ASH News Daily 2013 - Day 3 - (Page A-13)

Monday, December 9, 2013 PHARMACOLOGY Novel Drug Discovery and Development: More Than Meets the Eye BY PRASHANT KAPOOR, MD dition, three acclaimed researchers masterfully unraveled the modernday tortuous and complex drug discovery and development processes with a focus on novel cancer therapeutics. Dr. Mark Crowther, McMaster University, Ontario, Canada, delved into the intricacies of drug development pathways that go beyond the approval of drugs by the regulatory bodies. Additionally, he discussed the inherent limitations of traditional post-marketing surveillance, the challenges encountered during such unsupervised phase IV research, the lessons learned thereof, and the effective strategies to deftly overcome such difficulties. Attendees were also provided a D broad overview of the unconventional near "real-time" pharmacovigilance programs. Toxicities can potentially be missed even in the most well-conducted, large phase III trials and may come to light only in the post-approval phase, occasionally leading to an abrupt and tragic drug withdrawal in a style reminiscent of a tragic denouement in a cap- THROMBOSIS The Clot Thickens BY MARC S. ZUMBERG, MD, AND ANITA RAJASEKHAR, MD, MS the risk of bleeding, as does anticoagulant W e were taught in medical school that thrombocytopenia increases therapy. However, we know now that both can also be associated with thrombosis. Yesterday's session, Updates in Aggressive Thrombotic Disease, which will be repeated at 10:30 a.m. in Riverside Rooms R02-R03 in the convention center, highlighted some of these hematologic paradoxes. Hepa- rin-induced thrombocytopenia (HIT), antiphosholipid antibody syndrome (APLS), and cancer can all be associated with thrombocytopenia, yet they are some of the most aggressive thrombotic disorders hematologists treat. These diseases were the focus of this session. Chaired by Dr. Wendy Lim, McMaster University, the session began with a discussion on HIT by Dr. Gowthami Arepally, Duke University, Durham, NC. Heparin use is ubiquitous in most medical centers, and the majority of inpatients are therefore at risk for developing HIT, which occurs in 0.1 to 5 percent of hospitalized patients. Dr. Arepally reviewed the epidemiology and variable clinical presentations of HIT. She then focused on a diagnostic approach aiming to minimize both the over- and under-diagnosis of HIT. Dr. Arepally closed her portion of the session addressing the pitfalls of current diagnostic testing, including the high sensitivity but low specificity of many of the commercially available ELISA-based assays. Next, Dr. Lim focused on APLS, which is defined by venous, arterial, or obstetric thrombotic complications in conjunction with persistently positive antiphospholipid antibodies. She detailed the specific clinical and laboratory criteria required for the diagnosis of APLS. Dr. Lim stressed the differing throm- botic risks based on the laboratory pattern of antiphospholipid antibodies. Catastrophic APLS (CAPS), multi organ failure occurring over a short-time period and with histopathologic evidence of small vessel occlusion, was also reviewed. Dr. Lim finished with the controversies involving the length of anticoagulation, intensity of anticoagulation, and other adjunct therapy for both APLS and CAPS. Finally, Dr. Charles Francis, University of Rochester Medical Center, NY, covered the hot topic of thrombosis and cancer, which was recently the focus of a series of articles in the Blood journal. One in five VTEs occur in cancer patients, and VTE is the second leading cause of death, morbidity, delays in care, and cost in this group. Dr. Francis reviewed patient-related, cancer-related, and treatment-related factors that help predict thrombotic risk and better guide prophylactic anticoagulation. He shared with me that the real difficulty in treatment is that these patients have "frequent recurrences, yet significant bleeding complications, as well as side effects of chemotherapy including thrombocytopenia." The session ended with a review of the data highlighting the superior efficacy of LMWHs over VKA antagonists and approaches to difficult treatment scenarios. These talks each illustrated aggressive thrombotic conditions we routinely care for as hematologists. Each talk focused on prognostic models or risk factors to help predict risk and therefore minimize occurrence. Further, management and treatment decisions concerning each of these conditions were highlighted. This session should be considered a "must see" for anyone treating these difficult thrombotic disorders. Dr. Zumberg and Dr. Rajasekhar indicated no relevant conflicts of interest. uring yesterday's session, A Fresh Look at Drug Approval: Moving Away from Tra- tivating country story. The goal of expeditious drug development for diseases with limited effective therapies may be a lofty one, but not uncommonly reached in the current era of novel therapeutics. Dr. Crowther also reviewed two crucial FDA programs, the "breakthrough therapies" and "accelerated approval," that are critical for granting fast drug access to patients. Indeed, cancer drugs can get fast-track approval using such programs specifically designed for diseases with an unmet need for effective therapies, without compromising the punctiliousness of our traditional protocols. His talk culminated with an illustrative example of a recently approved oral anticoagulant, dabigatran etexilate. Dr. Victoria Richon, Sanofi On- cology, Cambridge, MA, beautifully outlined the impediments and opportunities associated with drug discovery for rare diseases. Ironically, many such rare diseases are all too familiar to 2013 annual meeting attendees. Dr. Richon took the audience back to 1983 when the Orphan Drug Act (ODA) that catapulted the growth of drugs for rare diseases was introduced. Her talk was peppered with examples of cancer drugs that received marketing approval in the last few years. She also highlighted the four crucial steps involved with the drug discovery process: a) identification of a "druggable" molecular target that drives the cancer subtype; b) pre-clinical validation of the target; c) selection of a drug candidate that inhibits the molecular target utilizing cell-based and animal models; and d) bringing the drug from bench to the bedside by testing the identified drugs in patients from defined cancer subpopulations. Using this four-step approach, she elucidated the development of one such class of drugs, the DOT1L inhibitors targeting methyltransferase activity of the unique enzyme DOT1L that plays a significant role in mixed lineage leukemia (MLL)AF9 driven leukemogenesis and is identified as a therapeutic target. To quote another speaker at the session, Dr. Michael Grever, Ohio State University Comprehensive Cancer Center, "We want to accelerate drug development, but we don't want to compromise safety." Dr. Grever guided the attendees through the ideal approach to safe drug development and approval. Post-marketing experience merely reflects the tip of the iceberg and often belies the arduous process of a successful drug development, which is typically associated with a staggering price tag. The "target" audience (no pun intended) appreciated the labor-intensive process of drug development. An apt case in study would be that of chronic lymphocytic leukemia (CLL) therapeutics, exemplifying the rather checkered and celebrated history of the drug development process. Fludarabine, a purine analog, has been the cornerstone of CLL treatment for over two decades. Ibrutinib, a Bruton's tyrosine kinase inhibitor that has recently been approved for mantle cell lymphoma, is a promising anti-CLL therapy as well and has received "breakthrough therapy" status, a coveted trophy of sorts, granted by the FDA to a select few, with the sole aim of streamlining the development process. If you missed the session, you can attend the repeat session this morning from 10:30 a.m. to 12:00 noon in Room 243-245 at the convention center. Dr. Kapoor indicated no relevant conflicts of interest. ASH NEWS DAILY Page A-13 ®

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ASH News Daily 2013 - Day 3

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