IMBRUVICA® (ibrutinib) Approved by FDA for Marginal Zone Lymphoma (MZL) Patients Who Require Systemic Therapy and Have Received At Least One Prior Anti-CD20-Based Therapy

HORSHAM, Pa., Jan. 19, 2017 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) has approved IMBRUVICA^® (ibrutinib) for the treatment of patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.¹ Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. IMBRUVICA is jointly developed and commercialized by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

MZL is a slow-growing B-cell lymphoma occurring in white blood cells (lymphocytes) at the edges of lymph nodes and various tissues, including the stomach, salivary glands, thyroid gland, eyes, lungs and spleen.² MZL accounts for approximately 12 percent of all cases of non-Hodgkin's lymphoma in adults.²

"Patients with relapsed/refractory marginal zone lymphoma are in critical need of treatment options to manage living with this rare, serious blood cancer," said Ariela Noy, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center in New York and lead investigator of the study.* "This approval of IMBRUVICA represents a welcome new oral option for the MZL community and is the first approved therapy for these patients." 

The approval is based on results from the multi-center, open-label single arm, Phase 2 PCYC-1121 trial assessing the safety and efficacy of IMBRUVICA in 63 patients with MZL who received at least one prior therapy, including all 3 subtypes: mucosa-associated lymphoid tissue (MALT; n=32), nodal MZL (NMZL; n=17), and splenic MZL (SMZL; n=14). The responses were assessed by an Independent Review Committee (IRC) using criteria adopted from the International Working Group criteria for malignant lymphoma and demonstrated a 46% ORR (95% CI: 33.4-59.1), with 3.2% of patients achieving complete responses (CR) and 42.9% achieving partial responses (PR).  Efficacy was observed across all three MZL subtypes (ORR of 46.9%, 41.2%, and 50.0% for MALT, nodal and splenic subtypes, respectively). The median duration of response (DOR) was not reached (range, 16.7-NR), with median follow-up of 19.4 months. The median time to initial response was 4.5 months (range, 2.3-16.4).¹ These data were presented at the 58th Annual American Society of Hematology (ASH) Meeting in December 2016.

Warnings and precautions for IMBRUVICA include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, tumor lysis syndrome and embryo-fetal toxicity. The most common (>20%) adverse events (AEs) of all Grades included thrombocytopenia** (49%), fatigue (44%), anemia** (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema and arthralgia (24% each), neutropenia** (22%), cough (22%), and dyspnea and upper respiratory tract infection (21% each). The most common (>10%) Grade 3 or 4 AEs were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).¹

**Based on laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased)

"This approval broadens the indication for IMBRUVICA to include relapsed/refractory marginal zone lymphoma. It addresses a great unmet need for patients living with this serious blood cancer," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. "Building on our longstanding commitment of providing meaningful treatment solutions for people living with hematological malignancies, this milestone marks the fifth blood cancer indication for this medication. We continue to research its potential across a range of B-cell malignancies based on the drug's mechanism of action."

Janssen and Pharmacyclics are continuing an extensive clinical development program for IMBRUVICA, including Phase 3 study commitments in multiple disease areas.

About Marginal Zone Lymphoma (MZL)
MZL is a rare B-cell lymphoma arising from white blood cells (lymphocytes) at the margins, or edges of lymph nodes and various tissues, including the stomach, salivary glands, thyroid gland, eyes, lungs and spleen.² There are three subtypes of MZL: mucosa-associated lymphoid tissue (MALT), nodal MZL, and splenic MZL. MZL accounts for approximately 12 percent of all non-Hodgkin's lymphoma cases in adults, and the median age of diagnosis is 65 years old.² Prior to the approval of IMBRUVICA, there were no FDA-approved therapies specifically for this disease.

About IMBRUVICA
IMBRUVICA was one of the first therapies to receive U.S. approval after having received the FDA's Breakthrough Therapy Designation. IMBRUVICA works by blocking a specific protein called Bruton's tyrosine kinase (BTK).¹ 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.³ IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread. For more information, visit www.IMBRUVICA.com.

Additional Information about IMBRUVICA^®
INDICATIONS
IMBRUVICA^® is indicated to treat people with:

• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
• Waldenström's macroglobulinemia (WM)
• 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 and description of clinical benefit in a confirmatory trial.
• Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy
  • Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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), 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 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.janssen.com. 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. Please visit www.janssen.com.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding research and development of IMBRUVICA^®. 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 known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Biotech, Inc. and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product development, including the uncertainty of clinical success and of obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. 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 January 3, 2016, including in Exhibit 99 thereto, and the company's 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. Noy served as an investigator of this Pharmacyclics-sponsored clinical study. Dr. Noy does not have a financial interest in the company.

PRC-02581 1/17

¹ IMBRUVICA U.S. Prescribing Information, December 2016.
² Lymphoma Research Foundation. "Marginal Zone Lymphoma." Available at: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6554677 Last Accessed December 2016.
³ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed December 2016.

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SOURCE Janssen Biotech, Inc.

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