Btk Inhibitors

Bruton's Tyrosine Kinase Inhibitor Program

Pharmacyclics is pioneering the development of orally bioavailable inhibitors of Bruton’s tyrosine kinase CloseKinase

An enzyme that activates other enzymes by addition of a chemical group (phosphate).

(Btk), a signaling molecule that is critical for the activity of B-cells (i.e. cells that lead to antibody CloseAntibody

A protein& CloseProtein

A class of molecules (including enzymes, antibodies, or structural proteins) that are built from amino acid components to perform a wide range of functions in the cell.

nbsp;produced by the immune system to recognize, bind, and destroy foreign materials in the body.

production) and mast cells (i.e. cells involved in allergic response). When B-cells are overactive, the immune system produces inflammatory cells and antibodies that begin to attack the body’s own tissues, leading to autoimmune CloseAutoimmune

An immune response by the body against its own cells or tissues.

diseases. Also, B-cell CloseB-cell

A cell type in the immune system that is responsible for producing antibodies.

lymphomas and leukemias, which are common blood cancers, result from mutations acquired during normal B-cell development that lead to uncontrolled B-cell proliferation and B-cell malignancies.

Specific hematologic malignancies being targeted for intervention include non-Hodgkin’s lymphoma CloseLymphomaA cancer that is detected in the lymph nodes and ducts as well as in the blood. (NHL) and chronic lymphocytic leukemia CloseLeukemiaA cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes).(CLL). In addition, preclinical ClosePreclinical

Studies done in animals or in cell cultures prior to testing a new drug in human clinical trials.

studies have shown that Btk inhibitors have potential for treatment of autoimmune diseases such as rheumatoid arthritis CloseRheumatoid arthritisAn auto-immune disease that causes the swelling and stiffening of the joints. (RA) and systemic CloseSystemic

Affecting the entire body.

lupus CloseLupus

A chronic inflammatory disease that occurs when the body's immune system attacks its own tissues and organs.

erythematosus CloseErythematosusA connective tissue disease such as lupus. (SLE).

Pharmacyclics has two programs based on a new class of proprietary Btk inhibitors. The first program is focusing on the clinical developoment of PCI-32765, a Btk inhibitor optimized for oncology CloseOncologyThe study and treatment of cancer. and currently in a Phase I clinical trial. ClosePhase I Clinical Trial

One step in the drug approval process during which doctors establish the safety of a new drug and its best dose, administration, and regimen.

The second program is at the preclinical stage and is optimizing Btk inhibitors for autoimmune indications with an IND submission anticipated for the first half of 2011.

Animation of the Mechanism of Action: Btk Inhibition

Btk plays a critical role in B-cell receptor (BCR) signaling. Btk inhibitors block B-cell activation and auto-antibody formation.

Human Genetics Provide Insights into the Clinical Safety of Selective Btk Inhibition

Our approach to disrupting B-cell signalling involves the identification of small molecules that potently and selectively inhbit the tyrosine kinase CloseTyrosine KinaseA type of enzyme involved primarily in signaling between cells.Btk. In a human genetic disorder known as X-linked agammaglobulinemia CloseAgammaglobulinemia

A genetic immunosuppressive disease in humans that results from a mutated and inactivated Btk gene.

(XLA), B cell development is blocked by mutations in the gene that codes for Btk on the X chromosome. As an X-linked disease, XLA occurs only in male offspring (approximately 1 in 250,000 males). Males with XLA have a total or almost total absence of B-cells and very low levels of circulating antibodies, but no significant abnormalities or loss of function outside of the immune system.

Market Size

Pharmacyclics will generate proof-of-concept data in both lymphoma and RA indications. Pharmacyclics is not aware of any competitors in clinical trials with other Btk inhibitors. The anti-B-cell biologics CloseBiologics

Medicinal products that have been isolated from natural sources such as animals or humans.

including Rituxan® CloseRituxan

An antibody therapy for certain types of non-Hodgkin lymphoma and autoimmune conditions including rheumatoid arthritis.

and Lymphostat B are associated with massive B-cell depletion and lack of convenient oral dosing. The overall Non-Hodgkin’s Lymphoma market is projected to increase from $3.3 billion in 2007 to $4.7 billion in 2017 (3.6% a year). The market for rheumatoid arthritis (RA) therapies will show robust growth between 2009 and 2017; major market sales will nearly double to $13.4 billion in 2017.

Patents

A variety of non-provisional PCT applications have been filed for methods, uses and composition of the lead clinical development compound (PCI-32765), the additional Btk inhbitors being optimized, and for the Btk fluorescent probe CloseFluorescent ProbeA fluorescent marker used for imaging. (PD marker). For PCI-32765, we expect global patent protection until at least December 2026 (this excludes pharmaceutical extensions).

Partnering

Pharmacyclics will be seeking strategic pharma / biotech partnership(s) to further develop and commercialize PCI-32765 and our series of Btk inhibitors.