December 6, 2015

Ibrutinib (IMBRUVICA®) Improves Survival in Treatment-Naive Chronic Lymphocytic Leukemia Patients in the Phase 3 RESONATE™-2 Trial

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-- Findings featured in the official press program at the 57th American Society of Hematology Annual Meeting & Exposition; simultaneously published online in The New England Journal of Medicine
-- Data show a 98% survival rate with ibrutinib treatment at 24 months
-- Ibrutinib significantly prolonged progression-free survival, demonstrating an 84% investigator-assessed reduction in the risk of progression compared to chemotherapy
-- Data submitted to U.S. Food and Drug Administration to support expanded indication for CLL

NORTH CHICAGO, Ill., Dec. 6, 2015 /PRNewswire/ -- Today, AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced the results of RESONATE-2 (PCYC-1115), a Phase 3 clinical trial in which ibrutinib (IMBRUVICA®) significantly decreased the risk of progression or death (progression-free survival, PFS; the primary endpoint) and significantly decreased the risk of death (overall survival, OS; a key secondary endpoint) versus chemotherapy (chlorambucil) in treatment-naive patients 65 years and older with chronic lymphocytic leukemia (CLL). This is the first Phase 3 head-to-head trial in the clinical program to evaluate the safety and efficacy of ibrutinib versus traditional chemotherapy in this patient population.

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

The results were presented today during the official American Society of Hematology (ASH) press program and simultaneously published online in The New England Journal of Medicine. IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.

These data will be presented in full by Dr. Alessandra Tedeschi, M.D., Azienda Ospedaliera Niguarda Ca Granda, Milan, Italy during the oral abstract session at ASH on Monday, December 7 in the CLL: Therapy, Excluding Transplantation: Upfront CLL Therapy Excluding Transplantation track at 7:30 a.m. ET.

"The data may signal a paradigm shift and demonstrate the value of ibrutinib in the treatment-naive setting," said Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and study lead investigator.* "These powerful clinical results show superiority over a traditional, standard-of-care chemotherapy and have the potential to alter how we treat patients with CLL."

Ibrutinib significantly prolonged PFS as determined by an Independent Review Committee (IRC), reducing the risk of progression or death by 84% versus chlorambucil (median not reached vs. 18.9 months; hazard ratio [HR] 0.16; 95% CI, 0.09-0.28; P<0.001), with a median of 18.4 months of follow-up. The 18-month PFS rate was 90% versus 52%, respectively. Additionally, ibrutinib significantly prolonged OS (HR, 0.16; 95% CI, 0.05, 0.56; P=0.001) with an estimated survival rate of 98% at 24 months, compared to 85% with chlorambucil. Ibrutinib was also associated with a significantly higher overall response rate (ORR; 86% vs. 35%; P<0.001), with a trend toward increased complete response rates. Of note, ibrutinib also significantly improved hematologic function as measured by sustained improvements in hemoglobin and platelets.

"Ongoing studies have continued to show the efficacy of ibrutinib in patients with CLL, however, RESONATE-2 represents the first comparative look at the degree of benefit it can offer to treatment-naive patients compared to a standard chemotherapy agent," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "The effectiveness of ibrutinib observed in this trial is extremely encouraging when you consider the magnitude of benefit observed in both progression-free survival and overall survival compared to chemotherapy. When you combine the efficacy of ibrutinib with a tolerable safety profile, collectively, the data suggest that ibrutinib may be an earlier option for some patients, rather than once a relapse occurs."

"The results from RESONATE-2 continue to reaffirm the clinical benefit of ibrutinib and signal its potential to treat CLL patients in earlier lines of therapy, serving as an alternative to the current standard of care," said Michael Severino, M.D., Executive Vice President of Research and Development and Chief Scientific Officer, AbbVie. "Ultimately, our goal is to continue advancing care for people affected by CLL and a host of other cancers, transforming these difficult-to-treat diseases that are prone to relapse into manageable, chronic and potentially curable conditions."

The most common adverse events (AEs >20%) of all Grades in the RESONATE-2 trial for ibrutinib were diarrhea (42%), fatigue (30%), cough (22%) and nausea (22%); AEs for chlorambucil included nausea (39%), fatigue (38%), neutropenia (23%) and vomiting (20%). Hypertension occurred at a higher rate with ibrutinib (14%; including Grade 3 in 4%; with no Grade 4 or 5 events). All six patients with Grade 3 hypertension were managed with hypertensive medication and did not require ibrutinib dose reduction or discontinuation. Atrial fibrillation occurred in eight patients (6%) in the ibrutinib arm and was primarily Grade 2 in six patients and Grade 3 in two patients. It was managed with discontinuation in two patients and without a dose modification in remaining patients.

Overall, AEs leading to treatment discontinuation were less frequent with ibrutinib than with chlorambucil (9% vs. 23%). There were three deaths in the ibrutinib arm and 17 deaths in the chlorambucil arm over the median follow-up of 18.4 months. None of the patients who progressed on ibrutinib died during the subsequent follow-up period.

The safety of ibrutinib in this patient population was consistent with previously reported studies. It is worth noting that exposure to treatment and AE follow-up was nearly 2.5 times longer for ibrutinib compared with chlorambucil, with 87% of patients continuing on single-agent ibrutinib treatment.

A supplemental New Drug Application has been submitted to the U.S. Food and Drug Administration based on these data seeking an expanded indication for the use of IMBRUVICA in patients with treatment-naive CLL.

About the RESONATE-2 Study 
RESONATE-2 is a Pharmacyclics-sponsored trial and its protocol and specific performance goals were established in a special protocol assessment (SPA) with the U.S. FDA. A SPA is an agreement with the FDA that an ongoing Phase 3 clinical trial design, its clinical endpoints, and other statistical analyses are acceptable to the Agency to support an approval. The trial enrolled 269 patients with CLL/SLL aged 65 years or older without prior treatment in the U.S., EU and other regions. CLL patients with deletion of the short arm of chromosome 17 (del 17p CLL) were excluded from the trial since single-agent chlorambucil is not an effective therapy in this population. Patients were randomized to receive either ibrutinib 420 mg orally, once daily until progression or 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 IRC according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with clarification for treatment-related lymphocytosis. Key secondary endpoints included ORR, OS, rate of hematologic improvement and safety.

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.3 IMBRUVICA is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.3 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 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. Over 6,100 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 13 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
  • 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.

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 taken orally with a glass of water. Capsules should be taken whole. Do not open, break, split 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 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. 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. 

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 December 2015. 
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

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