Ibrutinib (PCI-32765): BTK Inhibitor for Oncology

At Pharmacyclics, we have developed an orally administered, selective, and irreversible BTK inhibitor called ibrutinib (PCI-32765). Ibrutinib is currently in clinical development and is being investigated in patients with B cell malignancies that includes chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma (MM, cancer of plasma cells, a type of white blood cell present inbone marrow). Ibrutinib blocks BCR signaling in human B-cells, but does not appear to affect T cell (T-lymphocyte) receptor (TCR) signaling.

Preclinical Experience

In preclinical models, inhibition of BTK by ibrutinib led to apoptosis in multiple malignant B-cell lines in vitro and inhibited B-cell lymphoma progression in vivo. Preclinical data presented at the 2011 American Society of Hematology (ASH) Annual Meeting suggested a hypothesis whereby ibrutinib directly affects CLL cells by inducing programmed cell death, but also blocks the ability of CLL cells to migrate towards and adhere to lymph nodes, a protective environment where the tumors grow. Preliminary clinical results in CLL and in MCL also presented at the 2011 ASH Annual Meeting appear to support this hypothesis.

In MM, ibrutinib also inhibited cell migration and adhesion, blocked proliferation of putative myeloma (cancer of plasma cells)stem cells, and strongly inhibited the over activation of bone cells (osteoclasts) that is characteristic of this disease. These data were presented at the 2011 ASH annual meeting.

Clinical Development

Phase I in B-cell Malignancies

A Phase I doses escalation study evaluating the safety, tolerability and pharmacokinetics of single-agent ibrutinib has been completed in patients with relapsed / refractory B-cell malignancies; reported at the 2011 International Conference on Malignant Lymphoma Meeting in Lugano, Switzerland. The study examined the safety of ibrutinib, and whether the treatment schedule was tolerated by patients in the trial.

Phase I/II in B-cell Malignancies

The ongoing B-cell malignancy program includes several clinical trials:

• Phase Ib/II trials are ongoing in relapsed or refractory CLL/SLL
• Phase II trials in CLL/SLL, MCL, DLBCL, and MM

CLL/SLL: Updated results from the Phase Ib/II relapsed or refractory CLL trial was presented at the 2012 ASH Annual Meeting.

MCL: A Phase II relapsed or refractory MCL trial was also presented at the 2012 ASH Annual Meeting.

Overall, these data support Phase III evaluation of ibrutinib as a single agent in patients with previously treated CLL/SLL and MCL.

DLBCL: A Phase II trial of single agent ibrutinib in relapse and refractory DLBCL has been initiated.

Patients and caretakers are invited to visit ClinicalTrials.gov for more information regarding ibrutinib in clinical trials.

B-cell Lymphoma

Non-Hodgkin lymphoma (NHL) is a type of malignant disease that occurs within the lymphatic system and the fifth most common form of cancer. It is caused by the abnormal proliferation of white blood cells, which spreads through the lymphatic system. NHL can occur at any age and is often marked by lymph nodes that are larger than normal, fever, and weight loss. NHL can be broadly classified into two main clinical categories: indolent lymphomas, mainly characterized as follicular lymphomas, which tend to grow relatively slowly; and aggressive lymphomas, mainly typified as diffuse large B-cell lymphomas (DLBCL), which grow much more rapidly.

Partnering

Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson

In December 2011, the company entered into a worldwide collaboration with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to co-develop and co-commercialize ibrutinib. Pharmacyclics and Janssen will collaborate on the development of ibrutinib for oncology and other indications, excluding inflammation and immune mediated conditions.