase 3 induction study of upadacitinib, particularly in this difficult-to-treat refractory patient population," said Jean-Frederic Colombel, M.D., professor of medicine and director of Inflammatory Bowel Disease Center, Icahn School of Medicine, Mount Sinai, and U-EXCEED study investigator. "These results demonstrate upadacitinib's potential to achieve endoscopic response and clinical remission, including steroid-free clinical remission, at 12 weeks in patients living with Crohn's disease."

During the 12-week, double-blind, placebo-controlled period, the safety profile of upadacitinib 45 mg was consistent with the safety profile observed in previous studies across indications, with no new safety risks observed. ¹ The most common adverse event was nasopharyngitis for upadacitinib and exacerbation of Crohn's disease for placebo. ¹ Serious adverse events occurred in 9.3 percent of patients in the upadacitinib 45 mg group compared to 9.9 percent of patients in the placebo group. ¹ Rates of serious infections were 2.8 percent in those treated with upadacitinib 45 mg and 1.8 percent in patients who received placebo. ¹ All events of herpes zoster (1.5 percent of patients) were nonserious and reported in the upadacitinib group only. ¹ There was one case of adjudicated gastrointestinal perforation in the upadacitinib group. ¹

An additional 207 patients at week 12 received an upadacitinib 45 mg daily induction regimen (including non-responders to placebo or from an open label arm). ¹ Among these patients, there were two additional cases of adjudicated gastrointestinal perforation reported. ¹ Overall, the safety results in these patients were consistent with what was observed in the upadacitinib 45 mg group during the placebo-controlled period. ¹

In the study, no treatment-emergent cases of adjudicated cardiovascular event, malignancy, thromboembolic event or death were reported across treatment groups. ¹

Full results from the U-EXCEED study will be presented at upcoming medical conferences and published in a peer-reviewed medical journal. Use of upadacitinib in Crohn's disease is not approved and its safety and efficacy have not been evaluated by regulatory authorities.

About Crohn's Disease

Crohn's disease is a chronic, systemic disease that manifests as inflammation within the gastrointestinal (or digestive) tract, causing persistent diarrhea and abdominal pain. ^15-17 It is a progressive disease, meaning it gets worse over time in a substantial proportion of patients. ^16,17 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. ¹⁸

About U-EXCEED ^1,14

The U-EXCEED study is one of two Phase 3, multicenter, randomized, double-blind, placebo-controlled induction studies designed to evaluate the efficacy and safety of upadacitinib 45 mg induction treatment in adults with moderate to severe Crohn's disease. U-EXCEED enrolled patients who had inadequately responded to or are intolerant of biologic therapy. The second induction study evaluated patients who have had an inadequate response or intolerance to one or more conventional and/or biologic therapies. ¹⁹

The U-EXCEED study includes three study parts. Part 1 is the 12-week placebo-controlled induction portion. Part 2 is the open label arm of U-EXCEED evaluating an additional group of patients who received upadacitinib 45 mg for 12 weeks. In Part 3, patients who did not achieve clinical response in Part 1 or Part 2 received an extended treatment of upadacitinib 45 mg or 30 mg for 12 weeks.

The study included slightly different sets of primary and secondary endpoints for the U.S. Food and Drug Administration (FDA) and the EU European Medicines Agency (EMA). The primary endpoints were achievement of clinical remission (per CDAI for the U.S. FDA, and per SF/AP for the EU EMA, which was measured by average daily stool frequency and abdominal pain score) and endoscopic response (per SES-CD) at week 12. More information can be found on www.clinicaltrials.gov (NCT03345836).

About the Upadacitinib Phase 3 Crohn's Disease Program ^14,19,20

The global upadacitinib Phase 3 program evaluates more than 1,000 patients with moderate to severe Crohn's disease across two induction studies and a maintenance study. These studies include assessments of efficacy, safety and tolerability of upadacitinib. More information on these trials can be found at www.clinicaltrials.gov (NCT03345836, NCT03345849, NCT03345823).

About Upadacitinib (RINVOQ ^® )

Discovered and developed by AbbVie scientists, RINVOQ is a selective and reversible JAK inhibitor that is being studied in several immune-mediated inflammatory diseases. ^6-14,21 Based on enzymatic and cellular assays, RINVOQ demonstrated greater inhibitory potency for JAK-1 vs JAK-2, JAK-3, and TYK-2. ²¹ The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness 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. RINVOQ is also approved by the European Commission for adults (15 mg and 30 mg) and adolescents (15 mg) with moderate to severe atopic dermatitis. 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. 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. ^7-14 The use of upadacitinib in Crohn's disease is not approved and its safety and efficacy have not been evaluated by regulatory authorities.

Important Safety Information about RINVOQ ^® (upadacitinib) ²¹

RINVOQ U.S. Use and Important Safety Information

RINVOQ is a prescription medicine used to treat moderate to severe rheumatoid arthritis in adults when one or more tumor necrosis factor (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 the ability of your immune system to fight infections. Some people have had serious infections 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. Lymphoma and other cancers, including skin and lung cancers, can happen. People taking RINVOQ have a higher risk of certain cancers, including lymphoma and lung cancer, especially if you are a current or past smoker.
• 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 in some people taking 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 can happen. 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), or 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 that increase your risk of getting certain kinds of fungal infections, such as the Ohio and Mississippi River valleys and the Southwest. 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

Ask your HCP or pharmacist if you are not sure if you are taking any of these medicines.

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), nausea, cough, and fever. 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. RINVOQ is available in 15 mg extended-release tablets. Do not split, break, crush, or chew the tablet. Take RINVOQ exactly as your HCP tells you to use it.

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 .

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 its 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, 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 2020 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.

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SOURCE AbbVie