Clinical and pre-clinical data presentedat the 54th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA, December 8 – 11, 2012, demonstrates that the investigational agent PCI-32765 (ibrutinib; Pharmacyclics?) offers prolonged progression free survival with a manageable and predictable safety profile in high unmet need indications inrelapsed and refractory, high risk, advanced CLL/SLL and MCL patients and in addition in treatment naive elderly CLL patients.

Ibrutinib targets and selectively inhibit Bruton’s tyrosine kinase (Btk), a type of kinase enzyme implicated in agammaglobulinemia (Bruton’s agammaglobulinemia; XLA), a primary immunodeficiency X-linked (located on the X chromosome) disease (only male offspring being effected) occurring in approximately 1 in 250,000 males. At least 400 mutations of the Btk gene have been identified. XLAdisruptsthe function of BTK. In the absence of Btk, B-cells do not come about or mature. Males with XLA have a total or almost total absence of B-cells and very low levels of circulating antibodies.

Btk is known to be expressed in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and multiple myeloma (MM).

While the exact mechanism of action remains unknown, Bruton’s tyrosine kinase it plays a crucial role in B-cell maturation(B-cellsare involvedin the productions of antibodies) as well as mast cell activation (cells involved in allergic responses)through the high-affinity IgE receptor..

Btk isa key mediator of at least three critical B-cell pro-survival mechanisms occurring in parallel, regulating B-cell apoptosis, cell adhesion, and lymphocyte migration and homing. Researchers have shown that the pre-clinical and clinical datais consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to tumor-protective microenvironments.

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Overactive B calles
When B-cells are overactive, the immune system produces inflammatory cells and antibodies that begin to attack the body’s own tissue, leading to autoimmune diseases.

Also, B-cell lymphomas and leukemias, which are common blood cancers,
result from mutations acquired during normal B-cell development leading to uncontrolled B-cell proliferation and B-cell malignancies. Specific cancer indications include non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia(CLL), and as a potential inhibitor of tumor stem cells (also known as Tumor Initiating Cells or TIC’s) that have been identified in certain cancers. In addition, Btk inhibitors have potential for treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and allergic diseases such as eosoniphilic esophagitis.

Effectiveness of ibrutinib
The effectiveness of ibrutinib alone or in combination with other treatments is being studied in several B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, relapsed/refractory mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma and multiple myeloma. A comprehensive late-stage Phase II and III program is under way.

Single-agent study
Findings from an ongoing, open-label, Phase II, single-agent study (PCYC-1104-CA)suggests that in patients with relapsed (meaing that disease has returned after an initial partial or total remission)or refractory (indicating that the cancer does not respond to current treatment)mantle cell lymphoma (MCL), both those who were bortezomib-naive and bortezomib-exposed, the investigational oral agent ibrutinib resulted in high and durable responses and was generally well tolerated.

Mantle cell lymphoma(MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) that usually occurs in middle-aged or older adults. The disease typically begins in the lymph nodes but can spread to other tissues, such as bone marrow and liver. In the United States, there are approximately 70,130 new cases of NHL and 4,600 new cases of MCL each year.

In this study, 111 patients (63 bortezomib-naive and 48 bortezomib-exposed) received ibrutinib 560 mg daily for continuous dosing until disease progression.A total of 110 patientswere evaluable for efficacy. The primary endpoint of the study is ORR. Duration of response and safety evaluation are important secondary endpoints. The median follow-up time was 9.2 months, with a range of time to response to treatment of 1.4 to 16.4 months.

The study results presented by lead investigator Michael L. Wang, M.D., associate professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center,showed an overall response rate (ORR) of 68%, including a complete response (CR) of 22% and a partial response (PR) of 46% with a median progression free survival (PFS) estimated at 13.9 months. Results were similar between the bortezomib-naive and bortezomib-exposed patients.

Long-term follow up of the initial 51 patients enrolled in this study that were presented last year at Annual Meeting of the American Society of Hematology showingthat there was an incremental improvement in the response rate over time. The ORR increased for this patient subset from 69% in 2011 to an ORR of 75% in 2012, with the CR increasing from 16% to 39% over the same period.

Commenting on these results, Wang said: “With continued follow-up, the overall response rate is similar to what we’ve reported before. Now with a larger number of patients studied, we see the overall response rate remains durable and the safety profile continues to appear manageable.What is particularly encouraging is that with longer follow-up there is an incremental increase in the number of patients who achieve complete response. The data build on our knowledge and supports the continued study of ibrutinib to determine its potential role as a treatment option for patients with relapsed or refractory MCL, a population of patients that is currently difficult to treat.”

Treatment-emergent AEs
Safety data were available for 111 patients in the trial. Patients treated with ibrutinib experienced treatment-emergent adverse events (AEs) that were consistent with previously reported data. Treatment-emergent AEs were mainly grade 1 or 2. Treatment-emergent AEs of all grades occurring in 20% or more patients were diarrhea, fatigue, nausea, upper respiratory tract infection and dyspnea (shortness of breath). Pneumonia was the only grade 3 or higher treatment-emergent AE occurring in 5% or more patients.

“These resultsrealy suggest that ibrutinib provided a durable response in the treatment of mantle cell lymphoma in this PhaseII study,” notedBob Duggan, CEO and Chairman of the Board of Directors of Pharmacyclics. “This year, the meeting of the American Society of Hematology has been filled with exciting validations of ibrutinib and its potential in blood cancers.”

For more information:
Oral Presentation: Interim Results of an International, Multicenter, Phase 2 Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Author: Wang M (University of Texas MD Anderson Cancer Center).

Abstract 189 (Oral Presentation) The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Na?ve (TN) and Relapsed or Refractory (RR) CLL or SLL Patients Including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patien
ts in a Phase Ib/II Study. Author:Byrd JC (The Ohio State University, Columbus, OH)

Abstract 187 The Btk inhibitor Ibrutinib in combination with rituximab is well tolerated and displays profound activity in high-risk Chronic Lymphocytic Leukemia (CLL) patients. Author: Burger JA(Anderson Cancer Center, Houston, TX)

Oral presentation: The Bruton’s Tyrosine Inhibitor Ibrutinib (PCI-32765) is Active and Tolerated in Relapsed Follicular Lymphoma. Author:Fowler N.(UT MD Anderson Cancer Center, Houston, TX)

Figure 1: BTK plays a critical role in signaling via B-cell receptor (BCR) signaling. Btk inhibitors block B-cell activation and auto-antibody formation.Illustration courtesy ofPharmalytics Inc.

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