Pharmacyclics Hopes to Break Through With Blood Cancer Drug Ibrutinib

Published: Friday, Aug 30, 2013
Physicians' Financial News Sunnyvale, California-based Pharmacyclics has yet to lay claim to any FDA-approved therapeutics since it was formally incorporated in 1991, but that may very well change in the near future as a first-in-class drug for certain B-cell malignancies is proving quite effective in clinical trials and even receiving some new designations from the FDA designed to aid in its development.

The company’s goal is to discover and develop small-molecule drugs that can be used to treat cancer and certain immune disorders. The drug that is furthest along in development is ibrutinib (PCI-32765), a selective, irreversible Bruton’s tyrosine kinase (BTK) inhibitor being investigated in B-cell hematologic malignancies for its ability to inhibit tumor cell proliferation, disrupt tumor cell adhesion, and induce apoptosis in malignant cells. Pharmacyclics has a global partnership with Janssen Biotech, a division of Johnson & Johnson, for the development of this drug.

The company has had an active year in 2013, especially when it comes to ibrutinib. Since the beginning of the year, ibrutinib has received three separate FDA Breakthrough Therapy designations for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with deletion of the short arm of chromosome 17; relapsed or refractory mantle cell lymphoma (MCL) after prior treatment; and Waldenström’s macroglobulinemia. These are designed to allow for more meetings to take place during the development process, potentially reduce the number of patients required to enroll in further clinical trials, and subsequently shorten the length of those trials when it is appropriate.

Pharmacyclics Pipeline

Drug Development Stage
Ibrutinib (PCI-32765)*
Chronic Lymphocytic Leukemia NDA accepted by the FDA based on single-arm phase II study; phase III research is ongoing
Mantle Cell Lymphoma NDA accepted by the FDA based on single-arm phase II study; phase III research is ongoing
Diffuse Large B-Cell Lymphoma Phase II
Multiple Myeloma Phase II
Abexinostat Hydrochloride (PCI-24781)
Follicular Lymphoma and Mantle Cell Lymphoma Phase II
Pancreatic Cancer Phase II

*Partnering with Janssen Research & Development, LLC NDA indicates new drug application. (Sources:;

In July, Pharmacyclics announced that a new drug application had been submitted to the FDA for ibrutinib as a treatment for patients with previously treated CLL/SLL and previously treated MCL based on previously published phase II clinical trial results that showed robust activity, including high response rates and progression-free survival. In late August, the FDA accepted the filing, which triggered a $75 million milestone payment to Pharmacyclics under its Collaboration Agreement with Janssen Biotech.

Ibrutinib is not the only drug in Pharmacyclics’ oncology pipeline. Another compound under investigation is abexinostat hydrochloride (PCI-24781), an oral histone deacetylase (HDAC) inhibitor. This is another area of considerable interest, since HDACs are able to catalyze the removal of acetyl groups from lysine residues on histones, transcription factors, and heat shock proteins and are therefore responsible for widespread transcriptional changes and other cellular effects. A phase I dose escalation study found that abexinostat is well tolerated and demonstrated promising durable responses in patients with indolent lymphomas and Hodgkin lymphomas. A phase Ia/b dose escalation and expansion study designed to determine the safety, tolerability, and maximum-tolerated dose of abexinostat in combination with pazopanib (Votrient, GlaxoSmithKline) for the treatment of solid tumors is recruiting patients. Pharmacyclics acquired abexinostat in 2006 from Celera Genomics.

Pharmacyclics has identified another potential target expressed in several different tumors, the cell surface protein tissue factor. This is overexpressed in breast, colon, lung, prostate, ovarian, and pancreatic cancers. A proteolytic enzyme called Factor VII is able to bind to the tissue factor protein and induce intracellular signaling that can lead to increased expression of the tumor proteins interleukin-8 and vascular endothelial growth factor. The company has developed a small-molecule inhibitor called PCI-27483 that selectively inhibits activated Factor VII and is designed to inhibit intracellular signaling involved in tumor growth and metastases, as well as thromboembolism. A phase II trial in patients with metastatic or locally advanced pancreatic cancer who are being treated with gemcitabine is active but not recruiting.

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