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Pharmacyclics is getting a priority review of its blood cancer treatment by federal regulators. A priority review shortens a drug evaluation by the U.S. Food and Drug Administration from 10 months to six. The acceptance of the application triggers a $75 million milestone payment to Pharmacyclics from Johnson & Johnson’s Janssen unit.
Ibrutinib (USAN), also known as PCI-32765, is an experimental drug candidate for the treatment of various types of cancer. It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton tyrosine kinase (Btk). Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson’s Janssen Pharmaceutical division for B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.. Ibrutinib was first designed and synthesized at Celera Genomics by Zhengying Pan, who along with a team of chemists and biologists reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK. These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 (known as compound 13 in the Pan et al paper) that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo . Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug.    It also has potential effects against autoimmune arthritis.
It has given good results in two phase II clinical trials.
In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment. In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.
In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.
Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor. Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments.
- ^ Statement on a Nonproprietary Name Adopted by the USAN Council
- ^ Pan, Z; Scheerens, H; Li, SJ; Schultz, BE; Sprengeler, PA; Burrill, LC; Mendonca, RV; Sweeney, MD et al. (2007). “Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase”. ChemMedChem 2 (1): 58–61. doi:10.1002/cmdc.200600221. PMID 17154430.
- ^ Celera Genomics Announces Sale of Therapeutic Programs to Pharmacyclics
- ^ United States patent 7514444
- ^ Honigberg, LA; Smith, AM; Sirisawad, M; Verner, E; Loury, D; Chang, B; Li, S; Pan, Z; Thamm, DH; Miller, RA; Buggy (2010). “The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy”. Proceedings of the National Academy of Sciences of the United States of America 107 (29): 13075–80. doi:10.1073/pnas.1004594107. PMID 20615965. Unknown parameter
- ^ Janssen Biotech, Inc. Announces Collaborative Development and Worldwide License Agreement for Investigational Anti-Cancer Drug, PCI-32765
- ^ Clinical trials involve PCI-32765
- ^ Clinical trials involve ibrutinib
- ^ Chang, BY; Huang, MM; Francesco, M; Chen, J; Sokolove, J; Magadala, P; Robinson, WH; Buggy, JJ (2011). “The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells”. Arthritis Research & Therapy 13 (4): R115. doi:10.1186/ar3400. PMID 21752263.
- ^ Good News Continues for Ibrutinib in CLL. 8 Dec 2012
- ^ Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, Flynn J, Jones J, Blum KA, Buggy J.J., Hamdy A, Johnson AJ, Byrd JC. (2011) Bruton’s tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 117: 6287-6296
- ^ The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.J Clin Oncol 30, 2012 (suppl; abstr 6507)
- ^ Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O’Brien S, Chiorazzi N, Burger JA. (2012) The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 119: 1182-1189.
- ^ de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M. (2012) The clinically active BTK inhibitor PCI-32765 targets B-cell receptor (BCR)- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 119: 2590-2594.
Pharmacyclics Announces Third Breakthrough Therapy Designation for Ibrutinib from the U.S. Food and Drug Administration
SUNNYVALE, Calif., April 8, 2013
Pharmacyclics, Inc. announced today that the U.S. Food and Drug Administration (FDA) has granted an additional Breakthrough Therapy Designation for the investigational oral agent ibrutinib as monotherapy for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients with deletion of the short arm of chromosome 17 (deletion 17p). Patients harboring a deletion within chromosome 17 generally have poor response to chemoimmunotherapy and have limited treatment options. The presence of deletion 17p is one of the worst prognostic factors in patients with CLL.
In February 2013, FDA granted Breakthrough Therapy Designations for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) and as a monotherapy for the treatment of patients with Waldenstrom’s macroglobulinemia (WM), both of which are also B-cell malignancies. Ibrutinib is jointly being developed by Pharmacyclics and Janssen for treatment of B-cell malignancies.
The Breakthrough Therapy Designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases where “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” The designation of a drug as a Breakthrough Therapy was enacted as part of the 2012 Food and Drug Administration Safety and Innovation Act. Pharmacyclics, together with Janssen, is working with the FDA to determine the implications of this Breakthrough Therapy Designation to the ongoing and planned development and the FDA filing requirements for the use of ibrutinib in CLL patients with deletion 17p.
The FDA Breakthrough Therapy Designation for ibrutinib in CLL patients with deletion 17p was based on data from pre-clinical and clinical studies where ibrutinib as a monotherapy was used to treat patients with this disease. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease which has a poor prognosis. In addition, Pharmacyclics and Janssen have recently initiated a Phase II study of ibrutinib in patients with CLL deletion 17p, RESONATE™ -17, which is a single-arm, open-label, multi-center trial using ibrutinib as a monotherapy in patients who have deletion 17p and who did not respond to or relapsed after at least one prior CLL treatment (a high unmet need population). The primary endpoint of the study will be overall response rate. This global study opened this year and Pharmacyclics plans to enroll 111 patients worldwide.
About Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia (CLL) is a slow-growing blood cancer that starts in the white blood cells (lymphocytes), most commonly from B-cells. CLL is the second most common adult leukemia. Approximately 16,000 patients in the US are diagnosed each year with CLL. The prevalence of CLL is approximately 113,000 in the US. The disease is a chronic disease of the elderly with an average survival of about 5 years. Patients commonly receive multiple lines of treatment over the course of their disease.
In CLL the genetic mutation 17p deletion occurs when the short arm of chromosome 17 is missing. Del 17p is associated with abnormalities of a key tumor suppressor gene, TP53, which results in poor response to chemoimmunotherapy and worse treatment outcomes. It occurs in about 7% of treatment naive CLL patients and is estimated to be approximately 20% to 40% of relapsed or refractory patients harboring the mutation.
Ibrutinib , previously publicly known as PCI-32765, is an experimental drug candidate for the treatment of various types of cancer. It was first synthesized at Celera Genomics as a selective inhibitor of Bruton’s tyrosine kinase (Btk).It was later discovered to have anti-lymphoma properties in vivo by scientists at Pharmacyclics, Inc.Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson‘sJanssen Pharmaceutical division for chronic lymphocytic leukemia, mantle cell lymphoma,diffuse large B-cell lymphoma, and multiple myeloma. It also has potential effects against autoimmune arthritis.
Janssen Biotech, Inc. and Pharmacyclics entered a collaboration and license agreement in December 2011 to co-develop and co-commercialize ibrutinib. Ibrutinib was designed to specifically target and selectively inhibit an enzyme called Bruton’s tyrosine kinase (BTK). BTK is a key mediator of at least three critical B-cell pro-survival mechanisms occurring in parallel – regulation of apoptosis, adhesion, and cell migration and homing. Through these multiple signals, BTK regulation helps to direct malignant B-cells to lymphoid tissues, thus allowing access to a micro environment necessary for survival.
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, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Waldenstrom’s macroglobulinemia and multiple myeloma. To date five Phase III trials have been initiated with ibrutinib and a total of 26 trials are currently registered on www.clinicaltrials.gov.
Pharmacyclics® is a clinical-stage biopharmaceutical company focused on developing and commercializing innovative small-molecule drugs for the treatment of cancer and immune mediated diseases. Our mission and goal is to build a viable biopharmaceutical company that designs, develops and commercializes novel therapies intended to improve quality of life, increase duration of life and resolve serious unmet medical healthcare needs; and to identify promising product candidates based on scientific development and administrational expertise, develop our products in a rapid, cost-efficient manner and pursue commercialization and/or development partners when and where appropriate.
Presently, Pharmacyclics has three product candidates in clinical development and several preclinical molecules in lead optimization. The Company is committed to high standards of ethics, scientific rigor, and operational efficiency as it moves each of these programs to viable commercialization.
The Company is headquartered in Sunnyvale, California and is listed on NASDAQ under the symbol PCYC. To learn more about how Pharmacyclics advances science to improve human healthcare visit at http://www.pharmacyclics.com.