AbbVie Announces Ibrutinib (IMBRUVICA®) Supplemental New Drug Application for Previously Treated Chronic Graft-Versus-Host-Disease (cGVHD) Accepted for Review by U.S. FDA

NORTH CHICAGO, Ill., April 4, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced a supplemental New Drug Application (sNDA) was accepted for review by the U.S. Food and Drug Administration (FDA) for ibrutinib (IMBRUVICA®) in chronic graft-versus-host-disease (cGVHD) after failure of one or more lines of systemic therapy. cGVHD is a severe, potentially life-threatening consequence of stem cell or bone marrow transplant.^1,2 If approved by the U.S. FDA, ibrutinib will be the first therapy specifically approved to treat this condition. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"Patients with chronic-graft-versus-host-disease are traditionally prescribed corticosteroids, which often do not produce an adequate response and may cause serious health complications for some patients," said Lori Styles, M.D., Senior Medical Director and GVHD program clinical lead at Pharmacyclics LLC, an AbbVie company. "This regulatory filing is meaningful as it signifies the first potential indication for ibrutinib outside of hematological malignancies in a disease that severely impacts the patient's quality of life. We are pleased that these patients now have the potential for an effective treatment option."

The Company's sNDA is based on data from the single-arm Phase 1b/2 PCYC-1129 trial examining the safety and efficacy of ibrutinib in patients with cGVHD who failed first-line corticosteroid therapy and require further systemic therapy. The Pharmacyclics-sponsored study evaluated 42 previously treated patients with cGVHD in the U.S. who continued on steroid-based regimens. Patients received ibrutinib orally, once daily in combination with ongoing therapies, including corticosteroids and other immunosuppressants, until progression/worsening of cGVHD, recurrence of underlying malignancy or unacceptable toxicity. These data were presented as a late-breaker at both the American Society of Hematology Annual Meeting in December 2016 and the Blood and Marrow Transplantation Tandem Meeting in February 2017.

GVHD is a condition where the bone marrow recipient's tissues are attacked by bone marrow donor immune cells after a patient undergoes an allogeneic stem cell or bone marrow transplant.² GVHD can be acute or chronic; cGVHD typically begins three or more months following a transplant and can last several years.¹ The incidence of cGVHD has continued to increase over time and approximately 30-70 percent of post-allogeneic transplant patients will develop cGVHD.³ Symptoms can include skin problems, hair loss, mouth sores, eye irritation, severe lung injury, or liver dysfunction.² There are currently no therapies specifically approved for patients with cGVHD in the U.S. who have failed first-line corticosteroid therapy and require additional therapy. Most patients with cGVHD are prescribed high dose systemic corticosteroids, which suppress the immune system and are associated with an increased risk of relapse of the underlying disease, leaving a substantial percentage of patients needing additional treatment.^2,4

The U.S. 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.

IMBRUVICA is approved to treat patients with certain types of non-Hodgkin's lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with 17p deletion; patients with mantle cell lymphoma (MCL) who have received at least one prior therapy; patients with Waldenström's macroglobulinemia (WM); and patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.⁵ Continued approval for the MZL and MCL indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits 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.^5,6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.⁵

IMBRUVICA is FDA-approved in five distinct patient populations: CLL, SLL, WM, along with previously-treated MCL and MZL.⁵

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

Accelerated approval was granted for the MCL and MZL indication based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.⁵

IMBRUVICA was one of the first medicines to receive U.S. 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 nearly 30 company-sponsored trials underway, 14 of which are Phase 3. In addition, there are approximately 100 investigator-sponsored trials and external collaborations that are ongoing and active around the world. To date, more than 65,000 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 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), and 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 AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

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.

Contacts:

IMBRUVICA is a registered trademark of Pharmacyclics LLC.

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¹ MedlinePlus, U.S. National Library of Medicine. Graft-versus-host-disease. Available from: http://www.nlm.nih.gov/medlineplus/ency/article/001309.htm. Accessed March 2017.

² 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. Accessed March 2017.

³ 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: 22 (2016) 1781-1791.

⁴ National Cancer Institute. NCI Dictionary of Cancer Terms. Available from: http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45922. Accessed March 2017.

⁵ IMBRUVICA US Prescribing Information, January 2017.

⁶ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed March 2017.

SOURCE AbbVie

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