Ibrutinib (IMBRUVICA®) RESONATE™ Data Show Significant Improvements in Progression-Free Survival and Overall Survival in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

RARITAN, N.J., May 31, 2014 /PRNewswire/ -- Data from the international, multi-center Phase 3 PCYC-1112 (RESONATE™) trial in 391 patients suggest single-agent ibrutinib (IMBRUVICA^®) administered once-daily significantly lengthened progression-free survival (PFS) (median not reached vs. 8.1 months; HR 0.215, 95% CI, 0.146 to 0.317; P<0.0001) and overall survival (OS) (HR 0.434; 95 CI, 0.238 to 0.789; P=0.0049) versus ofatumumab administered intravenously in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Janssen Research & Development, LLC, announced today the data will be included in a presentation today during the official press program at the American Society of Clinical Oncology (ASCO) meeting in Chicago, IL and simultaneously published in a special edition of The New England Journal of Medicine.

PFS is the primary endpoint of the RESONATE study, with OS, overall response rate (ORR) and safety as key secondary endpoints. These data will be presented in full by Dr. John Byrd during the oral abstract session on Tuesday, June 3 during the Leukemia, Myelodysplasia, and Transplantation track at 11:57 a.m. CDT.

In 2011, Janssen Biotech, Inc. and Pharmacyclics, Inc. entered into an agreement to jointly develop and commercialize ibrutinib.

The results from the RESONATE study suggest ibrutinib significantly improved PFS, OS and ORR in this difficult-to-treat patient population, regardless of baseline characteristics. The median PFS in the ibrutinib arm was not reached because progression events occurred more slowly than in the ofatumumab arm. The PFS results represent a 79 percent reduction in the risk of progression or death in patients treated with ibrutinib compared to ofatumumab. The OS median also was not reached in either arm. The OS results represent a 57 percent reduction in the risk of death in patients receiving ibrutinib versus those in the ofatumumab arm.

Additionally, the ORR was significantly higher in patients taking ibrutinib versus ofatumumab, regardless of response criteria or baseline characteristics. Overall, 43 percent of ibrutinib patients achieved a partial response (PR) compared to only four percent of patients taking ofatumumab (p<0.0001), following the International Workshop on CLL (IWCLL) response criteria requiring response to be confirmed for at least two months. An additional 20 percent of ibrutinib-treated patients also achieved a PR with lymphocytosis. Investigator-assessed response rates were 85 percent for ibrutinib and 24 percent for patients receiving ofatumumab. Significantly higher response rates were seen in the ibrutinib arm consistently across all baseline sub-groups, including those with a deletion of the short arm of chromosome 17 (del 17p), a genetic mutation typically associated with poor prognoses, or refractory to a purine analogue.

"The Phase 3 RESONATE study demonstrated significant progression-free and overall survival benefits in relapsed or refractory CLL patients against the current standard of care," said John C. Byrd, M.D., director, Division of Hematology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, and lead investigator for RESONATE (PCYC-1112).** "The survival improvements seen with use of ibrutinib in this study are particularly encouraging as we look toward its potential for use in patients with difficult-to-treat disease and may offer physicians an effective single-agent treatment option."

RESONATE is a Phase 3, multi-center, international, open-label, randomized study that examined ibrutinib versus ofatumumab in relapsed or refractory patients with CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (n=391). Patients were administered either 420 mg oral ibrutinib (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 primary endpoint of the study was PFS evaluated by an Independent Review Committee (IRC), and key secondary endpoints were OS, ORR and safety. The median follow-up was 9.4 months.

"These data add to the body of clinical data supporting the use of ibrutinib in previously treated CLL patients," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. "These are the first Phase 3 data for ibrutinib.  We're pleased to see the particularly strong hazard ratios indicating positive results with ibrutinib for progression-free and overall survival and are encouraged that patients continue to do well on treatment with ibrutinib."

The most common Grade 3 or 4 adverse events (AEs) in the RESONATE trial (occurring in five percent or more of ibrutinib patients) were neutropenia (decreased amount of neutrophils in the blood; 16% in the ibrutinib arm vs. 14% in the ofatumumab arm), pneumonia (7% vs. 5%), thrombocytopenia (decrease in platelets in the blood; 6% vs. 4%) and anemia (5% vs. 8%). The most commonly occurring side effects (AEs in 20 percent or more of patients) were diarrhea (48% vs.18%), fatigue (28% vs. 30%), pyrexia (fever; 24% vs. 15%), nausea (26% vs.18%), anemia (23% vs. 17%) and neutropenia (21% vs. 15%). Atrial fibrillation of any grade was noted more frequently in patients receiving ibrutinib (n=10 patients) versus with ofatumumab (n=1 patient), leading to discontinuation of ibrutinib in one patient.

Treatment discontinuation due to progressive disease was five percent in the ibrutinib arm and 19 percent in the ofatumumab arm. Treatment discontinuations due to adverse events were low in both study arms, with four percent of patients in both treatment arms (eight patients in the ibrutinib arm and seven patients in the ofatumumab arm). Treatment discontinuation due to death occurred in four percent of patients in the ibrutinib arm (eight patients) and five percent of patients in the ofatumumab arm (nine patients). These events were most commonly infectious in nature. Total treatment exposure was longer for the ibrutinib arm (approximately 8.6 months, versus 5.3 months on ofatumumab).

In January 2014, RESONATE was stopped early at the unanimous recommendation of an Independent Data Monitoring Committee (IDMC) based on a planned interim analysis which concluded that the study showed a significant difference in PFS as compared to the control (the primary endpoint of the study). The IDMC recommended that the sponsor provide access to ibrutinib to patients in the ofatumumab arm. The data served as the basis of the April 2014 supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) in CLL patients who have received at least one prior therapy.  

CLL is a slow-growing blood cancer of white blood cells called lymphocytes, most commonly B cells.¹ CLL is the most common adult leukemia in the Western world and predominantly a disease of the elderly with a median age of diagnosis of 72.² This orphan disease often eventually progresses; patients are faced with fewer treatment options and are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.³ SLL is a slow-growing lymphoma in which too many immature white blood cells cause lymph nodes to become larger than normal.¹

Ibrutinib is marketed as IMBRUVICA in the U.S. for the treatment of patients with CLL who have received at least one prior therapy and the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.⁴ These indications are both based on ORR. An improvement in survival or disease-related symptoms has not been established.⁴

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage – Five percent of patients with mantle cell lymphoma (MCL) and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

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. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater according to NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Myelosuppression – Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity – Fatal and serious cases of renal failure have occurred with IMBRUVICA^® therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies – Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA^®. Four percent of patients with MCL had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

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
CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%).

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 non-hematological adverse reactions (> 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.0%), sinusitis (6%), skin infection (6%), dehydration (6.0%), and musculoskeletal pain (6%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients.

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

MCL: The most commonly occurring adverse reactions (> 20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%).

*Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

The most common Grade 3 or 4 non-hematological adverse reactions (> 5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients.

Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

DRUG INTERACTIONS
CYP3A Inhibitors – Avoid concomitant administration with strong or moderate inhibitors of CYP3A. 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 baseline hepatic impairment.

For the full prescribing information, visit http://www.IMBRUVICA.com/.

About IMBRUVICA^®
IMBRUVICA was one of the first therapies to receive U.S. approval via the FDA's Breakthrough Therapy Designation and was approved under the FDA's Subpart H regulation.⁵ IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy and the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.⁴ These indications are both based on an overall response rate (ORR). An improvement in survival or disease-related symptoms has not been established.⁴

IMBRUVICA works by blocking a specific protein called Bruton's tyrosine kinase (BTK).⁴ The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.^4,6 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread.⁴

About Janssen Research & Development, LLC
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development is part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit www.janssenrnd.com for more information.

About Janssen Biotech, Inc.
Janssen Biotech, Inc. redefines the standard of care in immunology, oncology, urology and nephrology. Built upon a rich legacy of innovative firsts, Janssen Biotech has delivered on the promise of new treatments and ways to improve the health of individuals with serious disease. Beyond its innovative medicines, Janssen Biotech is at the forefront of developing education and public policy initiatives to ensure patients and their families, caregivers, advocates and health care professionals have access to the latest treatment information, support services and quality care. For more information on Janssen Biotech, Inc. or its products, visit www.janssenbiotech.com.

Janssen Biotech is one of the Janssen Pharmaceutical Companies of Johnson & Johnson, which are dedicated to addressing and solving some of the most important unmet medical needs in oncology, immunology, neuroscience, infectious diseases and vaccines, cardiovascular and metabolic diseases. Driven by our commitment to patients, we work together to bring innovative ideas, products, services and solutions to people throughout the world. Follow us on Twitter at www.twitter.com/JanssenUS.

Janssen in Oncology
In oncology, our goal is to fundamentally alter the way cancer is understood, diagnosed, and managed, reinforcing our commitment to the patients who inspire us. In looking to find innovative ways to address the cancer challenge, our primary efforts focus on several treatment and prevention solutions. These include a focus on hematologic malignancies, prostate cancer and lung cancer; cancer interception with the goal of developing products that interrupt the carcinogenic process; biomarkers that may help guide targeted, individualized use of our therapies; as well as safe and effective identification and treatment of early changes in the tumor microenvironment.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in new product development, including obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; general industry conditions including trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2013, including in Exhibit 99 thereto, and our subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.)

**Disclaimer: Dr. Byrd serves as national principal 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. Byrd does not have a financial interest in either company.

¹ American Cancer Society. "Leukemia--Chronic Lymphocytic". http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed April 2014.
² Decision Resources estimate 2013.
³ Veliz M, Pinilla-Ibarz J. Treatment of relapsed or refractory chronic lymphocytic leukemia. Cancer Control. 2012 Jan;19(1):37-53.
⁴ IMBRUVICA Prescribing Information, February 2014.
⁵ The U.S. Food and Drug Administration. CFR - Code of Federal Regulations Title 21. Available from:  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314&showFR=1&subpartNode=21:5.0.1.1.4.8. Accessed April 2014.
⁶ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed April 2014.

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