FDA Staff Asks President to Straighten Up Agency

The clearance or approval of medical devices that was not made in accordance with federal laws, rules and regulations needs to be revisited, according to a recent letter sent to President Barack Obama by disgruntled FDA employees. This is the second letter FDA employees have written to the president. “The culture of wrongdoing and cover-up is nothing new, but is part of a longstanding pattern of behavior,” the letter says.

Update on Ipsen's botulinum toxin type A Product Regulatory Review Status in the US

Ipsen (Paris:IPN) and its partner Medicis (NYSE: MRX) announced today that the companies are in active labeling and Risk Evaluation and Mitigation Strategy ("REMS") discussions with the U.S. Food and Drug Administration (“FDA”) related to the Biologics License Application (“BLA”) for Ipsen’s botulinum toxin type A product in both therapeutic and aesthetic indications.

Pharmacyclics Initiates Phase 1 Clinical Trial of Novel Oral Btk Inhibitor for Refractory B-cell Non-Hodgkin's Lymphoma

SUNNYVALE, Calif., April 13 -- Pharmacyclics, Inc. (Nasdaq: PCYC) today announced that it has begun treating patients in a Phase 1 dose-escalation study to evaluate the safety and tolerability of PCI-32765, an orally available, selective inhibitor of Bruton's tyrosine kinase, or Btk, as a potential treatment for patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). This is the first Btk selective inhibitor to be tested in humans, and is Pharmacyclics' fourth product in clinical development.

Bruton's tyrosine kinase is the gene that is disrupted in the human disease X-linked agammaglobulenemia (XLA). Patients with XLA are devoid of mature B-lymphocytes and immunoglobulins in the bloodstream, but are otherwise healthy. XLA thus provides strong clinical rationale for development of a novel therapeutic drug targeting Btk for safe inhibition of B-cell mediated diseases. In preclinical studies, PCI-32765 has the remarkable ability to selectively inhibit human B-cell activation without effecting T cells. Strong preclinical validation of Btk as a target in lymphoma was generated using PCI-32765 in a mouse model of B-cell receptor-driven lymphoma and in spontaneous B-cell lymphoma in companion canines. These studies will be reported in presentations at the 2009 AACR annual meeting in Denver, Colorado (see below). Unlike anti-CD20 protein therapies, treatment with PCI-32765 in animal models is not myeloablative, which could result in prolonged and dangerous immunosuppression for the patient.

"This is a very selective compound for B-cells, and it could represent an important alternative to rituximab therapy for the treatment of B-cell NHL. Other obvious applications include autoimmune disorders such as rheumatoid arthritis and lupus, and Pharmacyclics also has strong preclinical efficacy with PCI-32765 in these disease models," said Dr. Mark Genovese, Professor of Medicine and Co-Chief of the Division of Immunology and Rheumatology at Stanford University Medical Center and member of Pharmacyclics' Scientific Advisory Board.

"Despite recent success with biologics in the treatment of B-cell NHL, there is still a large group of patients that do not respond to therapy or who experience recurrence," said Ranjana Advani, MD, Associate Professor, Stanford University Medical Center and principle investigator of the Phase 1 clinical trial. "A drug that could not only have an impact on this patient group, but also be delivered orally would represent a significant step forward in the treatment of this disease."

This Phase 1 study is evaluating the safety and pharmacokinetics of PCI-32765 in patients with refractory B-cell non-Hodgkin's lymphoma at Stanford University, MD Anderson Cancer Center and the University of Chicago using a 28-day dose-escalation design. The study is also utilizing a proprietary pharmacodynamic assay developed by Pharmacyclics to directly assess Btk drug occupancy. Preliminary results from the Phase I trial shows good patient tolerability under conditions of Btk-drug occupancy with potent bioactivity in targeted cell populations derived from the B-cell lymphoma patients.

Pharmacyclics Btk Presentations at AACR

Monday April 20, 2009

9:30 am - 1:00 pm; Minisymposium Novel Molecular Targets / Targeting Cell Death Pathways; Experimental and Molecular Therapeutics 12 Room 405-407, Colorado Convention Center 9:40am-9:55am

#1984 Btk is a Novel Therapeutic Target to Treat Large B-cell Lymphomas Ryan M. Young, Ashley Smith, Lee Honigberg, Yosef Refaeli. National Jewish Health, Denver, CO, Pharmacyclics, Inc., Sunnyvale, CA

Tuesday April 21, 2009

8:00 am - 12:00 pm Poster Session Kinase Inhibitors 3 Experimental and Molecular Therapeutics 24 Hall B-F, Poster Section 36

8:00 am - 12:00 pm Poster Board Number 24

#3740 A Clinical Trial of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Naturally Occurring Canine Lymphoma. Lee A. Honigberg, Ashley M. Smith, David J. Loury, Joseph J. Buggy, Douglas H. Thamm. Pharmacyclics, Sunnyvale, CA, Colorado State University Animal Cancer Center, Fort Collins, CO

About Pharmacyclics' Btk Inhibitor Program

PCI-32765 is currently targeted for oncology while other Pharmacyclics Btk inhibitors are being developed for application to autoimmune and inflammatory diseases. Bruton's tyrosine kinase is a critical enzyme involved in B-cell activation and function, and inhibition may be useful in the treatment of a number of immune mediated diseases. B-cells are a type of white blood cell that normally play an important role in the body's immune response. However, when B-cells are overactive, the immune system produces inflammatory cells and antibodies that begin to attack the body's own tissue, leading to autoimmune disorders. Also many lymphomas are caused by uncontrolled growth of B-cells where activation of the B-cell receptor and Btk signaling are thought to play important roles.

In addition to being studied in a Phase 1 trial for refractory B-cell non- Hodgkin lymphoma, PCI-32765 has been evaluated in preclinical studies in collagen-induced arthritis, an established animal model for RA. In these studies, PCI-32765 dramatically reduced inflammation and induced regression of established disease as reported at the Federation of Clinical Immunology Societies (FOCIS) 2008 annual meeting .

Therapeutic effect of imatinib improved with addition of chloroquine

(PHILADELPHIA) The therapeutic effects of the blockbuster leukemia drug imatinib may be enhanced when given along with a drug that inhibits a cell process called autophagy, researchers from the Kimmel Cancer Center at Jefferson reported in the Journal of Clinical Investigation.

The cell-death effect of imatinib (Gleevec) was potentiated when chloroquine, an autophagy inhibitor, was given with imatinib for the in vitro treatment of chronic myeloid leukemia (CML) cells including the CML stem cells, according to Bruno Calabretta, M.D., Ph.D., professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University.

Autophagy is a process that allows cells to adapt to environmental stresses, and enables drug-treated CML cells to escape cell death. Imatinib is a tyrosine kinase inhibitor that suppresses proliferation and induces death of the malignant cells that cause CML. However, additional effects of the drug have not been studied in detail, according to Dr. Calabretta.

In this study, Dr. Calabretta's team, along with Dr. Paolo Salomoni's team from the MRC Toxicology Unit at the University of Leicester in the United Kingdom, found that imatinib induces autophagy in CML stem cells that overexpress a protein called p210BCR/ABL. Stem cells that express this protein have been historically resistant to imatinib and also to second-generation tyrosine kinase inhibitors, including dasatinib, nilotinib and bosutinib.

The autophagy process allows stem cells to survive treatment with imatinib, and continue to survive. The researchers used chloroquine to see if it would have an effect on imatinib treatment. The dual treatment with imatinib and chloroquine eliminated most CML stem cells. Also, imatinib-induced cell death was significantly increased in mice inoculated with p210BCR/ABL-expressing cells.

"Imatinib's primary effect is inhibiting the proliferation of CML cells, but the frequency of resistance increases in advanced stages of the disease," Dr. Calabretta said. "There is a need to develop new therapeutic approaches that, in combination with tyrosine kinase inhibitors, eliminate CML stem cells that escape imatinib treatment. We show that imatinib induces autophagy, which enables these cells to survive and eventually resume proliferation. We also show that chloroquine, an autophagy inhibitor, combined with imatinib actually appears to potentiate imatinib-induced cell death."

Enhancing the effects of the drug used to treat chronic myeloid leukemia

Individuals with chronic myeloid leukemia (CML) are first treated with a drug known as imatinib mesylate. Although very effective, as the disease progresses it often becomes resistant to the drug. However, a team of researchers, at the University of Leicester, United Kingdom, and Thomas Jefferson University, Philadelphia, has identified a class of drugs that might enhance the therapeutic effects of imatinib mesylate and other drugs that target the same molecule.

The team, led by Paolo Salomoni and Bruno Calabretta, observed that for several different CML cell lines and primary cells, although imatinib mesylate killed the majority of cells, a marked proportion underwent a process known as autophagy. Consistent with studies indicating that the induction of autophagy can provide a mechanism of cellular survival, suppression of autophagy using either drugs or RNA interference enhanced imatinib mesylate–induced death of CML cell lines, primary CML cells, and CML stem cells. The authors therefore suggest that inhibitors of autophagy might be used with imatinib mesylate or other drugs that target the same molecule to enhance their therapeutic benefits.