Analysis of Phase III RESONATE™ Data Shows Adherence to the Recommended 420mg Dose of IMBRUVICA® (ibrutinib) Results in Improved Efficacy Benefits in Patients with Chronic Lymphocytic Leukemia

SUNNYVALE, Calif., May 31, 2015 /PRNewswire/ -- Pharmacyclics LLC today highlighted results from a sub-analysis of the Phase III RESONATE^™ (PCYC-1112) trial, which found that previously-treated patients with chronic lymphocytic leukemia (CLL) who adhered to the recommended 420 mg dose of IMBRUVICA^® (ibrutinib) experienced improved progression-free survival (PFS; the primary endpoint) as assessed by an Independent Review Committee (IRC), compared to patients who took lower doses or missed doses, regardless of high-risk genetic factors. The data will be presented today at the 51^st American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL at 8:00 a.m. CT. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

"These data show that when patients take IMBRUVICA daily, at the recommended dose, it can improve their chance of achieving a sustained treatment response and delay disease progression," said Paul Barr, M.D., Assistant Professor of Medicine and Director of the Clinical Trials Office, Wilmot Cancer Institute, Rochester, NY and lead presenter of the sub-analysis data. "As clinicians, it is important that we ensure that patients take this once-daily, oral medication as recommended in order to achieve the best possible outcome in treating their cancer."

The poster provides insights from the RESONATE trial specific to the importance of adhering to the recommended 420 mg once-daily dose of IMBRUVICA in previously-treated CLL patients (n=195). After 8.3 months of treatment, patients treated with IMBRUVICA had a mean dose intensity – defined as the proportion of actually administered versus planned doses of IMBRUVICA 420 mg – of 95% (median 100%). The majority of dose interruptions restarted at 420 mg; 3.6% of patients experienced one dose reduction and 0.5% experienced two dose reductions due to adverse events (AEs).

Notably, the recommended 420 mg dose was associated with longer PFS rates (median not reached) compared to those patients who took lower doses (11 months), regardless of high-risk factors including del 17p, del 11q or p53 mutations. Patients who consistently missed their IMBRUVICA dose for eight or more consecutive days experienced more events compared to patients who did not experience such dose holds (31% vs. 13%, respectively). The mean duration of missed doses in patients who missed more than one week of therapy was 26 days.

"This sub-analysis confirms the strength of IMBRUVICA's clinical benefit when the recommended dose is taken correctly and consistently," said Elizabeth Faust, Ph.D., Head of Medical Affairs at Pharmacyclics. "We are encouraged to see many of the patients in the RESONATE trial who take the therapy as directed continue to do well, demonstrating the importance of using IMBRUVICA at the recommended daily dose to achieve the best possible response."

The most frequent (>20%) non-hematologic AEs seen in the broader RESONATE trial were diarrhea, fatigue, pyrexia and nausea in the IMBRUVICA-treated group and fatigue, infusion-related reactions and cough in the ofatumumab-treated group. Treatment exposure was longer among patients receiving ibrutinib vs. ofatumumab (median duration, 8.6 vs. 5.3 months).

RESONATE is a randomized, multi-center, international, head-to-head comparison of single-agent, orally-administered IMBRUVICA versus the intravenous, monoclonal antibody ofatumumab targeting the CD20 antigen. This study enrolled 373 patients with CLL and 18 patients with small lymphocytic lymphoma (SLL), who had received at least one prior therapy. The median number of prior treatments was two (range, 1 to 13 treatments). At baseline, the median age of these patients was 67 years, 58% of whom had at least one tumor larger than 5 cm, and 32% of whom had the del 17p mutation. In the trial, patients receiving IMBRUVICA demonstrated a statistically significant improvement in PFS, overall survival (OS) and overall response rate (ORR) as compared to patients treated with ofatumumab.

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 first-line therapy, patients are faced with fewer treatment options and often are prescribed multiple lines of therapy as they relapse or become resistant to treatments.³

In CLL/SLL, the genetic mutation del 17p occurs when part of chromosome 17 has been lost or deleted. CLL/SLL patients with del 17p have poor treatment outcomes.⁴ Del 17p is reported in approximately 7% of treatment-naïve CLL/SLL cases,⁵ and approximately 20% to 40% of relapsed/refractory patients harbor the mutation.⁶

About IMBRUVICA
IMBRUVICA is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, all CLL patients (including treatment-naïve) who have del 17p, a genetic mutation that occurs when part of chromosome 17 has been lost, and all patients (including treatment-naïve) with Waldenström's macroglobulinemia.⁷ IMBRUVICA is also approved under accelerated approval for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.⁷ 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.⁷

IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).⁷ IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway, and is the only product to have received three Breakthrough Therapy 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.^7,8 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.⁷

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 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.

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, 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.

NOTE: This announcement may contain forward-looking statements made in reliance upon the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements, among others, relating to our future capital requirements, including our expected liquidity position and timing of the receipt of certain milestone payments, and the sufficiency of our current assets to meet these requirements, our future results of operations, our expectations for and timing of ongoing or future clinical trials and regulatory approvals for any of our product candidates, and our plans, objectives, expectations and intentions. Because these statements apply to future events, they are subject to risks and uncertainties. When used in this announcement, the words "anticipate", "believe", "estimate", "expect", "expectation", "goal", "should", "would", "project", "plan", "predict", "intend", "target" and similar expressions are intended to identify such forward-looking statements. These forward-looking statements are based on information currently available to us and are subject to a number of risks, uncertainties and other factors that could cause our actual results, performance, expected liquidity or achievements to differ materially from those projected in, or implied by, these forward-looking statements. Factors that may cause such a difference include, without limitation, our need for substantial additional financing and the availability and terms of any such financing, the safety and/or efficacy results of clinical trials of our product candidates, our failure to obtain regulatory approvals or comply with ongoing governmental regulation, our ability to commercialize, manufacture and achieve market acceptance of any of our product candidates, for which we rely heavily on collaboration with third parties, and our ability to protect and enforce our intellectual property rights and to operate without infringing upon the proprietary rights of third parties. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, performance or achievements and no assurance can be given that the actual results will be consistent with these forward-looking statements. For more information about the risks and uncertainties that may affect our results, please see the Risk Factors section of our filings with the Securities and Exchange Commission, including our Form 10-K for the year ended December 31, 2013 and quarterly reports on Form 10-Q. We do not intend to update any of the forward-looking statements after the date of this announcement to conform these statements to actual results, to changes in management's expectations or otherwise, except as may be required by law.

*Disclaimer: Dr. Barr served as an 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. Barr does not have a financial interest in either company.

Contacts:

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 May 2015.

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

⁴ NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkins Lymphomas. Version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed May 2015.

⁵ Schnaiter A, Stilgenbauer S. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin North Am. 2013;27:289-301.

⁶ Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010: 481-8.

⁷ IMBRUVICA Prescribing Information, January 2015  

⁸ Genetics Home Reference. Isolated growth hormone deficiency. Available at: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed May 2015.

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