U.S. FDA Approves IMBRUVICA® (ibrutinib) as First and Only Approved Treatment for Adult Patients with Chronic Graft-Versus-Host-Disease (cGVHD) After Failure of One or More Lines of Systemic Therapy

HORSHAM, Pa., Aug. 2, 2017 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) has approved IMBRUVICA^® (ibrutinib) for the treatment of adult patients with chronic graft-versus-host-disease (cGVHD) after failure of one or more lines of systemic therapy.¹ IMBRUVICA is the first and only FDA-approved medication for adult patients with cGVHD, a potential consequence of an allogeneic stem cell or bone marrow transplant, which can be life-threatening and debilitating.² IMBRUVICA is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

"Chronic graft-versus-host-disease can occur after allogeneic stem cell or bone marrow transplant and results from donor immune cells attacking the patient's tissue. For most patients, the diagnosis of cGVHD comes after a long and already arduous battle with a blood-related disease," said David Miklos, M.D., Ph.D., Associate Professor of Medicine (Blood and Marrow Transplantation), Stanford University, and lead investigator of the IMBRUVICA cGVHD clinical study.* "This approval provides physicians and the cGVHD patient community with a welcome new approach for patients who fail initial therapy, as data show treatment with IMBRUVICA resulted in encouraging and sustained clinical responses."  

The approval is based on results from an open-label, multi-center, single-arm Phase 1b/2 trial (PCYC-1129) evaluating the safety and efficacy of ibrutinib in 42 patients with cGVHD who failed first-line corticosteroid therapy and required additional therapy (median age of 56 years; range, 19 to 74 years old). In the study population, the most common underlying malignancies leading to transplantation were acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was two (range, one to three treatments), and 60% of patients had a Karnofsky performance score of ≤ 80. The majority of patients (88%) had at least two organs involved at the beginning of the trial, with the most commonly involved organs being mouth (86%), skin (81%) and gastrointestinal tract (33%). Fifty-two percent of patients were receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.¹

The overall response rate (ORR) was 67% (95% CI: 51%, 80%), with 21% of patients achieving complete responses (CR; n=9) and 45% achieving partial responses (PR; n=19). Sustained response rate of at least 20 weeks was 48% (n=20). The median time to best response coinciding with the first scheduled response assessment was 12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all involved organs for cGVHD (i.e., skin, mouth, gastrointestinal tract and liver).¹ 

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 in the cGVHD trial included fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%), and pneumonia (21%). Atrial fibrillation occurred in one patient (2%), which was Grade 3. Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.¹

"We are very pleased to bring IMBRUVICA to physicians and patients battling chronic graft-versus-host-disease," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. "This indication for previously-treated cGVHD represents the first approved use of IMBRUVICA outside of the hematology-oncology category, and we are deeply proud of this development."

The data was presented as a late-breaker at the American Society of Hematology Annual Meeting in December 2016 and the Blood and Marrow Transplantation Tandem Meeting in February 2017. A Phase 3 double-blind, placebo-controlled study was initiated in December 2016 to examine ibrutinib with corticosteroid versus placebo with corticosteroid as a first-line therapy for patients with new onset moderate or severe cGVHD; the study is ongoing.

Patients can develop GVHD, a potentially life-threatening complication, following an allogeneic stem cell or bone marrow transplant.² The condition occurs when donor immune cells mistakenly attack the patients' normal tissues.² The effects of cGVHD can be seen throughout the body, affecting almost any organ, which may include loss of patches of skin, hair loss, excessive dryness of the body resulting in ulcers and scarring of the lungs, and liver injury leading to liver failure.² The incidence of cGVHD has continued to increase over time,³ with approximately 30-70% of post-allogeneic transplant patients developing the condition.⁴

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

About IMBRUVICA
IMBRUVICA^® (ibrutinib) 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.⁵ IMBRUVICA targets and blocks BTK, inhibiting the survival and spread of cancer cells, and impacting signaling associated with other serious conditions. For more information, visit www.IMBRUVICA.com.

Additional Information about IMBRUVICA^®
INDICATIONS

IMBRUVICA^® is indicated to treat adults with¹:

• 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) patients 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) patients 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.
• Chronic Graft-Versus-Host-Disease (cGVHD) patients who failed one or more lines of systemic therapy

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 post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) 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^®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and 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 with B-cell malignancies 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 (e.g., 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 anti-hypertensive medications and/or initiate anti-hypertensive 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 (e.g., 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

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

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.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%), muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%), and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%), pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA^® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA^® 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 the continuing development and exploration of the potential benefits of ibrutinib (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, 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 1, 2017, including under "Item 1A. Risk Factors," its most recently filed Quarterly Report on Form 10-Q, including in the section captioned "Cautionary Note Regarding Forward-Looking Statements," 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. Miklos served as an investigator of this Pharmacyclics-sponsored clinical study. Dr. Miklos does not have a financial interest in the company.

PRC-02994 07/17

¹ IMBRUVICA U.S. Prescribing Information, August 2017. 
² Leukemia and Lymphoma Society. Graft Versus Host Disease. Available from: https://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation/graft-versus-host-disease. Accessed April 2017.
³ Arai, et al. Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant: 21 (2015) 266-274.
⁴ Grube, et al. Risk Factors and Outcome of Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation—Results from a Single-Center Observational Study. Biol Blood Marrow Transplant: 2016; 22 (11): 1781-1791.
⁵ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed April 2017.

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