Long-Term IMBRUVICA® (ibrutinib) Efficacy and Safety Data at ASCO 2017 Show Sustained Survival Rates in Up to Four Years in Previously-Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Patients, Including Those with High-Risk Disease

NORTH CHICAGO, Ill., June 5, 2017 /PRNewswire/ -- Long-term follow-up results from the pivotal Phase 3 RESONATE™ trial (PCYC-1112) showed continued survival rates in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) treated with IMBRUVICA (ibrutinib) up to four years, according to new data presented today at the 53^rd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (poster session: 8:00 a.m. – 11:30 a.m. CDT; poster discussion: 1:15 p.m. – 2:30 p.m. CDT). The data regarding IMBRUVICA, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor and the first chemotherapy-free treatment for patients with CLL, were announced by AbbVie (NYSE: ABBV), a global biopharmaceutical company. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

According to the study results, IMBRUVICA was associated with significantly longer progression free survival (PFS; 59 percent) in R/R CLL/SLL with median follow-up of 44 months, including in patient subgroups with genomic abnormalities that are traditionally considered high-risk for poor outcomes. In addition, 3-year overall survival (OS; 74 percent) was longer in IMBRUVICA-treated patients. Further, the overall response rate (ORR) was 91 percent with complete response (CR) rates increasing over time (9 percent) (abstract #7510).¹ 

"These results suggest ibrutinib continues to provide persistent responses over the long-term in patients with chronic lymphocytic leukemia, including those who are difficult to treat," said John C. Byrd, MD, Distinguished University Professor at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and lead investigator of the study.* "As a clinician who has treated patients with CLL for more than 20 years, I'm pleased to see the potential for efficacy and safety responses to continue over an extended period of time."

CLL, the most common form of leukemia in adults, is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer (leukemia) cells start in the bone marrow but then spread into the blood. There are more than 20,000 newly diagnosed CLL patients every year.² CLL is predominately a disease of the elderly, with a median age of 71 at diagnosis.² SLL is similar to CLL and affects the same lymphocytes; the only difference between the two is the location where the cancer primarily occurs.³ To-date, more than 25,000 CLL patients have been treated in the U.S. with IMBRUVICA since approval in 2014.

"The first pivotal RESONATE data on IMBRUVICA were presented three years ago at ASCO and represented the promise of a new standard of care in blood cancer treatment. We are pleased to continue to see very favorable responses and survival outcomes to IMBRUVICA in relapsed and refractory CLL patients now into the fourth year of study," said Danelle James, M.D., M.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "We believe in the potential of IMBRUVICA across a range of blood cancers and other serious diseases, and are continuing to explore its potential as part of our robust clinical research program."

About the Study

Abstract #7510: Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study (Poster Board: #272)

• Poster Session on Monday, June 5, 2017, 8:00 a.m. – 11:30 a.m. CDT at Hall A
• Poster Discussion on Monday, June 5, 2017, 1:15 p.m. – 2:30 p.m. CDT at E354b

At up to 4 years of follow up, PFS was significantly longer for IMBRUVICA than ofatumumab (median NR versus 8 months, [HR 0.133; P<0.0001]; 3-year PFS 59 percent versus 3 percent). Significant benefit was observed across patient subgroups with genomic abnormalities that are traditionally considered high-risk for poor outcomes. Specifically, the high-risk genomic abnormalities were deletion 11q (del 11q), deletion 17p (del 17p), complex karyotype (CK), unmutated immunoglobulin heavy-chain variable-region (IGHV), NOTCH1 mutation, TP53 mutation, SF3B1 mutation, BIRC3 mutation and XP01 mutation. Patients with del 11q trended to have the most favorable outcome; however, PFS was not statistically different for patients with del 17p or del 11q or without these FISH abnormalities. At analysis, with the majority of patients (68 percent) randomized to ofatumumab crossing over to IMBRUVICA, OS was longer for IMBRUVICA versus ofatumumab (median OS not reached for either arm). The OS rate for IMBRUVICA at 3 years was 74 percent, and ORR was 91 percent, with CR and incomplete bone marrow recovery (CRi) increasing over time (now 9 percent).¹

RESONATE is a Pharmacyclics-sponsored, randomized, multi-center, open-label, international Phase 3 study, which enrolled 391 patients with R/R CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (median age 67). Patients were administered either 420 mg oral IMBRUVICA (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). The study met its primary endpoint, demonstrating improved PFS.¹

The adverse event (AE) profile of IMBRUVICA was consistent with previous reports. Major hemorrhage, Grade ≥3 atrial fibrillation, and Grade ≥3 hypertension occurred in 6 percent, 6 percent, and 8 percent of patients, respectively, over a follow-up of up to 4 years. The incidence of most Grade ≥3 AEs decreased from year 1 versus year 2-3: neutropenia (18 percent versus 8 percent); pneumonia (11 percent versus 4 percent); atrial fibrillation (4 percent versus 2 percent), respectively. Discontinuations were most frequently due to progressive disease (27 percent) and AEs (12 percent). At analysis, 90 IMBRUVICA patients (46 percent) continue on therapy in the study.¹

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.^4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.⁴

IMBRUVICA is FDA-approved in five distinct patient populations: CLL, SLL, Waldenström's macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL).⁴

• 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 CLL/SLL patients.
• 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 indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.⁴

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA has been granted four Breakthrough Therapy Designations from the FDA, spanning CLL/SLL, WM, MCL and chronic graft-versus-host-disease (cGVHD). In addition, IMBRUVICA is the first standard therapy specifically approved for patients with previously-treated MZL and WM.

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 approximately 130 ongoing clinical trials. There are a total of 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and approximately 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 70,000 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-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.

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. Byrd served as investigators of Pharmacyclics-sponsored clinical studies as noted. Dr. Byrd does not have a financial interest in the company.

¹ Byrd, et al. Long-term Efficacy and Safety with Ibrutinib (ibr) in Previously Treated Chronic Lymphocytic Leukemia (CLL): Up to Four Years Follow-up of the RESONATE Study. ASCO 2017. Abstract #7510
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 May 2017.
³ Lymphoma Research Foundation. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).
Available from: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300147. Accessed May 2017.
⁴ IMBRUVICA U.S. Prescribing Information, January 2017.
⁵ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed May 2017.

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