Ibrutinib RESONATE(TM) Data Show Significant Improvements in Progression-Free Survival and Overall Survival in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymph

Beerse, Belgium (ots/PRNewswire) -

/NOT INTENDED FOR UK MEDIA/

Phase 3 data (Abstract LBA7008) featured in the official press
programme of the 50th annual meeting of the American Society of
Clinical Oncology and simultaneously

published in The New England Journal of Medicine

Data from the international, multicentre Phase 3 PCYC-1112
(RESONATE(TM)) trial in 391 patients suggest monotherapy ibrutinib
administered once-daily significantly lengthened progression-free
survival (PFS) (median not reached vs. 8.1 months; HR 0.215, 95% CI,
0.146 to 0.317; P<0.0001) and overall survival (OS) (HR 0.434; 95 CI,
0.238 to 0.789; P=0.0049) versus ofatumumab administered
intravenously in patients with relapsed or refractory chronic
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Ibrutinib is an investigational compound in the EU within a class of
medicines called Bruton's tyrosine kinase (BTK) inhibitors*.

Janssen announced today that the data will be included in a
presentation during the official press programme at the American
Society of Clinical Oncology (ASCO) meeting in Chicago, IL and
simultaneously published in a special edition of The New England
Journal of Medicine.[1]

*Ibrutinib is defined as an investigational compound as it is not
yet approved by any regulatory authority in the EU. On October 30,
2013, Janssen submitted a New Marketing Authorisation Application
(MAA) to the European Medicines Agency (EMA) for ibrutinib for the
treatment of adult patients with relapsed or refractory CLL/SLL or
relapsed or refractory mantle cell lymphoma (MCL). Ibrutinib is
marketed as IMBRUVICA(R) in the U.S., where it received approval from
the U.S. Food and Drug Administration (FDA) for the treatment of
patients with MCL who have received at least one prior therapy[2] and
for the treatment of patients with CLL who have received at least one
prior therapy.[3]

PFS is the primary endpoint of the RESONATE study, with OS,
overall response rate (ORR) and safety as key secondary endpoints.
These data will be presented in full by Dr. John C. Byrd, M.D
director, Division of Hematology, The Ohio State University
Comprehensive Cancer Center - Arthur G. James Cancer Hospital &
Richard J. Solove Research Institute and lead investigator for
RESONATE (PCYC-1112) during the oral abstract session on Tuesday,
June 3 during the Leukemia, Myelodysplasia, and Transplantation track
at 11:57 a.m. CDT.

In 2011, Janssen and Pharmacyclics Inc. entered into an agreement
to jointly develop and commercialise ibrutinib.

The results from the RESONATE study showed ibrutinib monotherapy
significantly improved PFS, OS and ORR in the difficult-to-treat
patient population, regardless of baseline characteristics. The
median PFS in the ibrutinib arm was not reached because progression
events occurred more slowly than in the ofatumumab arm. The PFS
results represent a 79 percent reduction in the risk of progression
or death in patients treated with ibrutinib compared to ofatumumab.
The OS median was also not reached in either arm because progression
events occurred slowly. The OS results represent a 57 percent
reduction in the risk of death in patients receiving ibrutinib versus
those in the ofatumumab arm.

Additionally, the ORR was significantly higher in patients taking
ibrutinib monotherapy versus ofatumumab monotherapy, regardless of
response criteria or baseline characteristics. Overall, 43 percent of
ibrutinib patients achieved a partial response (PR) compared to only
four percent of patients taking ofatumumab (p<0.0001), following the
International Workshop on CLL (IWCLL) response criteria requiring
response to be confirmed for at least two months. An additional 20
percent of ibrutinib treated patients also achieved a PR with
lymphocytosis. Investigator-assessed response rates were 85 percent
for ibrutinib and 24 percent for patients receiving ofatumumab.
Significantly higher response rates were seen in the ibrutinib arm
consistently across all baseline sub-groups, including those with a
deletion of the short arm of chromosome 17 (del 17p), a genetic
mutation typically associated with poor prognoses, or refractory to a
purine analogue.

"The Phase 3 RESONATE study demonstrated significant
progression-free and overall survival benefits in relapsed or
refractory CLL patients against the current standard of care," said
Professor Ulrich Jäger, Medical University of Vienna, Department of
Medicine, Division of Haematology and Hemostaseology. "The survival
improvements seen with use of ibrutinib in this study are
particularly encouraging as we look toward its potential for use in
patients with difficult-to-treat disease and may offer physicians an
effective single-agent treatment option."

RESONATE is a Phase 3, multicentre, international, open-label,
randomised study that examined ibrutinib monotherapy versus
ofatumumab monotherapy in relapsed or refractory patients with
CLL/SLL who had received at least one prior therapy and were not
considered appropriate candidates for treatment with a purine analog
(n=391). Patients were administered either 420 mg oral ibrutinib
(n=195) once-daily until progression or unacceptable toxicity or
intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300
mg followed by 11 doses at 2,000 mg, per dose and schedule consistent
with local labeling).

The primary endpoint of the study was PFS evaluated by an
Independent Review Committee (IRC), and key secondary endpoints were
OS, ORR and safety. The median follow-up was 9.4 months.

"These data add to the body of clinical data supporting the use of
ibrutinib in previously treated CLL patients," said Jane Griffiths,
Company Group Chairman of Janssen Europe, the Middle East and Africa
(EMEA). "These are the first Phase 3 data for ibrutinib. We're
pleased to see the particularly strong hazard ratios for
progression-free and overall survival and are encouraged that
patients continue to do well on treatment with ibrutinib."

The most common Grade 3 or 4 adverse events (AEs) in the RESONATE
trial (occurring in five percent or more of ibrutinib patients) were
neutropenia (decreased amount of neutrophils in the blood; 16% in the
ibrutinib arm vs. 14% in the ofatumumab arm), pneumonia (7% vs. 5%),
thrombocytopenia (decrease in platelets in the blood; 6% vs. 4%) and
anaemia (5% vs. 8%). The most commonly occurring side effects (AEs in
20 percent or more of patients) were diarrhoea (48% vs.18%), fatigue
(28% vs. 30%), pyrexia (fever; 24% vs. 15%), nausea (26% vs.18%),
anaemia (23% vs. 17%) and neutropenia (21% vs. 15%). Atrial
fibrillation of any grade was noted more frequently in patients
receiving ibrutinib (n=10 patients) versus with ofatumumab (n=1
patient), leading to discontinuation of ibrutinib in one patient.

Treatment discontinuation due to progressive disease were 5% in
the ibrutinib arm and 19% in the ofatumumab arm. Treatment
discontinuations due to adverse events were low in both study arms,
with 4% of patients in both treatment arms (eight patients in the
ibrutinib arm and seven patients in the ofatumumab arm). Treatment
discontinuation due to death occurred in 4% of patients in the
ibrutinib arm (eight patients) and 5% of patients in the ofatumumab
arm (nine patients). These events were most commonly infectious in
nature. Total treatment exposure was longer for the ibrutinib arm
(approximately 8.6 months, versus 5.3 months on ofatumumab).

In January 2014 [http://www.investor.jnj.com/releaseDetail.cfm?Re
leaseID=817572&year=2014 ], RESONATE was stopped early at the
unanimous recommendation of an Independent Data Monitoring Committee
(IDMC) based on a planned interim analysis which concluded that the
study showed a significant difference in PFS as compared to the
control (the primary endpoint of the study). The IDMC recommended
that the sponsor provide access to ibrutinib to patients in the
ofatumumab arm. The data served as the basis of the April 2014 [http
://www.investor.jnj.com/releaseDetail.cfm?ReleaseID=838979&year=2014
] supplemental New Drug Application (sNDA) to the U.S. Food and Drug
Administration (FDA) in relapsed or refractory CLL patients who have
received at least one prior therapy.

CLL is a slow-growing blood cancer of white blood cells called
lymphocytes, most commonly B cells.[4] CLL is the most common adult
leukemia in the Western world and predominantly a disease of the
elderly with a median age of diagnosis of 72.[4],[5] This orphan
disease often eventually progresses; patients are faced with fewer
treatment options and are often prescribed multiple lines of therapy
as they relapse or become resistant to treatments.[6] SLL is a
slow-growing lymphoma in which too many immature white blood cells
cause lymph nodes to become larger than normal.[4]

About Ibrutinib

Ibrutinib is an investigational compound within a class of
medicines called Bruton's tyrosine kinase (BTK) inhibitors. BTK is an
important protein involved in mediating the cellular signalling
pathways which control B cell maturation and survival. In malignant B
cells, there is excessive signalling through the B cell receptor
signalling (BCR) pathway, which includes BTK. The malignant cell
ignores the natural signal to die and continues to develop and
proliferate. Malignant cells migrate and adhere to protective
environmental areas such as the lymph nodes where they proliferate
and survive. Ibrutinib is specifically designed to target and inhibit
BTK. Ibrutinib forms a strong covalent bond with BTK, which inhibits
the excessive transmission of cell survival signals within the
malignant B cells and stops their excessive build up in these
protected environmental areas. The efficacy and safety of ibrutinib
alone and in combination with other treatments is being studied in
several blood cancers including CLL, MCL, Waldenstrom's
macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL),
follicular lymphoma (FL) and multiple myeloma (MM).[7-11]

Ibrutinib is marketed as IMBRUVICA(R) in the U.S., where it
received approval from the U.S. Food and Drug Administration (FDA)
for the treatment of patients with MCL who have received at least one
prior therapy on November 13, 2013,[2] followed by further indication
approval for the treatment of patients with CLL who have received at
least one prior therapy on February 12, 2014.[3] The approval made
ibrutinib one of the first medications to receive FDA approval via
the Breakthrough Therapy Designation pathway (a new U.S. FDA
mechanism intended to expedite the review and development for new
medicines showing great promise to treat serious or life-threatening
conditions where there is currently an unmet medical need).

About Janssen

Janssen Pharmaceutical Companies of Johnson and Johnson are
dedicated to addressing and solving the most important unmet medical
needs of our time, including oncology (e.g. multiple myeloma and
prostate cancer), immunology (e.g. psoriasis), neuroscience (e.g.
schizophrenia, dementia and pain), infectious disease (e.g. HIV/AIDS,
hepatitis C and tuberculosis), and cardiovascular and metabolic
diseases (e.g. diabetes). Driven by our commitment to patients, we
develop sustainable, integrated healthcare solutions by working
side-by-side with healthcare stakeholders, based on partnerships of
trust and transparency. More information can be found on
http://www.janssen-emea.com/ [http://www.janssen-emea.com ]. Follow
us on http://www.twitter.com/janssenEMEA for our latest news.

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 us. In looking to find innovative ways to
address the cancer challenge, our 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 tumour
microenvironment.

(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 unknown risks or uncertainties materialize,
actual results could vary materially from the expectations and
projections of Janssen Research & Development, LLC, any of the other
Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and
uncertainties include, but are not limited to: challenges inherent in
new product development, including obtaining regulatory approvals;
competition, including technological advances, new products and
patents attained by competitors; challenges to patents; changes in
behavior and spending patterns or financial distress of purchasers of
health care products and services; changes to governmental laws and
regulations and domestic and foreign health care reforms; general
industry conditions including trends toward health care cost
containment; and increased scrutiny of the health care industry by
government agencies. 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 December 29,
2013, including in Exhibit 99 thereto, and our subsequent filings
with the Securities and Exchange Commission. Copies of these filings
are available online at http://www.sec.gov, http://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.)

[*]Disclaimer: Dr. Byrd serves as national principal investigator
of this Pharmacyclics-sponsored clinical study. He has served as an
unpaid advisor to both Pharmacyclics and Janssen in developing the
compound ibrutinib. Dr. Byrd does not have a financial interest in
either company.

References

1) Byrd, JC. Ibrutinib versus Ofatumumab in Previously Treated Chronic
Lymphoid Leukemia. NEJM. 2014. Available from: http://www.nejm.org/
[http://www.nejm.org ]. Accessed May 2014.
2) U.S. Food and Drug Administration. Press Announcement: FDA approves Imbruvica
for rare blood cancer. Nov 2013. Available from:
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm374761.htm. Accessed
May 2014.
3) U.S. Food and Drug Administration. Press Announcement: FDA approves Imbruvica
to treat chronic lymphocytic leukemia. Feb 2014. Available from:
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm385764.htm. Accessed
May 2014.
4) American Cancer Society. "Leukemia--Chronic Lymphocytic". Available from:
http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed
April 2014.
5) Parker, T. Chronic lymphocytic leukemia: prognostic factors and impact on
treatment. Discovery Medicine. 2011; 57.
6) Veliz M, Pinilla-Ibarz J. Treatment of relapsed or refractory chronic
lymphocytic leukemia. Cancer Control. 2012 Jan;19(1):37-53.
7) Qiu Y, Kung HJ. Signaling network of the Btk family kinases. Oncogene
2000;19:5651-61.
8) Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of
B-cell differentiation. Nat Rev Immunol. 2002;2:920-32.
9) Puri KD, di Paolo JA, Gold MR. B-cell receptor signaling inhibitors for
treatment of autoimmune inflammatory diseases and B-cell malignancies. Int Rev Immunol
2013;32:397-427.
10) Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a
therapeutic target in CLL. Blood 2012;120:1175-84.
11) Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK
inhibitors in clinical development. J Hematol Oncol 2013;6:59.

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