Late-breaking Phase 2 Ibrutinib Study in Chronic Graft-Versus-Host-Disease (cGVHD) Showed Complete or Partial Response in Up to Two-Thirds of Steroid Dependent or Refractory Patients

Data at the American Society of Hematology Annual Meeting highlight potential role of ibrutinib therapy beyond hematologic cancers

cGVHD is a major cause of stem cell or bone marrow transplant-related illness, death and functional impairment with no FDA-approved treatments specifically for this condition1

This release corresponds to abstract #LBA-3

News provided by

Janssen Research and Development LLC

Dec 06, 2016, 10:35 ET

SAN DIEGO and RARITAN, N.J., Dec. 6, 2016 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen) today announced Phase 2 ibrutinib (IMBRUVICA^®) data showing encouraging results in patients with chronic graft-versus-host-disease (cGVHD), a life-threatening consequence of stem cell or bone marrow transplant, who failed prior systemic therapy.² Study findings indicate ibrutinib demonstrated clinically meaningful and durable responses and reduced symptom severity, with an overall response rate (ORR) of 67% in patients with cGVHD.³ The late-breaking data will be presented today in an oral session at the 58^th American Society of Hematology (ASH) Annual Meeting in San Diego, Calif. (abstract #LBA-3). 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.

Experience the interactive Multimedia News Release here: http://www.multivu.com/players/English/7990431-janssen-oncology-online-press-kit/

At a median follow-up of 14 months (0.5-25) in 42 patients, one third of all responders achieved a complete response (CR); 71% of patients with a complete or partial response showed a sustained response of at least 5 months. Over the course of the study, 61% of responders experienced a clinically meaningful improvement in symptoms, as measured by at least a 7-point decrease in Lee Symptom Scale score. Additionally, a reduction in steroid dose <0.15 mg/kg/day was reached in 62% of patients with a complete or partial response. Twelve patients (29%) remained on treatment at the time of this analysis.³

"There is an urgent need for effective new therapies for patients with steroid-resistant chronic graft-versus-host-disease, a condition that can be incapacitating and even fatal when it is not controlled," said lead investigator David Miklos, M.D., Ph.D., Associate Professor of Medicine, Blood and Marrow Transplantation, Stanford University.* "These data are promising as they suggest that ibrutinib may offer a new approach for managing this common post-transplant complication."

Patients can develop GVHD, a serious and debilitating condition in which their body is attacked by donor immune cells, after undergoing an allogeneic stem cell or bone marrow transplant.[4] The condition can be acute or chronic; cGVHD usually starts more than 3 months after a transplant and can last a lifetime.⁴ Symptoms of GVHD may include skin problems, hair loss, dryness of the mouth, eye irritation, severe lung injury, or liver injury.⁴ There are currently no FDA-approved treatments specifically indicated for patients with active cGVHD who have failed first-line corticosteroid therapy and require additional therapy. Patients with cGVHD are typically prescribed glucocorticoids, a group of systemic steroids that suppresses the immune system and puts them at risk for serious infections.⁴

"We are excited to explore the potential of ibrutinib in treating conditions beyond hematologic cancers," said Mark Wildgust, Vice President, Global Medical Affairs, Janssen Oncology. "We are encouraged by these Phase 2 results in steroid-resistant chronic graft-versus-host-disease where there is a significant unmet patient need. We look forward to further exploring the potential of ibrutinib as initial therapy for this serious condition with the initiation of a Phase 3 trial in the first-line setting."

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation and Orphan Drug Designation in June 2016 for ibrutinib as a potential treatment for cGVHD after failure of one or more lines of systemic therapy.

The most common adverse events (AEs) were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%) and bruising (24%). Serious AEs (SAEs) occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2) and pyrexia (n=2).³

The single-arm study (PCYC-1129) examined the safety and efficacy of ibrutinib in 42 patients with cGVHD who failed at least one prior therapy (median age 56 years) and were in need of additional therapy. Patients were treated with ibrutinib once daily until cGVHD progression or unacceptable toxicity. The primary endpoint was cGVHD response based on the National Institutes of Health (NIH) consensus response criteria. Key secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time and safety endpoints.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).⁵ 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.⁶ To date, more than 65,000 patients around the world have received treatment with IMBRUVICA. For more information, visit www.IMBRUVICA.com. IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread. For more information, visit www.IMBRUVICA.com.

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 the potential of ibrutinib and its further 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 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. Miklos served as an investigator of this Pharmacyclics-sponsored clinical study. Dr. Miklos does not have a financial interest in the company.

¹ Pidala J, et al., The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality. Haematologica 2011 Nov; 96(11): 1678–1684.
² MedlinePlus, U.S. National Library of Medicine. Graft-versus-host-disease. Available from: http://www.nlm.nih.gov/medlineplus/ency/article/001309.htm. Accessed November 2016.
³ Miklos, D, et al. Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft Versus Host Disease (cGVHD) After Failure of Corticosteroids. ASH 2016 Abstract #LBA-3.
⁴ The Leukemia and Lymphoma Society. Graft Versus Host Disease. Available from" http://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation/graft-versus-host-disease.
⁵ IMBRUVICA U.S. Prescribing Information, May 2016.
⁶ Genetics Home Reference. Isolated growth hormone deficiency. Available from:
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2016.