Ibrutinib (IMBRUVICA®)
Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration
(FDA) for the Development of a Treatment for Chronic Graft-Versus-Host Disease
(cGVHD)
- In current clinical
practice, there are no FDA-approved treatments for this life-threatening
condition
- FDA designation
suggests potential use of ibrutinib beyond hematologic malignancies
- The FDA also granted
ibrutinib orphan drug designation for cGVHD
RARITAN, N.J., June 29,
2016 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) has granted a
fourth Breakthrough Therapy Designation (BTD) for ibrutinib (IMBRUVICA(®)): as
monotherapy for the treatment of patients with chronic
graft-versus-host-disease (cGVHD) after failure of one or more lines of systemic
therapy, Janssen Research & Development, LLC announced today. The FDA also
granted the therapy Orphan Drug Designation (ODD) for cGVHD. This marks the
first time ibrutinib has been granted BTD or ODD for an indication beyond
hematologic malignancies. In current clinical practice, there are no approved
treatments or established standards of care specifically indicated for patients
with active cGVHD who have failed first-line corticosteroid therapy and require
additional therapy. 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],[2] )Currently, most GVHD patients are
prescribed glucocorticoids, a type of steroid treatment, but many do not
respond. IMBRUVICA is jointly developed and commercialized by Janssen Biotech,
Inc. and Pharmacyclics LLC, an AbbVie company.
"We are excited to
learn if the mechanism of action for ibrutinib may allow its use beyond its
current indications in hematologic malignancies," said Sen Zhuang, M.D.,
Ph.D., Vice President, Clinical Development, Hematology for Janssen Research
& Development, LLC. "Two key kinase enzymes are believed to be
involved in the cell signaling associated with chronic graft-versus-host-disease:
Bruton's tyrosine kinase and interleukin-2-inducible T-cell kinase, known as
BTK and ITK respectively. Chronic GVHD is a debilitating condition with limited
treatment options. We're hopeful ibrutinib can make a difference and look
forward to working with the FDA and our strategic partner, Pharmacyclics, on
this development program."
The FDA granted ibrutinib
BTD for cGVHD based on data from a Phase 1b/2 study. Overall, ibrutinib showed
early clinical activity in the reduction of cGVHD based on the National
Institutes of Health (NIH) Consensus Response Criteria. Preliminary results
from this trial were previously presented at the 42nd Annual Meeting of the
European Society for Blood and Marrow Transplantation (ESBM) in April 2016 and
the 51st American Society of Clinical Oncology (ASCO) Annual Meeting in May
2015.
According to the FDA, BTD
is intended to expedite the development and review of treatments for serious or
life-threatening diseases where "preliminary clinical evidence indicates that
the drug may demonstrate substantial improvement over existing therapies on one
or more clinically significant endpoints, such as substantial treatment effects
observed early in clinical development."([3]) ODD provides special status
to a therapy developed to treat a rare condition or disease.([4])
In February 2013, the FDA
granted BTD to IMBRUVICA for the treatment of patients with relapsed or
refractory mantle cell lymphoma (MCL) and for the treatment of patients with
Waldenström's macroglobulinemia (WM). In April 2013, IMBRUVICA was awarded a
third BTD for the treatment of patients with chronic lymphocytic leukemia (CLL)
or small lymphocytic lymphoma (SLL) with a deletion of the short arm of
chromosome 17 (del 17p).
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.([5],[6]) IMBRUVICA
targets and blocks BTK, inhibiting cancer cell survival and spread.([5] )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/docs/librariesprovider7/default-document-library/prescribing_information.pdf.
About the Janssen
Pharmaceutical Companies
At the Janssen
Pharmaceutical Companies of Johnson & Johnson, we are working to create a
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Cautions Concerning
Forward-Looking Statements
This press release
contains "forward-looking statements" as defined in the Private
Securities Litigation Reform Act of 1995 regarding product 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 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 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.
[1] 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 June 2016.
[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 June 2016.
[3] U.S. Food and Drug
Administration. Fact Sheet: Breakthrough Therapies. Available from:
http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm.
Accessed June 2016.
[4] U.S. Food and Drug
Administration. Developing Products for Rare Diseases & Conditions.
Available from:
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm.
Accessed June 2016.
[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 June 2016.