AbbVie Announces Submission of a Supplemental New Drug Application for Ibrutinib (IMBRUVICA®) for Treatment of Marginal Zone Lymphoma

NORTH CHICAGO, Ill., Sept. 26, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced that it submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for ibrutinib (IMBRUVICA^®) to treat patients with marginal zone lymphoma (MZL). MZL is a slow-growing form of non-Hodgkin's lymphoma. The Company's sNDA submission is based on data from a multi-center, open-label Phase II PCYC-1121-CA trial assessing ibrutinib as a single-agent treatment for MZL. If approved, MZL will be the fifth unique type of blood cancer indication for IMBRUVICA. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc.

"We continue to explore the use of ibrutinib in non-Hodgkin's lymphoma, including marginal zone lymphoma and its three sub-types, given its unique mechanism of action and ability to target the B-cell receptor pathway," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics. "MZL in its advanced stages is currently an incurable form of hematologic cancer and new treatment options are needed. We look forward to working with the FDA and our partners at Janssen to bring this promising treatment to patients with MZL."

The Phase II PCYC-1121-CA trial is a Pharmacyclics-sponsored study that enrolled 63 previously treated patients with MZL, including splenic MZL (SMZL), nodal MZL (NMZL) and extranodal MZL (EMZL), in the U.S., EU and other regions. Patients received monotherapy ibrutinib orally, once daily until progression or unacceptable toxicity. The primary endpoint of the study was overall response rate as assessed by an Independent Review Committee. A key secondary endpoint was safety.

These clinical data have been submitted for publication in a peer-reviewed journal and presentation at an upcoming medical conference. More information about the study can be found on www.clinicaltrials.gov.

IMBRUVICA is currently approved to treat patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström's macroglobulinemia (WM).

About Marginal Zone Lymphoma
Marginal zone lymphoma (MZL) is a slow-growing B-cell lymphoma arising from white blood cells (lymphocytes) at the edges of lymphoid tissue.¹ MZL accounts for approximately 12 percent of all cases of non-Hodgkin's lymphoma in adults, and the median age of diagnosis is 65 years old.² There are currently no approved treatments or standards of care specifically indicated for patients with MZL.²

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.^3,4 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.³

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with MCL who have received at least one prior therapy and patients with WM. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.³

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA^®. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA^®.

The mechanism for the bleeding events is not well understood. IMBRUVICA^® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA^® for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and nonfatal infections have occurred with IMBRUVICA^® therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA^®. Evaluate patients for fever and infections and treat appropriately.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA^®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA^®, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA^® treatment and follow dose modification guidelines.

Hypertension - Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA^® with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA^®. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies - Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA^®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome - Tumor lysis syndrome has been infrequently reported with IMBRUVICA^® therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA^® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA^® and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors - Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA^® dose.

CYP3A Inducers - Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA^® dose.

Please see Full Prescribing Information: https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing_information.pdf.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be 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, 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," in AbbVie's 2015 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. 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.

IMBRUVICA is a registered trademark of Pharmacyclics LLC

¹ El-Zimaity, H. "Marginal Zone B-cell Lymphoma." Available from: http://emedicine.medscape.com/article/1610599-overview#showall. Accessed August 2016.
² Lymphoma Research Foundation. "Marginal Zone Lymphoma." Available from: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6554677. Accessed August 2016.
³ IMBRUVICA US Prescribing Information, May 2016.
⁴ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed August 2016.

SOURCE AbbVie Inc.

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