Ibrutinib Data Published in The Lancet Oncology Suggest a Positive Effect in Previously Untreated Chronic Lymphocytic Leukemia

 Ibrutinib Data Published in The Lancet Oncology Suggest a Positive Effect in
    Previously Untreated Chronic Lymphocytic Leukemia Patients Over Age 65

Encouraging Data from a Phase 1b/2, Open-label, Multicenter Study

PR Newswire

RARITAN, N.J., Dec. 9, 2013

RARITAN, N.J., Dec. 9, 2013 /PRNewswire/ --Janssen Research & Development,
LLC (Janssen) today announced data from a study published in The Lancet
Oncology, evaluating the safety and activity of ibrutinib as a single-agent
therapy in patients over the age of 65 with previously untreated chronic
lymphocytic leukemia (CLL, N=29) or small lymphocytic lymphoma (SLL, N=2). The
study met its primary endpoint of safety, with data demonstrating treatment
with ibrutinib as an initial therapy was associated with adverse events (AEs)
that were predominantly Grade 1 or 2 in nature.

Efficacy data were also collected and showedthat 71 percent (95% CI,
52.0-85.8) of patients treated with ibrutinib achieved an objective response
(defined as a complete or partial response).Although estimates of
progression-free survival (PFS) and overall survival (OS) were not reached at
the median follow up of 22.1 months, it is estimated that more than 95% of
patients would be alive and progression-free at two years.

"This early stage study in previously untreated patients suggests a positive
effect with ibrutinib in CLL and SLL," said lead author Susan O'Brien, M.D.,
Department of Leukemia, Division of Cancer Medicine, The University of Texas
MD Anderson Cancer Center. "The results of this study are encouraging given
the average age, overall health and unmet needs of the typical CLL

Primary Endpoint: Safety

Adverse events were predominantly Grade 1 or 2 in severity, with the most
frequently (greater than or equal to 25 percent) reported being diarrhea (68
percent) which was often self-limited and resolved without discontinuation of
treatment. Other common mild to moderate AEs that were reported included
nausea (48 percent), fatigue (32 percent), hypertension (29 percent),
peripheral edema (29 percent), dizziness (26 percent), dyspepsia (26 percent)
and upper respiratory tract infection (26 percent).

The most common Grade 3 AEs included diarrhea (13 percent), infection (10
percent) and hypertension (7 percent). Grade 3 or greater hematological
adverse events included one instance of Grade 3 neutropenia and one instance
of Grade 4 thrombocytopenia. Two patients discontinued treatment due to Grade
3 fatigue and Grade 2 viral infection.

Secondary Endpoints: Efficacy

Secondary endpoints included the proportion of patients achieving an objective
response, PFS, long-term tolerability and pharmacodynamics. Median follow-up
for all patients was 22.1 months (interquartile range (IQR), 18.4-23.2 months)
and the median treatment duration was 21 months (IQR, 0.3-26.6 months).

At 22 months, median PFS and OS were not reached. PFS and OS rates at 24
months (based on Kaplan-Meier projections) were estimated to be 96.3 percent
(95% CI, 76.5-99.5) and 96.6 percent (95% CI, 77.9-99.5) respectively.

The objective response rate (ORR) was 71 percent, including;

  o55 percent partial responses (PR)
  o13 percent complete responses (CR)
  o3 percent nodular partial responses (nPR)

An additional 13 percent of patients (N=4) achieved a PR with on-going
lymphocytosis (PR-L). Response was assessed on the basis of the International
Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines with the exception
that lymphocytosis was not a sole criterion for disease progression. Disease
response to ibrutinib therapy was independent of high-risk clinical and
genomic factors.

The median time to initial response was 1.9 months (IQR,1.5-7.4 months), while
the median time to best response and complete response were 5.9 months
(IQR,1.8-22.1 months) and 12 months (IQR, 7.1-15.6 months).

"This is the first study to investigate the safety and efficacy of ibrutinib
as a first-line therapy in the CLL patient population. It is building on our
understanding of ibrutinib as a potential treatment for older patients who
struggle to tolerate and adhere to currently available treatments," said Peter
F. Lebowitz, M.D., Ph.D., Global Oncology Therapeutic Area Head, Janssen.
"Through these studies we are beginning to understand more about how ibrutinib
works. Lymphocytosis is an interesting example: of the 13 patients who
achieved a partial response with lymphocytosis at some time during their
treatment, two achieved a complete response and seven achieved a partial
response with resolution of their lymphocytosis."

Study Design

The Phase 1b/2 open-label multi-center study (PCYC-1102, NCT01105247)
evaluated 31 previously untreated patients 65 years old and older, with CLL or
SLL. The median age was 71 years (range 65-84 years) and 23 patients (74
percent) were older than 70 years. Fifty-five percent of patients' disease was
categorized as Rai stage 3 or 4. The primary endpoint of the study was the
safety of two fixed dose regimens, as assessed by the frequency and severity
of AEs. The secondary objectives assessed the clinical activity of oral,
once-daily ibrutinib 420 mg (27 patients) or 840 mg (4 patients) based on
overall response rate (ORR), PFS, long-term tolerability and pharmacodynamics.
Because few patients received an ibrutinib dose of 840 mg and the results for
the two dose cohorts were similar, data for all patients were pooled for

The data were presented in part at the annual meetings of the American Society
of Hematology, 2012, and the American Society of Clinical Oncology, 2012.

Ibrutinib was recently approved in the U.S. under the tradename IMBRUVICA™, as
a single agent for the treatment of patients with mantle cell lymphoma (MCL)
who have received at least one prior therapy.^1 This indication is based on
overall response rate. An improvement in survival or disease-related symptoms
has not been established. Ibrutinib has been submitted to the European
Medicines Agency (EMA) for the treatment of adult patients with relapsed or
refractory CLL/SLL or adult patients with relapsed or refractory MCL. Use of
ibrutinib in markets and for indications in which it has not been approved, is

Ibrutinib is being jointly developed and commercialized by Janssen and
Pharmacyclics, Inc. Pharmacyclics, Inc. sponsored the study.



Hemorrhage – Five percent (5%) of patients with MCL had Grade 3 or higher
bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria).
Bleeding events including bruising of any grade occurred in 48% of patients
with MCL treated with 560 mg daily. The mechanism for the bleeding events is
not well understood. Consider the benefit-risk of ibrutinib in patients
requiring antiplatelet or anticoagulant therapies and the benefit-risk of
withholding ibrutinib 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. At least 25% of
patients with MCL had infectionsgreater than or equal to Grade 3, according
to NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor
patients for fever and infections and evaluate promptly.

Myelosuppression – Treatment-emergent Grade 3 or 4 cytopenias were reported in
41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and
anemia (9%). Monitor complete blood counts monthly.

Renal Toxicity – Fatal and serious cases of renal failure have occurred.
Treatment-emergent increases in creatinine levels up to 1.5 times the upper
limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper
limit of normal in 9% of patients. Periodically monitor creatinine levels.
Maintain hydration.

Second Primary Malignancies – Other malignancies (5%) have occurred in
patients with MCL who have been treated with IMBRUVICA, including skin cancers
(4%), and other carcinomas (1%).

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 commonly occurring adverse reactions (greater
than or equal to 20%) in the clinical trial were thrombocytopenia*, diarrhea
(51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%),
peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%),
bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain
(24%), vomiting (23%) and decreased appetite (21%).

* Treatment-emergent decreases (all grades) of platelets (57%), neutrophils
(47%) and hemoglobin (41%) were based on laboratory measurements and adverse

The most common Grade 3 or 4 non-hematological adverse reactions (greater than
or equal to 5%) were: pneumonia (7%), abdominal pain (5%), atrial
fibrillation, diarrhea (5%), fatigue (5%), and skin infections (5%).
Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients.

Ten patients (9%) discontinued treatment due to adverse reactions in the trial

The most frequent adverse reaction leading to treatment discontinuation was
subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred
in 14% of patients.

Drug Interactions:

CYP3A Inhibitors – Avoid concomitant administration with strong or moderate
inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the

CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.

Special Populations – Hepatic Impairment – Avoid use in patients with baseline
hepatic impairment.

For the full prescribing information, visit

About CLL
Chronic Lymphocytic Leukemia (CLL) is a slow-growing blood cancer that most
commonly originates from B cells, a type of white blood cell (lymphocyte). B
cells are part of the immune system and play an important role in fighting
infection in the body. CLL is the most common adult leukemia in the Western
World. Approximately 15,680 patients in the U.S. are diagnosed each year with
CLL.^2 CLL is a chronic disease of the elderly, and is primarily diagnosed in
those over 70 years old.^3 The five-year survival rate is approximately 82
percent.^2 Patients commonly receive multiple lines of treatment over the
course of their disease. When cancer cells are located mostly in the lymph
nodes, the disease is called SLL.

About ibrutinib
Ibrutinib is approved in the U.S., under the trade name IMBRUVICA^™ and is
indicated for the treatment of patients with mantle cell lymphoma (MCL) who
have received at least one prior therapy. This indication is based on overall
response rate (ORR). An improvement in survival or disease-related symptoms
has not been established.^1 Outside the U.S. and for other indications
including CLL, ibrutinib is investigational.

Ibrutinib works by blocking a specific protein called Bruton's tyrosine kinase
(BTK).^1 BTK is a signaling molecule of the B-cell antigen receptor (BCR)
pathway, which is emerging as a target in some B-cell malignancies.^4,5,6
BTK's role in signaling through the B-cell surface receptors results in
activation of pathways necessary for B cell trafficking, chemotaxis and

For more information, visit www.IMBRUVICA.com.

About Janssen Research & Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most
important unmet medical needs of our time in oncology, immunology,
neuroscience, infectious diseases and vaccines, and cardiovascular and
metabolic diseases. Driven by our commitment to patients, we develop
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throughout the world. Janssen Research & Development and Janssen Biotech are
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for more information.

Janssen in Oncology

In oncology, our goal is to fundamentally alter the way cancer is understood,
diagnosed, and managed, reinforcing our commitment to the patients who inspire
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primary efforts focus on several treatment and prevention solutions. These
include a focus on hematologic malignancies, prostate cancer and lung cancer;
cancer interception with the goal of developing products that interrupt the
carcinogenic process; biomarkers that may help guide targeted, individualized
use of our therapies; as well as safe and effective identification and
treatment of early changes in the tumor microenvironment.

(This press release contains "forward-looking statements" as defined in the
Private Securities Litigation Reform Act of 1995. The reader is cautioned not
to rely on these forward-looking statements. These statements are based on
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year ended December 30, 2012. Copies of this Form 10-K, as well as subsequent
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Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson &
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1. IMBRUVICA Prescribing Information, November 2013.

2. Cancer.net. "Leukemia – Chronic Lymphocytic - CLL".
Accessed June 2013.

3. American Cancer Society. "Leukemia--Chronic Lymphocytic".
Accessed March 2013.

4. Buggy JJ and Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell
malignancy. Int Rev Immunol. 2012;31:119-132.

5. Woyach JA, Johnson AJ, and Byrd JC. The B-cell receptor signaling pathway
as a therapeutic target in CLL. Blood. 2012;120(6):1175-1184.

6. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell receptor signaling
in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88-92.

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