May 31, 2016
- This decision follows April 29 recommendation from the Committee for Medicinal Products for Human Use (CHMP) in the EU in favor of approval
- IMBRUVICA is now indicated across all lines of chronic lymphocytic leukemia (CLL) in the EU

NORTH CHICAGO, Ill., May 31, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced that the European Commission (EC) approved IMBRUVICA® (ibrutinib) as a first-line treatment option for adult patients with chronic lymphocytic leukemia (CLL), expanding upon the initial EC approval in October 2014 for certain patients with CLL. This decision comes just one month after the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued an opinion in favor of the use of IMBRUVICA for the treatment of adult patients with first-line chronic lymphocytic leukemia (CLL) in the European Union (EU).

The broadened indication is based on data from the Phase 3 RESONATE™-2 (PCYC-1115) trial, which also served as the basis for the March 2016 U.S. approval in the first-line CLL/SLL treatment setting and the May 2016 update to the U.S. Prescribing Information to include positive overall survival data.1

This approval marks a number of significant landmarks for IMBRUVICA: this is the drug's fifth treatment indication in the EU and this approval means that IMBRUVICA is now available to treat all lines of CLL in the EU. Patients with treatment-naive CLL, relapsed/refractory CLL and those with the genetic mutations del 17p or TP53, can all now benefit from treatment with single-agent IMBRUVICA.

IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc. In Europe, Janssen-Cilag International NV (Janssen) holds the marketing authorization and its affiliates market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world. IMBRUVICA is already approved in Europe to treat adult patients with relapsed/refractory mantle cell lymphoma (MCL), adult patients with CLL who have received at least one prior therapy or who have del 17p or TP53 mutations, and adult patients with Waldenström's macroglobulinemia (WM) who have received at least one prior therapy, or as a first-line treatment for WM patients unsuitable for chemo-immunotherapy.2

The approval was based on data from the Phase 3, randomized, open-label RESONATE™-2 (PCYC-1115) trial, which were presented at the American Society of Hematology (ASH) Annual Meeting in December 2015 and simultaneously published in The New England Journal of Medicine (NEJM). After a median of 18 months of follow-up, IMBRUVICA was associated with a significant improvement in several efficacy endpoints versus chlorambucil in patients aged 65 or older with newly diagnosed CLL. Specifically, IMBRUVICA was associated with a 90% progression-free survival rate (PFS; the primary endpoint) versus 52% for chlorambucil. Moreover, IMBRUVICA showed statistically significant prolonged overall survival (OS; a key secondary endpoint). The safety of IMBRUVICA in the treatment-naïve CLL patient population was consistent with previously reported studies.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored study which enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The primary endpoint of the study was PFS as assessed by an Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included overall response rate (ORR; based on the same iWCLL criteria), OS and safety.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).1 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,[3] IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.1

IMBRUVICA is approved in the U.S. to treat patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström's macroglobulinemia (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.1

IMBRUVICA is approved in the EU to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL), previously untreated adult patients with chronic lymphocytic leukaemia (CLL) or those who have received at least one prior therapy, and adult patients with Waldenström's macroglobulinemia (WM) who have received at least one prior therapy, or first line patients unsuitable for chemo-immunotherapy.2

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. 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 nuetropenia (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: http://www.imbruvica.com/downloads/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, 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 2014 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. Jan Burger served as the primary investigator of this Pharmacyclics-sponsored clinical study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. Dr. Burger does not have a financial interest in either company.

Contacts:






Media

Ilke Limoncu

Phone: 669-224-1836

Investors
Liz Shea
Phone: 847-935-2211

Physicians

U.S. Medical Information
Phone: 877-877-3536

IMBRUVICA is a registered trademark of Pharmacyclics LLC

1IMBRUVICA U.S. Prescribing Information, May 2016. 
2IMBRUVICA Summary of Product Characteristics, October 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003791/WC500177775.pdf. Accessed: April 2016. 
3Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed May 2016. 

SOURCE AbbVie

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