Janssen R&D Release: New Ibrutinib (IMBRUVICA) Phase 2 Data Demonstrate Promise In Relapsed/Refractory Marginal Zone Lymphoma (MZL), A Rare, Incurable Type Of Non-Hodgkin's Lymphoma

SAN DIEGO and RARITAN, N.J., Dec. 5, 2016 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen) today announced results from a Phase 2 study demonstrating a 48% overall response rate (ORR) as assessed by an Independent Review Committee (IRC) with single-agent ibrutinib (IMBRUVICA^®) in patients with relapsed/refractory (r/r) marginal zone lymphoma (MZL). These data will be presented today in an oral presentation at the 58^th Annual American Society of Hematology (ASH) Meeting and Exposition in San Diego, Calif. (abstract #1213).

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At a median follow-up of 19.4 months in 60 patients, 3% (n=2) treated with ibrutinib achieved complete responses (CR) and 45% (n=27) achieved partial responses (PR). Overall, 78% of patients experienced tumor reduction. Median duration of response (DOR) was not reached (95% CI: 16.7-NR), with 62% of responders alive and progression-free at the 18-month analysis. Median progression-free survival (PFS) was 14.2 months (95% CI: 8.3-NR) and median overall survival (OS) was not reached (95% CI: NR-NR). Patients in the study included those with splenic MZL (SMZL), nodal MZL (NMZL) and extranodal MZL (EMZL).¹

IMBRUVICA, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Janssen Biotech, Inc and Pharmacyclics LLC, an AbbVie company.

"The responses and clinical benefit seen with single-agent ibrutinib in patients with marginal zone lymphoma who have already failed at least one other therapy are very encouraging," said Ariela Noy, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center in New York and lead investigator of the study.* "It is important for these patients to have treatment options." There are currently no approved treatments or standards of care specifically indicated for patients with MZL in the United States.

The most common (>20%) adverse events (AEs) included fatigue (44%), diarrhea (43%), anemia (33%), nausea (25%), arthralgia, peripheral edema and thrombocytopenia (24% each), cough (22%), dyspnea and URTI (21% each). Treatment-emergent Grade 3 or higher AEs occurred in 67% of patients; the most frequent (>5%) were anemia (14%), pneumonia (8%) and fatigue (6%).¹

The multicenter, open-label Phase 2 study (PCYC-1121) assessed the safety and efficacy of ibrutinib in patients with r/r MZL. Patients had a median of two prior treatments (up to nine), with 35% of patients receiving three or more prior treatments. The study's primary endpoint was ORR as assessed by an IRC. Key secondary objectives included DOR and PFS, OS and safety.¹ In September 2016, data from this study were submitted to the U.S. Food and Drug Administration (FDA) as part of a supplemental New Drug Application (sNDA) seeking a fifth unique indication for IMBRUVICA.

"Findings from this study broaden the scientific knowledge of the potential benefit of ibrutinib in a range of hematologic cancers, including marginal zone lymphoma," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. "This study served as the basis for our recent supplemental New Drug Application submission pursuing a fifth indication for ibrutinib. We are committed to further investigating and understanding the potential clinical benefit of IMBRUVICA in a broad spectrum of patients in need of safe and effective treatment options."

MZL is a B-cell lymphoma arising from 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, and the median age of diagnosis is 65 years old.³

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).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.⁵ IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread. To date, more than 65,000 patients around the world have received treatment with IMBRUVICA. 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 of clinical benefit in confirmatory 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) 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, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) 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, 5% 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, 4% 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.

ADVERSE REACTIONS
The most common adverse reactions (20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), 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%). Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL 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 the Janssen Pharmaceutical Companies
At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenUS and www.twitter.com/JanssenGlobal.

Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding potential expanded benefits of, and indications for, ibrutinib. 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 Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in product research and development, including the uncertainty of clinical success and obtaining regulatory approvals; uncertainty of commercial success for new products or new indications; 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.

¹ Noy, A, et al. Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study. ASH 2016. Abstract #1213.
² El-Zimaity, H. "Marginal Zone B-cell Lymphoma." Available from: http://emedicine.medscape.com/article/1610599-overview#showall. Accessed November 2016.
³ Lymphoma Research Foundation. "Marginal Zone Lymphoma." Available from: http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6554677. Accessed November 2016.
⁴ IMBRUVICA U.S. Prescribing Information, May 2016. 
⁵ Genetics Home Reference. Isolated growth hormone deficiency. Available from:
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2016.

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