IMBRUVICA® (ibrutinib) Data Provide Insights Into Its Potential Treatment Benefits for Previously-Treated Chronic Graft-Versus-Host Disease -- A Serious, Possibly Life-Threatening Condition

NORTH CHICAGO, Ill., Dec. 11, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced new data on the biologic and cellular mechanisms of IMBRUVICA® (ibrutinib) in patients with chronic graft-versus-host disease (cGVHD), a potentially life-threatening consequence of an allogeneic stem cell or bone marrow transplant.¹ New results showed ibrutinib selectively inhibited pre-germinal center B cells and follicular helper T cells (Tfh) that are believed to play a critical role in treating cGVHD. In addition, the data also showed that ibrutinib preserved immune memory and Th1 T cells, which suggests the potential for additional treatment benefit. These results were observed in a Phase 1b/2 trial (PCYC-1129).

The data will be presented at the 59^th American Society of Hematology (ASH) Annual Meeting and Exposition on Dec. 11 in Atlanta (abstract #4481). IMBRUVICA is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"These new data further underscore the potential benefit of IMBRUVICA in chronic graft-versus-host disease, and provide encouraging signs for its mechanism of action in a way that's meaningful to advancing treatment," said Lori Styles, M.D., Senior Medical Director and GVHD program clinical lead at Pharmacyclics LLC, an AbbVie company. "The full potential of IMBRUVICA continues to unfold."

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 patient's normal tissues.² The effects of GVHD can be seen throughout the body, affecting almost any organ and manifesting through rashes and skin thickening, joint pain and stiffness, eye dryness and irritation, diarrhea, jaundice, mouth sores and ulcers, and severe lung dysfunction.¹ The incidence of cGVHD has continued to increase over time,³ with approximately 30 to 70 percent of post-allogeneic transplant patients developing the condition.⁴

The U.S. Food and Drug Administration (FDA) recently granted approval of IMBRUVICA for the treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy. This approval was based on data recently published in Blood.

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH 2017, which includes 12 oral presentations, please click here.

About the Presentation

Abstract #4481: Ibrutinib Inhibits cGVHD Pathogenic Pre-Germinal Center B-cells and Follicular Helper Cells While Preserving Immune Memory and Th1 T-cells
Poster Presentation: Monday, December 11, 6:00 – 8:00 p.m. ET

Data derived from the use of Nanostring gene expression analysis showed ibrutinib reduced inflammatory genes, including NFkB-1 and chemokines CXCL10, CCL7 and CCL3 (2.6, 2.3, 25, and 1.8-fold decrease, respectively), over the first three months. Additionally, a luminex plasma quantification showed several additional chemotactic, inflammatory, and fibrotic factors (CCL22, CXCL9, CXCL10, IL-8, sCD25, CCL4, and ST2) decreased in 69-80% of patients treated with ibrutinib. A 42-parameter CyTOF single cell analysis also revealed a 10-fold reduction in absolute numbers of cGVHD implicated pre-germinal center B cells (CD19+, CD27+, CD38+, IgD+), and notably diminished Tfh, Th17, and total B cells (2.6, 1.5, and 1.4-fold decrease, respectively) over the first three months following ibrutinib therapy.

The relative numbers of CD4+ and CD8+ T cells remained unchanged, although the total number of CD8+ cells seemed to follow an increasing trend. An analysis of relative numbers of T-cell subsets indicated a trend towards increasing numbers of Th1 and T regulatory cells, while Tfh cells and iNKT cells showed a trend towards decreasing numbers when compared with pretreatment numbers and 343 days of follow up. IgG plasma levels persisted while IgM significantly decreased supporting an ibrutinib germinal center effect that did not deplete long-lived plasma cells. Further, T cell reactivity against influenza increased, and antibodies against EBV and tetanus remained unchanged. However, single cell phosphorylation analysis showed BTK and interleukin-2-inducible T-cell kinase (ITK) signaling decreased following ibrutinib treatment in defined B and T-cell subsets.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton's tyrosine kinase (BTK). 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 as well as other serious, debilitating conditions.⁵ IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).⁶

• IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
• Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
• IMBRUVICA was approved for adult patients with WM in January 2015.
• In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
• In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
• In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.

Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.⁵ IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 90,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical 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 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 co-administration 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.

About AbbVie
AbbVie is a global, research-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2015 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

IMBRUVICA is a registered trademark of Pharmacyclics LLC.

¹ Janssen Biotech, Inc., Pharmacyclics LLC. IMBRUVICA U.S. prescribing information.  https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing_information.pdf. Accessed December 2017.

² Leukemia and Lymphoma Society. Graft versus host disease. https://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation/graft-versus-host-disease. Accessed December 2017.

³ Arai S, Arora M, Wang T, 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. 2015 Feb;21(2):266-274.

⁴ Grube M, Holler E, Weber D, Holler B, Herr W, Wolff D. 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 Oct;22(10):1781-1791.

⁵ Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed December 2017.

⁶ U.S. Food and Drug Administration. Fact sheet: breakthrough therapies. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed December 2017.

SOURCE AbbVie

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