U.S. FDA Approves IMBRUVICA® (ibrutinib) as First Treatment Specifically Indicated for Relapsed/Refractory Marginal Zone Lymphoma (MZL) - a Rare Type of Non-Hodgkin's Lymphoma

NORTH CHICAGO, Ill., Jan. 19, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) approved IMBRUVICA® (ibrutinib) for the treatment of patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.¹ This indication is approved under accelerated approval based on overall response rate (ORR), and continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"The FDA approval of IMBRUVICA for relapsed/refractory marginal zone lymphoma is significant, and we are proud of the culmination of this extensive clinical research program, representing the first approved treatment specifically for patients with this rare type of non-Hodgkin's lymphoma," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "This milestone marks the fifth patient population for whom IMBRUVICA is now approved and broadens the number of patients who may be treated with the medication. We continue to research IMBRUVICA across many disease areas, including but not limited to other B-cell malignancies."

The approval in MZL is based on data from the Phase 2, open-label, multi-center, single-arm PCYC-1121 study, which evaluated the safety and efficacy of IMBRUVICA in MZL patients who require systemic therapy and have received at least one prior anti-CD20-based therapy. The efficacy analysis included 63 patients with three sub-types of MZL: mucosa-associated lymphoid tissue (MALT; N=32), nodal (N=17) and splenic (N=14). The ORR was achieved in nearly half (46%) of the patients (95% CI: 33.4-59.1) as assessed by an Independent Review Committee (IRC) using criteria adopted from the International Working Group criteria for malignant lymphoma, with efficacy observed across all three MZL sub-types. The median time to response was 4.5 months (range, 2.3-16.4 months).  In the trial, 3.2% of patients had a complete response (CR) and 42.9% of patients had a partial response (PR). The median duration of responses was not reached (NR) (range 16.7 months to NR).¹ The data were previously presented at the American Society of Hematology (ASH) Annual Meeting (December 2016).

"In the Phase 2 trial, IMBRUVICA demonstrated impressive response rates and duration of response in relapsed/refractory marginal zone lymphoma patients," said Ariela Noy, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center in New York and lead investigator of the study.* "The hematology-oncology community welcomes a new option like IMBRUVICA, which helps fill a significant treatment gap for previously treated MZL patients who are in need of non-chemotherapy options."

Overall, the safety data from this study was consistent with the known safety profile of IMBRUVICA in B-cell malignancies. The most common adverse events (AEs) of all Grades (occurring in ?20% of MZL patients treated with IMBRUVICA) included thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema and arthralgia (24% each), neutropenia and cough (22% each), and dyspnea and upper respiratory tract infection (21% each). The most common (>10%) Grade 3 or 4 AEs were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).¹

The risks associated with IMBRUVICA as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome and embryo fetal toxicities.

IMBRUVICA is now approved to treat patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy, as well as patients with other non-Hodgkin's lymphomas, including 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).¹ Continued approval for the MZL and MCL indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

About the Study
The Phase 2 PCYC-1121 trial is a Pharmacyclics-sponsored study that evaluated the safety and efficacy of ibrutinib in patients with R/R MZL. The primary objective of the trial was ORR as assessed by an IRC. Duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety were secondary objectives.²

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.³ MZL accounts for approximately 8% of all cases of non-Hodgkin's lymphoma in adults, and the median age of diagnosis is 65 years old.^3,4 There are three sub-types of MZL: mucosa-associated lymphoid tissue, nodal and splenic.³

About IMBRUVICA
IMBRUVICA (ibrutinib) 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.^1,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.¹

IMBRUVICA is FDA-approved in five distinct patient populations: CLL, SLL, WM, along with previously-treated MCL and MZL.¹

• IMBRUVICA was first approved for patients with MCL who have received at least one prior therapy in November 2013.
• Soon after, IMBRUVICA was initially approved in CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
• IMBRUVICA was approved for patients with WM in January 2015.
• In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for patients with previously treated CLL/SLL.
• In January 2017, IMBRUVICA was approved for patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.

Accelerated approval was granted for the MCL and MZL indication based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.¹

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. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry with nearly 30 company-sponsored trials underway, 14 of which are Phase 3. In addition, there are approximately 100 investigator-sponsored trials and external collaborations that are ongoing and active around the world. To date, more than 65,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

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) and Pneumocystis jirovecii pneumonia (PJP) 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, 13% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 13%) 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, 3% 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, 2% 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. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia** (61%), thrombocytopenia** (62%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (30%), nausea (29%), bruising (30%), fatigue (29%), hemorrhage (22%), 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%). The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MZL patients were pneumonia (10%), fatigue (6%), diarrhea (5%), rash (5%), and hypertension (5%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions. Most common adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia (1% each) in CLL/SLL patients and subdural hematoma (1.8%) in MCL patients. The most common adverse reactions leading to discontinuation were interstitial lung disease, diarrhea, and rash (1.6% each) in WM and MZL 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/prescribing-information.

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

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

PRC-02580 1/17

¹ IMBRUVICA US Prescribing Information, January 2017.
² Noy, A, et al. Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study. ASH 2016. Abstract #1213.
³ Lymphoma Research Foundation. "Marginal Zone Lymphoma." Available from: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6554677. Accessed January 2017.
⁴ Lymphoma Research Foundation. "Getting the Facts: Marginal Zone Lymphoma." Available from: http://www.lymphoma.org/atf/cf/%7baaf3b4e5-2c43-404c-afe5-fd903c87b254%7d/lrf_factsheet_marginal_zone_lymphoma.pdf. Accessed January 2017.
⁵ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed January 2017.

SOURCE AbbVie