AbbVie Submits IMBRUVICA® (ibrutinib) Phase III Combination Data to U.S. FDA

NORTH CHICAGO, Ill., Nov. 13, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced today that it submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for labeling considerations based on safety and efficacy results from the Phase III HELIOS (CLL3001) trial investigating the use of IMBRUVICA^® (ibrutinib) plus bendamustine and rituximab (BR) versus placebo plus BR in relapsed or refractory patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

"The HELIOS study will provide additional information on the safety and efficacy of IMBRUVICA in patients with previously treated chronic lymphocytic leukemia," said Simon Rule, M.D., Consultant Haematologist, Department of Haematology and Head of the Lymphoma Service, Derriford Hospital, Plymouth, UK and HELIOS study investigator.* "The data confirm the therapy's ability to enhance the effectiveness of a commonly used treatment option in these patients when it is added to the bendamustine and rituximab combination."

In June 2015, the interim data were presented and included in the official press program at the American Society of Clinical Oncology (ASCO) Annual Meeting. These data demonstrated that IMBRUVICA plus BR significantly reduced the risk of progression or death by 80% and significantly improved overall response rate (ORR) compared to placebo plus BR in previously-treated CLL/SLL patients. Based on positive results from a pre-planned interim analysis, an Independent Data Monitoring Committee (IDMC) recommended HELIOS be unblinded at that point and patients receiving placebo plus BR be offered the option to receive IMBRUVICA as their next treatment.

"IMBRUVICA has demonstrated that it is an effective treatment option as a single-agent in patients with relapsed or refractory chronic lymphocytic leukemia and the results of HELIOS confirm the therapy's ability to also provide a significant benefit to these patients when added to the commonly used and effective bendamustine and rituximab treatment combination," said Erik von Borcke, President of Pharmacyclics. "We are dedicated to fully understanding the utility of IMBRUVICA and have several studies underway designed to evaluate the impact of the therapy as a single-agent and in combination in a number of blood cancers. Ultimately, our goal for IMBRUVICA is to be a treatment option that extends the lives of patients across a variety of types of cancers."

HELIOS, a Janssen-sponsored trial, enrolled 578 CLL or SLL patients who had received at least one prior systemic therapy. Patients were randomized to receive IMBRUVICA or placebo, once daily continuing until disease progression or unacceptable toxicity with six cycles of BR, or placebo plus BR. The study met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival. The safety profile of IMBRUVICA in combination with BR was consistent with BR and prior clinical experience with IMBRUVICA.

About Chronic Lymphocytic Leukemia (CLL)
The prevalence of CLL/SLL is approximately 115,000 patients in the United States,[1] with approximately 16,000 newly diagnosed patients every year.[2] As this orphan disease frequently progresses following treatment with existing first-line therapies, patients are faced with fewer treatment options and often are prescribed multiple lines of therapy as they relapse or become resistant to current standard of care treatments.[3]

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 Waldenström's macroglobulinemia.[4] 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.[4]

IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).[4] 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.[4],[5] IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.[4]

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 III 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
• Waldenström'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.

The recommended dose of IMBRUVICA for CLL or WM is 420mg (or three 140mg capsules) orally, once daily.

The recommended dose of IMBRUVICA for MCL is 560mg (or four 140mg capsules) orally, 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 LLC, 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 three 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 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.

* Dr. Rule served as an investigator for the HELIOS study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. He does not have a financial interest in either company.

IMBRUVICA is a registered trademark of Pharmacyclics LLC

[1] IMS Database [Data on File]

[2] American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Available from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed October 2015.

[3] Veliz M, Pinilla-Ibarz J. Cancer Control. Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia. January 2012, Vol. 19, No. 1.

[4] IMBRUVICA Prescribing Information, January 2015

[5] Genetics Home Reference. Isolated growth hormone deficiency. Available at: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed October 2015.

SOURCE AbbVie

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