SUNNYVALE, Calif., May 31, 2015 /PRNewswire/ -- Pharmacyclics LLC
today announced interim results from the ongoing Phase Ib/II
PCYC-1129 study suggesting that ibrutinib (IMBRUVICA®)
may be a safe and effective treatment for patients with chronic
graft-versus-host-disease (cGVHD) who were either refractory to
steroid treatment or were steroid-dependent. The data will be
presented today at the 51st American Society of Clinical
Oncology (ASCO) Annual Meeting in Chicago, IL at 8:00 a.m. CT. IMBRUVICA is jointly developed and
commercialized by Pharmacyclics and Janssen Biotech, Inc.
Lead investigator David Miklos,*
M.D., Ph.D., Stanford University,
Stanford, CA, presented the data
in full in a poster session.
cGVHD is a life-threatening condition in which newly
transplanted cells attack the patient's body.1 Patients
may develop this common complication after undergoing allogenic
stem cell or bone marrow transplantation.1 There are
currently no therapies specifically approved for this
condition.
The ongoing Phase Ib/II study evaluated the safety and efficacy
of ibrutinib for the treatment of patients with steroid-dependent
or refractory cGVHD. The Phase Ib portion of the study was
open-label and designed to determine the recommended Phase II dose
of ibrutinib, starting at 420 mg. Six patients (median age 56
years, median Karnofsky score 85**) were enrolled in the Phase Ib
portion. The median time from transplant was 23 months and the
median time on ibrutinib was 19.3 weeks. The Phase II study is
currently ongoing.
"Patients and physicians alike have long been searching for safe
and effective non-steroidal options to treat this condition," said
Danelle James, M.D., M.S., Head of
Oncology at Pharmacyclics. "The initial data presented today
provide compelling results that support the potential of ibrutinib
as a promising therapy for chronic GVHD."
In a preliminary analysis, data show all five evaluable patients
who had received at least three months of ibrutinib achieved a
partial response (PR), and two patients who were evaluable at six
months maintained a PR. Improvements in clinician-assessed
GVHD-score, skin erythema (4 PRs at three months and one complete
response [CR]) and mouth score (4 PRs at three months and 1 case of
stable disease) were observed in patients during the initial
analysis. Early pharmacokinetic data in the patients were within
range with exposure in indications currently included in the
IMBRUVICA product label. Overall, ibrutinib showed early clinical
activity in the reduction of cGVHD based on the NIH consensus cGVHD
Activity Assessment. As a result of the preliminary evaluation of
the available data, researchers determined the Phase II dose of
ibrutinib to be 420 mg.
The most common treatment-emergent adverse events (AEs) in this
study included fatigue (n=5), diarrhea (n=4), ecchymosis or
bruising (n=3) and stomatitis (n=2), all of which were Grade 1 or
2. Serious AEs (SAEs) occurred in two patients and included Grade 3
pneumonia, as well as pyrexia and fungal brain abscess; the latter
was the only event leading to ibrutinib discontinuation, which
occurred at 10.9 weeks. No dose-limiting toxicities were reported
in Phase Ib.
About IMBRUVICA
IMBRUVICA is currently approved for the treatment of patients
with chronic lymphocytic leukemia (CLL) who have received at least
one prior therapy, all CLL patients (including treatment-naive) who
have del 17p, a genetic mutation that occurs when part of
chromosome 17 has been lost, and all patients (including
treatment-naïve) with Waldenstrom's
macroglobulinemia.2 IMBRUVICA is also approved
under accelerated approval for the treatment of patients with
mantle cell lymphoma (MCL) who have received at least one prior
therapy.2 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.2
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily
therapy that inhibits a protein called Bruton's tyrosine kinase
(BTK).2 IMBRUVICA was one of the first medicines to
receive U.S. FDA approval via the new Breakthrough Therapy
Designation pathway, and is the only product to have received three
Breakthrough Therapy Designations.
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.2,3 IMBRUVICA blocks signals that tell
malignant B cells to multiply and spread
uncontrollably.2
IMBRUVICA is being studied alone and in combination with other
treatments in several blood cancers. Over 6,100 patients have been
treated in clinical trials of IMBRUVICA conducted in 35 countries
by more than 800 investigators. Currently, 13 Phase III trials have
been initiated with IMBRUVICA and 67 trials are registered on
www.clinicaltrials.gov.
To learn more about the medical terminology used in this news
release, please visit
http://stedmansonline.com/.
INDICATIONS
IMBRUVICA is indicated to treat people with:
- Chronic lymphocytic leukemia (CLL) who have received at least
one prior therapy
- Chronic lymphocytic leukemia (CLL) with 17p deletion
- Waldenstrom's macroglobulinemia
- Mantle cell lymphoma (MCL) who have received at least one prior
therapy – accelerated approval was granted for this indication
based on overall response rate. Continued approval for this
indication may be contingent upon verification of clinical benefit
in confirmatory trials.
Patients taking IMBRUVICA for CLL or WM should take 420 mg taken
orally once daily (or three 140 mg capsules once daily).
Patients taking IMBRUVICA for MCL should take 560 mg taken
orally once daily (or four 140 mg capsules once daily).
Capsules should be taken orally with a glass of water. Capsules
should be taken whole. Do not open, break, split or chew the
capsules.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage - Fatal bleeding events have occurred in
patients treated with IMBRUVICA®. Grade 3
or higher bleeding events (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. 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 have occurred
with IMBRUVICA® therapy. Grade 3 or greater
infections occurred in 14% to 26% of patients. Cases of progressive
multifocal leukoencephalopathy (PML) have occurred in patients
treated with IMBRUVICA®. Monitor patients
for fever and infections and evaluate promptly.
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%) occurred in patients treated
with 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, 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. If atrial fibrillation persists, consider
the risks and benefits of IMBRUVICA®
treatment and dose modification.
Second Primary Malignancies - Other malignancies (range,
5 to 14%) including non-skin carcinomas (range, 1 to 3%) have
occurred in patients treated with
IMBRUVICA®. The most frequent second
primary malignancy was non-melanoma skin cancer (range, 4 to
11%).
Tumor Lysis Syndrome - Tumor lysis syndrome has been
reported with IMBRUVICA® therapy. Monitor
patients closely and take appropriate precautions in patients at
risk for tumor lysis syndrome (e.g., high tumor burden).
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®. 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 (≥25%) in patients with B-cell
malignancies (MCL, CLL, WM) were thrombocytopenia+ (57%,
52%, 43%), neutropenia+ (47%, 51%, 44%), diarrhea (51%,
48%, 37%), anemia+ (41%, 36%, 13%), fatigue (41%, 28%,
21%), musculoskeletal pain (37%, 28%++,
NA+++), bruising (30%, 12%++,
16%++), nausea (31%, 26%, 21%), upper respiratory tract
infection (34%, 16%, 19%), and rash (25%, 24%++,
22%++).
+Based on adverse reactions and/or laboratory
measurements (noted as platelets, neutrophils, or hemoglobin
decreased).
++Includes multiple ADR terms.
+++Not applicable; no associated ADRs.
The most common Grade 3 or 4 non-hematological 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 events.
Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients
discontinued due to adverse events. Most frequent adverse events
leading to discontinuation were infections, subdural hematomas, and
diarrhea in CLL patients and subdural hematoma (1.8%) in MCL
patients.
DRUG INTERACTIONS
CYP3A Inhibitors - Avoid co-administration with strong
and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must
be used, reduce the IMBRUVICA® dose.
CYP3A Inducers - Avoid co-administration 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:
http://www.imbruvica.com/downloads/Prescribing_Information.pdf.
About Pharmacyclics, An AbbVie Company
Pharmacyclics, a wholly-owned subsidiary of AbbVie (NYSE: ABBV),
is focused on developing and commercializing innovative
small-molecule drugs for the treatment of cancer and
immune-mediated diseases. Pharmacyclics' mission is to develop and
commercialize novel therapies intended to improve quality of life,
increase duration of life and resolve serious unmet medical
needs.
Pharmacyclics markets IMBRUVICA and has three product candidates
in clinical development and several preclinical molecules in lead
optimization. Pharmacyclics is committed to high standards of
ethics, scientific rigor and operational efficiency as it moves
each of these programs toward commercialization. To learn more,
please visit www.pharmacyclics.com.
NOTE: This announcement may contain forward-looking
statements made in reliance upon the safe harbor provisions of
Section 27A of the Securities Act of 1933, as amended, and Section
21E of the Securities Exchange Act of 1934, as amended, including
statements, among others, relating to our future capital
requirements, including our expected liquidity position and timing
of the receipt of certain milestone payments, and the sufficiency
of our current assets to meet these requirements, our future
results of operations, our expectations for and timing of ongoing
or future clinical trials and regulatory approvals for any of our
product candidates, and our plans, objectives, expectations and
intentions. Because these statements apply to future events, they
are subject to risks and uncertainties. When used in this
announcement, the words "anticipate", "believe", "estimate",
"expect", "expectation", "goal", "should", "would", "project",
"plan", "predict", "intend", "target" and similar expressions are
intended to identify such forward-looking statements. These
forward-looking statements are based on information currently
available to us and are subject to a number of risks, uncertainties
and other factors that could cause our actual results, performance,
expected liquidity or achievements to differ materially from those
projected in, or implied by, these forward-looking statements.
Factors that may cause such a difference include, without
limitation, our need for substantial additional financing and the
availability and terms of any such financing, the safety and/or
efficacy results of clinical trials of our product candidates, our
failure to obtain regulatory approvals or comply with ongoing
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and achieve market acceptance of any of our product candidates, for
which we rely heavily on collaboration with third parties, and our
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forward-looking statements are reasonable, we cannot guarantee
future results, performance or achievements and no assurance can be
given that the actual results will be consistent with these
forward-looking statements. For more information about the risks
and uncertainties that may affect our results, please see the Risk
Factors section of our filings with the Securities and Exchange
Commission, including our Form 10-K for the year ended December 31, 2013 and quarterly reports on Form
10-Q. We do not intend to update any of the forward-looking
statements after the date of this announcement to conform these
statements to actual results, to changes in management's
expectations or otherwise, except as may be required by law.
* Disclaimer: Dr. Miklos served as an investigator of this
Pharmacyclics-sponsored clinical study. Dr. Miklos does not have a
financial interest in the company. This study was sponsored by
Pharmacyclics.
** The Karnofsky Performance Scale Index allows patients to
be classified by functional impairment. This can be used to assess
the efficacy of therapies and/or patients' prognosis. A lower
Karnofsky score indicates worsening survival rates for most serious
illnesses. More information is available here.
IMBRUVICA is a registered trademark of Pharmacyclics LLC
1 MedlinePlus, U.S. National Library of Medicine.
Graft-versus-host-disease.
http://www.nlm.nih.gov/medlineplus/ency/article/001309.htm.
Accessed May 2015.
2 IMBRUVICA Prescribing Information, January
2015
3 Genetics Home Reference. Isolated growth hormone
deficiency. Available at:
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency.
Accessed May 2015.
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