Agreement covers Phase I and II trials with Btk inhibitor against malignancies including NHL and multiple myeloma.

Pharmacyclics inked a five-year Cooperative Research and Development Agreement (CRADA) with the National Cancer Institutes (NCI) to progress development of its Bruton’s tyrosine kinase (Btk) inhibitor, PCI-32765, for the treatment of hematologic malignancies. Under terms of the deal, NCI’s Division of Cancer Treatment and Diagnosis plans to sponsor Phase I and II studies with the oral drug against various blood cancers including non-Hodgkin lymphoma (NHL) and multiple myeloma. The PCI-32765 is currently in Phase I trials for the treatment of lymphoma/CLL, and is being prepared for Phase II studies in CLL, mantle cell lymphoma, and diffuse large B-cell lymphoma, either as monotherapy or in combination with other anticancer treatments. Positive data from a Phase Ib/II study evaluating PCI-32765 patients with chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL) were presented in June.

Btk is a tyrosine kinase that plays a critical role in B cell maturation and activation, Pharmacyclics explains. PCI-32765 is a small molecule inhibitor that has been shown to lead to apoptosis in multiple malignant B-cell lines as well as inhibited B-cell lymphoma progression in vivo. Studies have suggested a model whereby PCI-32765 directly affects CLL cells by inducing programmed cell death, and blocking the ability of CLL cells to migrate to and to adhere to lymph nodes.

Btk is also a key component of signaling Fc-gamma signaling in myeloid cells, and inhibition of Btk activity is expected to reduce two major components of autoimmune diseases: pathogenic autoantibody production by B cells, and pro-inflammatory cytokines produced by myeloid cells, Pharmacyclics adds. To this end the firm is in addition evaluating Btk inhibitors for their potential use in the treatment of autoimmune diseases. It says lead candidate PCI-45292 has been shown to be more potent in a mouse model of collagen-induced arthritis than either PCI-32765 or methotrexate.

Pharmacyclics’ clinical pipeline is headed by its histone deacetylase (HDAC) inhibitor candidate, PCI-24781, which is in Phase II development for the treatment of lymphoma, and Phase I development for sarcoma. The HDAC inhibitor program has been partnered with Servier, under a 2009 agreement under which the French firm has an exclusive license to Pharmacyclics’ pan-HDAC inhibitors worldwide, excluding the U.S.

Pharmacyclics’ radiation and chemotherapy sensitizing agent, motexafin gadolinium (MGd; PCI-0120), is also in Phase II development. The program is being sponsored by the NCI, which is funding a Phase I/II multicenter study evaluating MGd administered in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma multiforme.

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