CHICAGO, May 30, 2015 /PRNewswire/ -- Today,
Pharmacyclics LLC announced the results of the Phase III HELIOS
trial (CLL3001), which found that patients with previously treated
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) who received ibrutinib (IMBRUVICA®) in combination
with bendamustine and rituximab (BR) experienced an 80% reduction
in the risk of progression or death compared to patients receiving
placebo in combination with BR. Patients also experienced a higher
overall response rate (ORR, a key secondary endpoint), including
achieving a higher rate of complete responses (CR), after a median
follow-up of 17 months.
These data will be presented in an oral, late-breaking abstract
session by lead investigator Asher
Chanan-Khan, M.D., Mayo Clinic, Jacksonville, FL during the Leukemia,
Myelodysplasia, and Transplantation track at 2:27 p.m. CT today at the 51st
American Society of Clinical Oncology (ASCO) Annual Meeting in
Chicago, IL.* IMBRUVICA is jointly
developed and commercialized by Pharmacyclics and Janssen Biotech,
Inc.
On March 16th, an independent data monitoring
committee (IDMC) unanimously recommended that the HELIOS trial be
unblinded based on clinically meaningful and statistically
significant treatment benefit observed in the ibrutinib arm
compared to placebo+BR.
"We knew ibrutinib was an effective single-agent treatment
option with an established safety profile and we now have
additional evidence suggesting that ibrutinib improves outcomes
when combined with existing treatment regimens," said Simon Rule, M.D., Consultant Haematologist,
Department of Haematology and Head of the Lymphoma Service,
Derriford Hospital, Plymouth, UK
and HELIOS study investigator.* "The results from the HELIOS trial
are very encouraging for previously-treated patients with CLL or
SLL and suggest that the ibrutinib combination may be an option for
these patients moving forward."
HELIOS is a Janssen-sponsored, randomized, double-blind,
placebo-controlled, international, multicenter Phase III study
conducted in 21 countries, which evaluated the safety and efficacy
of ibrutinib+BR in 578 patients with relapsed/refractory CLL/SLL
who had received at least one prior therapy. Patients were
randomized to receive either the combination of oral, once-daily
ibrutinib 420 mg and six cycles of BR, or a matching regimen of
oral, once-daily placebo and six cycles of BR. Treatment with
ibrutinib or placebo continued until disease progression or
unacceptable toxicity.
PFS was the primary endpoint of the study, as assessed by an
independent review committee (IRC). At 18 months, IRC-assessed PFS
rates were 79% for patients in the ibrutinib+BR arm compared with
24% for patients in the placebo+BR arm. Key secondary endpoints
included IRC-assessed ORR and overall survival (OS). At a median
follow-up of 17 months, PFS was significantly longer with
ibrutinib+BR versus placebo+BR (median not reached vs. 13.3 months;
HR: 0.203, 95% CI: 0.150-0.276, P<0.0001). Patients with
the genetic mutation del 17p CLL were excluded from the study, but
PFS rates were consistent across all other high-risk subgroups.
Patients in the ibrutinib+BR arm experienced higher rates of ORR
and CR/CRi (CR with incomplete hematopoietic recovery), 82.7% and
10.4%, respectively, compared to patients in the placebo+BR arm,
67.8% and 2.8%, respectively. The median OS has not yet been
reached after a median follow up of 17 months.
Six cycles of BR were completed in the majority of patients in
the ibrutinib and placebo arms (83% and 78%, respectively). The
safety profile of ibrutinib+BR was consistent with the known
individual safety profiles for the therapies. The addition of
ibrutinib had no impact on the ability of BR to be administered in
patients, with a similar number of BR cycles administered in both
arms of the study.
"HELIOS demonstrated that when added, ibrutinib enhanced the
treatment effect of standard bendamustine and rituximab treatment,
resulting in a significant improvement in the outcomes for CLL and
SLL patients, reducing the risk of progression or death by 80%
compared to BR alone," said Danelle
James, M.D., M.S., Head of Oncology at Pharmacyclics. "These
findings support our belief that ibrutinib can become the backbone
of CLL therapy."
The most common adverse events (AEs ≥20%) of all Grades in the
HELIOS trial were neutropenia (58.2% in the ibrutinib+BR arm vs.
54.7% in the placebo+BR arm); nausea (36.9% vs. 35.2%); diarrhea
(35.5% vs. 23.7%); thrombocytopenia (30.7% vs. 24.4%); pyrexia
(24.7% vs. 22%); anemia (22.6% vs. 28.9%); and fatigue (21.6% vs.
22.6%). The most common Grade 3/4 AEs ( ≥15%) were neutropenia
(53.7% vs. 50.5%) and thrombocytopenia (15% in both arms). Higher
rates of Grade 1/2 bleeding such as hematoma (8% vs. 1%), contusion
(7.7% vs. 3.1%), epistaxis (5.9% vs. 3.1%), ecchymosis (3.1% vs.
0.7%) and petechiae (2.8% vs. 0.3%) were observed in patients
taking ibrutinib+BR, compared with those in the placebo+BR arm.
Rates of Grade 3 or greater hemorrhage were 3.8% versus 1.7%,
respectively. Rates of treatment-emergent Grade 3/4 atrial
fibrillation and hemorrhage were 2.8% vs. 0.7% and 2.1% vs. 1.7%,
respectively. The incidence of most AEs was similar between both
arms.
Ninety patients (31%) in the placebo+BR arm with confirmed
progressive disease crossed over to receive ibrutinib, as permitted
in the protocol. AEs were the primary reason for discontinuation in
patients taking ibrutinib+BR (14.2% vs. 11.8% in patients taking
placebo+BR).
A full study report will be submitted to health authorities for
future labeling considerations and will also be submitted to a
peer-reviewed journal for potential publication.
About Chronic Lymphocytic Leukemia (CLL)
The prevalence of CLL/SLL is approximately 115,000 patients in
the United States,[1]
with approximately 16,000 newly diagnosed patients every
year.[2] As this orphan disease frequently progresses
following first-line therapy, patients are faced with fewer
treatment options and often are prescribed multiple lines of
therapy as they relapse or become resistant to
treatments.[3]
In CLL/SLL, the genetic mutation del 17p occurs when part of
chromosome 17 has been lost or deleted. CLL/SLL patients with del
17p have poor treatment outcomes.[4] Del 17p is reported
in approximately 7% of treatment-naïve CLL/SLL cases,[5]
and approximately 20% to 40% of relapsed/refractory patients harbor
the mutation.[6]
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-naïve) 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.[7] 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.[7]
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily
therapy that inhibits a protein called Bruton's tyrosine kinase
(BTK).[7] 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.[7],[8] IMBRUVICA blocks signals that
tell malignant B cells to multiply and spread
uncontrollably.[7]
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
governmental regulation, our ability to commercialize, manufacture
and achieve market acceptance of any of our product candidates, for
which we rely heavily on collaboration with third parties, and our
ability to protect and enforce our intellectual property rights and
to operate without infringing upon the proprietary rights of third
parties. Although we believe that the expectations reflected in the
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. Chanan-Khan served as the primary
investigator of this Janssen-sponsored clinical study. He has
served as an unpaid advisor to both Pharmacyclics and Janssen in
developing the compound ibrutinib. Dr. Chanan-Khan does not have a
financial interest in either company. Prof. Rule also served as an
investigator of this study. He has served as an unpaid advisor to
both Pharmacyclics and Janssen in developing the compound
ibrutinib. Prof. Rule does not have a financial interest in either
company.
IMBRUVICA is a registered trademark of Pharmacyclics LLC
[1] IMS Database [Data on File]
[2] American Cancer Society. What are the key
statistics for chronic lymphocytic leukemia? Available
from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics.
Accessed May 2015.
[3] Veliz M, Pinilla-Ibarz J. Cancer Control.
Treatment of Relapsed or Refractory Chronic Lymphocytic
Leukemia. January 2012, Vol. 19, No. 1.
[4] NCCN Clinical Practice Guidelines in Oncology.
Non-Hodgkins Lymphomas. Version 1.2014.
http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.
Accessed May 2015.
[5] Schnaiter A, Stilgenbauer S. 17p deletion in
chronic lymphocytic leukemia: risk stratification and therapeutic
approach. Hematol Oncol Clin North Am. 2013;27:289-301.
[6] Stilgenbauer S, Zenz T. Understanding and
managing ultra high-risk chronic lymphocytic leukemia. Hematology
Am Soc Hematol Educ Program. 2010;2010: 481-8.
[7] IMBRUVICA Prescribing Information, January
2015
[8] 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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