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NORTH CHICAGO, Ill., Dec. 7, 2015 /PRNewswire/ -- Today, AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced Phase 2 data demonstrated that the combination of ibrutinib (IMBRUVICA^®) plus rituximab was well tolerated and associated with an overall response rate of 82%, (ORR; the primary endpoint of the study), in treatment-naive patients with follicular lymphoma (FL). These data will be presented today in an oral presentation at the 57^th Annual American Society of Hematology (ASH) Meeting and Exposition in Orlando, FL at 7:15 a.m. ET by Nathan Fowler, M.D., University of Texas, MD Anderson Cancer Center, Houston, TX, and lead study investigator.* IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.

FL is a slow-growing type of non-Hodgkin lymphoma. It originates from B cells, a type of white blood cell (lymphocyte) that develops in the bone marrow.¹ The median age at diagnosis is 60 years and the median overall survival is up to 14 years.^1,2

"The results of this study are very encouraging, as ibrutinib in combination with rituximab demonstrated efficacy in treatment-naive patients with follicular lymphoma," said Dr. Fowler. "There are patients who may not be good candidates for chemoimmunotherapy, therefore it is vital we have additional treatment options for previously untreated patients with follicular lymphoma."

The multicenter, open-label Phase 2 study evaluated the safety and efficacy of ibrutinib plus rituximab in 60 treatment-naive patients with histologically confirmed FL. Patients received oral ibrutinib once daily until disease progression or unacceptable toxicity, plus intravenous rituximab once weekly for four doses for the first four weeks of the study. The primary endpoint was investigator-assessed ORR and secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

At a median follow-up of 13.8 months, the investigator-assessed ORR was 82%. The median time to best response was 2.7 months (range, 1.1–13.6). Overall, the combination used in this study was well tolerated and adverse events (AEs) were primarily Grade 1 and 2, and were as anticipated based on experience with single-agent ibrutinib and previously tested ibrutinib combinations.

"Follicular lymphoma is a disease that continues to need additional treatment options for patients. We will continue exploring the potential of ibrutinib as a front-line combination therapy for patients in need," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics. "We are currently studying ibrutinib as a single-agent and in combination with established therapies as a potential treatment option for a wide range of hematologic malignancies, including follicular lymphoma."

The most common treatment-emergent AEs (AEs ≥20%) of all Grades in this study were fatigue, diarrhea, nausea, constipation, headache, cough, maculopapular rash, vomiting, dry eye, pyrexia, myalgia, infusion-related reaction, dizziness and anthralgia. AEs were primarily Grade 1-2. Grade 3-4 AEs occurring in >1 patient included: fatigue (5%), maculopapular rash (5%), neutropenia (5%), hypertension (3%), and arthritis (3%). Of note, median PFS, OS and DOR were not reached.

Separately, Phase 1 dose-escalation data will also be presented at the meeting. Ibrutinib in combination with rituximab and lenalidomide was evaluated in treatment-naive FL patients (N=22). The combination was associated with a 91% ORR (secondary endpoint) among all patients and a 94% ORR in cohort 2, which received the combination regimen including 560 mg ibrutinib. Although protocol-defined dose-limiting toxicities were not observed, ibrutinib plus rituximab and lenalidomide was associated with varying degrees of rash (41% was Grade 1/2 and 32% was Grade 3) and 11 patients required a dose reduction. Investigators hypothesized this could be due to the concomitant use of allopurinol to prevent tumor lysis syndrome, the individual study drugs or interactions between the therapies. The data will be presented during an oral session on Monday, December 7 at 7:30 a.m. ET.

About IMBRUVICA

IMBRUVICA is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients who have del 17p and patients with Waldenstrom's macroglobulinemia.³ IMBRUVICA is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. 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 is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).³ IMBRUVICA was one of the first medicines to receive a U.S. FDA approval after being granted a Breakthrough Therapy Designation, and IMBRUVICA is one of the few therapies to receive three separate designations.

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 being studied alone and in combination with other treatments in several blood cancers. More than 6,100 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 16 Phase 3 trials have been initiated with IMBRUVICA and 67 trials are registered on www.clinicaltrials.gov.

To learn more about the medical terminology used in this news release, please visit http://stedmansonline.com/.

INDICATIONS

IMBRUVICA is indicated to treat people with:

• Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
• Chronic lymphocytic leukemia (CLL) with 17p deletion
• Waldenstrom's macroglobulinemia
• Mantle cell lymphoma (MCL) who have received at least one prior therapy – accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Patients taking IMBRUVICA for CLL or WM should take 420 mg taken orally once daily (or three 140 mg capsules once daily).

Patients taking IMBRUVICA for MCL should take 560 mg taken orally once daily (or four 140 mg capsules once daily).

Capsules should be swallowed whole with a glass of water. Do not open, break or chew the capsules.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA^®. Grade 3 or higher bleeding events (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. Consider the benefit-risk of withholding IMBRUVICA^® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA^® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA^®. Monitor patients for fever and infections and evaluate promptly.

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%) occurred in patients treated with 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, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA^® treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA^®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA^® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g., high tumor burden).

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^®. 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 (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%†, NA‡), bruising (30%, 12%†, 16%†), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%†, 22%†).

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

†Includes multiple ADR terms.
‡Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematological 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 events.

Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

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

CYP3A Inducers - Avoid co-administration 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:
http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

About Pharmacyclics, An AbbVie Company

Pharmacyclics, a wholly-owned subsidiary of AbbVie (NYSE: ABBV), is focused on developing and commercializing innovative small-molecule drugs for the treatment of cancer and immune-mediated diseases. Pharmacyclics' mission is to develop and commercialize novel therapies intended to improve quality of life, increase duration of life and resolve serious unmet medical needs.

Pharmacyclics markets IMBRUVICA and has two product candidates in clinical development and several preclinical molecules in lead optimization. Pharmacyclics is committed to high standards of ethics, scientific rigor and operational efficiency as it moves each of these programs toward commercialization. To learn more, please visit www.pharmacyclics.com.

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, the likelihood that the transaction is consummated, the expected benefits of the transaction, 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.

* Disclaimer: Dr. Fowler served as an investigator of this Pharmacyclics-sponsored clinical study. Dr. Fowler does not have a financial interest in the company.

IMBRUVICA is a registered trademark of Pharmacyclics LLC

¹ The American Cancer Society. Types of non-Hodgkin lymphoma. Available at: http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-types-of-non-hodgkin-lymphoma. Accessed December 2015.
² Ghielmini M.  Follicular lymphoma. Ann Oncol. 2010;21(Suppl.7):vii151-3.
³ IMBRUVICA Prescribing Information, January 2015
⁴ Genetics Home Reference. Isolated growth hormone deficiency. Available at: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed December 2015.

SOURCE AbbVie