Late-Breaking Ibrutinib (IMBRUVICA®) Data Show Complete or Partial Response in Two-Thirds of Patients with Chronic Graft-Versus-Host-Disease, a Frequent and Potentially Life-Threatening Complication of Stem Cell Transplant

NORTH CHICAGO, Ill., Dec. 6, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced positive results from a Phase 2 study (PCYC-1129) evaluating ibrutinib (IMBRUVICA^®) in patients with chronic graft-versus-host-disease (cGVHD), a serious and debilitating potential consequence of stem cell or bone marrow transplant,¹ who failed prior systemic therapy. The study found ibrutinib demonstrated efficacy, sustained responses and reduced symptom severity, with an overall response rate (ORR) of 67%.² Final results from this study presented today as a late-breaking oral presentation at the 58^th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, CA (abstract #LBA-3). IMBRUVICA, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

At a median follow-up of 14 months in 42 patients, the study found an ORR of 67%. One-third of all responders achieved a complete response (CR). In addition, 71% of patients showed a sustained response of at least 5 months. Similar response rates were seen across all involved organs, and patients with multiple organ involvement generally responded in multiple organs. 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. In addition, 62% of all patients were able to reduce steroid dose to an acceptable minimal level and five completely discontinued steroids with response. Twelve patients (29%) remain on treatment with ibrutinib.²

"These results are encouraging as they suggest ibrutinib has clinically meaningful potential in patients with steroid-refractory chronic graft-versus-host-disease," said David Miklos, M.D., Ph.D., Associate Professor of Medicine (Blood and Marrow Transplantation), Stanford University and lead investigator of the study.* "cGVHD patients face a challenging treatment journey with the majority of patients being prescribed steroids, with which long-term use can lead to serious health complications. With no FDA-approved therapies available specifically for cGVHD, new treatment options are critically needed."

GVHD is a life-threatening condition in which the body is attacked by donor immune cells after a patient undergoes an allogeneic stem cell or bone marrow transplant.^1,3 GVHD can be acute or chronic; chronic GVHD (cGVHD) usually starts more than 3 months after a transplant and can last many years.³ Symptoms can include skin problems, hair loss, mouth sores, eye irritation, severe lung injury, or liver dysfunction.³ There are currently no therapies specifically approved for patients with cGVHD who have failed first-line corticosteroid therapy and require additional therapy. Most patients with cGVHD are prescribed high dose glucocorticoids, a systemic steroid that suppresses the immune system and is associated with substantial morbidity and relapse of the underlying disease.³

"Ibrutinib works as a BTK inhibitor, which is showing to have a potential impact beyond blood cancers, including chronic graft-versus-host-disease," said Lori Styles, M.D., Senior Medical Director and GVHD program clinical lead at Pharmacyclics LLC, an AbbVie company. "We recognize the critical need for new treatments for patients with cGVHD and are encouraged by the results of this well-designed study, giving us confidence to proceed with a Phase 3 trial evaluating the impact of ibrutinib as part of initial therapy for this severe and potentially life-threatening condition. We are committed to exploring the full potential of ibrutinib in a range of health conditions with unmet needs."

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.

About the Study
PCYC-1129 evaluated the safety and efficacy of ibrutinib in 42 patients (median age 56 years) with cGVHD who failed at least one prior therapy, including corticosteroids. 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. Secondary endpoints included rate of sustained response, change in Lee cGVHD Symptom Scale, changes in corticosteroid requirement over time, and safety endpoints. Overall, reported adverse events (AEs) were consistent with those treated with ibrutinib for B-cell malignancies and in patients with cGVHD on corticosteroids.²

The most common 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).² 

Preliminary results from this trial were previously presented at the 42^nd Annual Meeting of the European Society for Blood and Marrow Transplantation (ESBM) in April 2016 and the 51^st American Society of Clinical Oncology (ASCO) Annual Meeting in May 2015.

About IMBRUVICA
IMBRUVICA 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.^4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.⁴

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with MCL who have received at least one prior therapy and patients with WM. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. ⁴

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 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 patients around the world have been treated with IMBRUVICA in clinical practice and in 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) 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 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.

IMBRUVICA is a registered trademark of Pharmacyclics LLC.

*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 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 2016.
² 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.
³ 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.
⁴ IMBRUVICA US 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 May 2016.

SOURCE AbbVie

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