Ibrutinib Phase 2 Data: Analyses Show Efficacy with Ibrutinib Monotherapy in Patients with Relapsed or Refractory Mantle Cell or Diffuse Large B-cell Lymphoma

RARITAN, N.J., June 16, 2013 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen), today announced the results of two separate Phase 2 studies suggesting that ibrutinib, an investigational oral Bruton's tyrosine kinase (BTK) inhibitor, shows efficacy when used as a monotherapy in patients with relapsed/refractory mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL). The studies were presented today at the European Hematology Association (EHA) 18^th Annual Congress in Stockholm, Sweden. Ibrutinib is being jointly developed by Janssen and Pharmacyclics, Inc.

"Our comprehensive clinical development program is studying ibrutinib across a variety of B-cell malignancies; these patients, including those with DLBCL and MCL, are in real need of new treatment options," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Therapeutic Area Head, Janssen R&D. "It's particularly exciting to observe the differences in response rates now as compared to earlier data from this study that were presented several months ago."

Ibrutinib in Relapsed/Refractory MCL
In relapsed/refractory MCL patients treated with ibrutinib monotherapy the key results include:

• An overall response rate (ORR) of 68%, including a complete response (CR) of 21% and a partial response (PR) of 47%.
• The estimated median duration of response (DOR) in all responding patients was 17.5 months. Median progression-free survival (PFS) was 13.9 months. Median overall survival (OS) has not yet been reached, but is estimated to be 58% at 18 months.
• Treatment-emergent adverse events (AEs) were seen in greater than 20% of patients and included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%) and decreased appetite (21%) and were consistent with previously reported data. Only 7% of patients discontinued due to an AE.

"The results of this single-agent study are encouraging. It is exciting to see how active ibrutinib is in the treatment of relapsed and refractory mantle cell lymphoma, particularly as the responses appear to last.," said Professor Simon Rule, Consultant Haematologist in the Department of Haematology at the Derriford Hospital in Plymouth, United Kingdom. "What is equally important is that no new safety signals were observed during this study."

The MCL study was a Phase 2 multicenter, open-label, study including 111 patients with relapsed/refractory MCL at 18 sites internationally. Patients had received a median of three prior therapies and were enrolled into two cohorts based on prior bortezomib exposure – either bortezomib-naive (n=63) or bortezomib-exposed (n=48), with both groups receiving 560 mg of ibrutinib orally, once a day. The primary endpoint of the study was ORR. Secondary endpoints included DOR, PFS, OS and frequency and severity of adverse events.

Ibrutinib in Relapsed/Refractory DLBCL
In the second Phase 2 study involving patients with relapsed/refractory DLBCL (n=70), investigators tested the hypothesis that ibrutinib would be more active in the Activated B-cell-like (ABC) subtype compared to the Germinal Center B-cell-like (GCB) subtype, given that the ABC subtype is dependent on the B-cell antigen receptor (BCR) pathway. Ibrutinib targets the BCR pathway by inhibiting BTK, a critical mediator in malignant B-cell growth and proliferation. Results of the study show that:

• Patients with the ABC subtype showed a significantly greater response to ibrutinib monotherapy compared to those with the GCB subtype (ORR = 41% vs 5%, p=0.007, Fisher's exact test).
• Median OS was 9.76 months for the ABC subtype, compared to 3.35 months for the GCB subtype (p=0.05).
• Within the ABC subtype group, only patients who had a CD79B mutation responded to treatment; patients with only an MYD88 mutation did not respond to treatment, suggesting a MYD88-dependent but BCR-independent pathogenesis for some DLBCL tumors.
• Safety data from 70 patients identified no new safety signals. Grade 3 or higher AEs were seen in greater than 3% of patients and included fatigue (9%), hyponatremia (9%), pneumonia (7%), dehydration (4%), and pleural effusion (4%).

"These results indicate the important function BTK plays in the survival of ABC type DLBCL," explained presenting investigator Sven de Vos, M.D., Ph.D., Associate Professor in the Department of Medicine at the UCLA Medical Center, Los Angeles, who reported the results at the EHA Congress today. "Seeing clinically meaningful responses among the ABC subtype was encouraging, as patients at this stage are challenging to treat. Additional trials among this patient group are ongoing."

The DLBCL study was a Phase 2 multicenter, open-label, study that included 70 patients with relapsed/refractory DLBCL with a median of three prior therapies. All patients underwent gene expression profiling to determine their DLBCL subtype, 29 patients were identified with the ABC subtype, and 20 with the GCB subtype. Patients received ibrutinib 560 mg orally, once a day, until disease progression or unacceptable toxicity. The primary objective of the study was to assess ORR categorized by subtype, with secondary objectives being to assess the safety and tolerability of ibrutinib in people with DLBCL.

About Ibrutinib
Ibrutinib is an investigational, oral BTK inhibitor. The effectiveness and safety of ibrutinib alone or in combination with other treatments is being studied in several B-cell malignancies.

Janssen Biotech, Inc. and Pharmacyclics entered into a collaboration and license agreement in December 2011 to co-develop and co-commercialize ibrutinib. The regulatory filing for ibrutinib in MCL is expected to be made prior to the end of the third quarter of 2013. Details about the complete ibrutinib clinical program is posted on clinicaltrials.gov.

To date, ibrutinib has been granted three Breakthrough Therapy Designations by the U.S. Food & Drug Administration (FDA) as a monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with deletion of the short arm of chromosome 17 (del17p); patients with relapsed/refractory MCL who have received prior therapy, and in patients with Waldenstrom's macroglobulinemia (WM). The implications of Breakthrough Therapy Designation cannot be determined at this time.

About B-Cell Malignancies
Both MCL and DLBCL are part of a family of blood cancers which originate from malignant B-cells. Unlike healthy B-cells, malignant B-cells ignore signals to die and continue to develop and reproduce in the lymph.[1][2][3] When a malignancy is described as 'relapsed', it means that it has returned after an initial partial or total remission.[4] 'Refractory' refers to cancer that has become resistant to current treatment.[5]

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 innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development and Janssen Biotech are part of the Janssen Pharmaceutical Companies. Please visit http://www.janssenrnd.com for more information.

(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 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 and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; 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; 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 Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2012. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

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References

[1] Murphy K, Travers P, Walport M. Janeway's Immunobiology. 7th ed. Garland Science; 2008:257-320.
[2] Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol. 2002. Dec; 2(12):920-32.
[3] LeBien TW, Tedder, TF. B lymphocytes: how they develop and function. Blood. 2008; 112(5):1570-1580.
[4] PubMed Health. Relapse Definition. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032674/def-item/glossary_CDR0000045866/?report=objectonly. Accessed November 19, 2012.
[5] PubMed Health. Refractory Cancer Definition. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032674/def-item/glossary_CDR0000045863/?report=objectonly. Accessed November 19, 2012.

SOURCE Janssen