Immunomodulating Therapies and Progressive Multifocal Leukoencephalopathy (PML)

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Immunomodulating Therapies and Progressive Multifocal Leukoencephalopathy (PML)

Tuesday, November 10, 2009

The New York Academy of Sciences

Presented By

 

The aim of this symposium is to provide a forum to discuss whether Progressive multifocal leukoencephalopathy (PML) that has been seen in multiple drug trials is a direct consequence of the mechanism of therapeutic action or whether it’s an off-target adverse effect of the therapeutic agent. Progressive multifocal leukoencephalopathy (PML) is a rare, but fatal disease that leads to severe brain inflammation and neural demyelination for presenting patients. This disease is caused by the JC Virus, a polyomavirus generally widespread but latent in human populations. While rare in the general population, the prevalence of PML is increased in HIV patients and notably, has recently been associated with several immunomodulating drug therapies. In order to gain broader perspective on PML and JC virus biology, the impact on clinical practice, and associated regulatory issues, this one day symposium will bring together experts from academia and medicine as well as representatives from drug discovery and the FDA for an interactive series of discussions.

Image credit: Mark Cohen

Networking Reception to Follow

Agenda

*Presentation times are subject to change.


7:30 AM

Registration & Breakfast

8:00 AM

Welcome Address
William Loging, PhD, Boehringer Ingelheim Pharmaceuticals, Inc

Session I: Keynote Address: Overview and Clinical Perspective of PML and Biology of the JC Virus

8:15 AM

Joseph Berger, MD, University of Kentucky Medical Center

Session II: Biology of the JC Virus

9:15 AM

Eugene Major, PhD, National Institutes of Health

Session III: Hypotheses of PML Pathogenesis

10:15 AM

Richard Ransohoff, MD, Cleveland Clinic Foundation

11:15 AM

Leonid Gorelik,PhD, Biogen IDEC

12:15 AM

Lunch

1:30 PM

Introduction to Afternoon Sessions
Patricia Giblin, PhD, Boehringer Ingelheim Pharmaceuticals, Inc

Session IV: PML Association With Tysabri, Raptiva and Rituxan Theraputics

2:00 PM

Mariska Kooijmans-Coutinho , Biogen IDEC

2:45 PM

David Yocum, Genentech

3:30 PM

Panel Discussion
Christian K. Schneider, EMEA, Paul-Ehrlich-Institut Federal Agency for Sera and Vaccines
Alice Hughes, MD, Food and Drug Administration
All speakers

5:00 PM

Networking Reception

Speakers

Organizers

David W. Brewster

Hoffmann-La Roche Inc.

Matthew S. Bogdanffy

Boehringer Ingelheim Pharmaceuticals, Inc.

Patricia Giblin

Boehringer Ingelheim Pharmaceuticals, Inc.

Dr. Patricia Giblin is a Senior Research Fellow in the Department of Immunology and Inflammation Research at Boehringer Ingelheim Pharmaceuticals. Her major field of expertise is immune cell trafficking and activation. Over the past 12 years Dr. Giblin's research has focused on integrin and chemokine receptor biology with the goal of advancing therapies for the treatment of multiple sclerosis and psoriasis. Prior to joining Boehringer Ingelheim, Dr. Giblin completed postdoctoral training in the laboratory of Dr. Steven Rosen at UCSF after receiving her Ph.D. at Yale University.

William Loging, PhD

Boehringer Ingelheim Pharmaceuticals, Inc.

William Loging is a Director in the Biologics and Integrative Biology Group within Research at Boehringer-Ingelheim Pharmaceutics Inc. The team under his supervision conducts high through-put analysis of biological/chemical content data for disease and mechanisms of toxicity understandings. His previous work lead to advancements in the use of CCR5 (Chemokine (C-C motif) receptor 5) inhibitors for the treatment of Human Immunodeficiency Virus (HIV); as well as making contributions to the successful launch of Maraviroc.

Donna L. Mendrick

National Center for Toxicological Research

Speakers

Joseph R. Berger

University of Kentucky College of Medicine

Works Professor and Chairman of the Department of Neurology at the University of Kentucky College of Medicine where he is director of the Multiple Sclerosis Clinic and the Neuro-AIDS Program. Dr. Berger’s research interests include the neurological complications of HIV/AIDS, progressive multifocal leukoencephalopathy, multiple sclerosis, and other inflammatory disorders of the brain. He has published more than 140 refereed papers, more than 80 chapters, and has edited three textbooks. Dr. Berger is an Associate of the Journal of Neurovirology and has served or is serving on several other editorial boards. He is a fellow of the American Academy of Neurology and a member of the American Neurological Association, currently serving as Treasurer of the latter.

Leonid Gorelik

Biogen Idec Inc.

Leonid Gorelik is Principal Scientist in Neurobiology Department at Biogen Idec. Dr. Gorelik leads discovery research efforts at Biogen Idec to identify ways of mitigating risk of PML via discovery of PML risk factors as well as identification of new potential treatments for PML. He received a M.S. degree in physics from the Moscow Institute of Physics and Technology, and a Ph.D. in tumor immunology from the University of Illinois at Chicago. He conducted his postdoctroral studies with Richard Flavell at Yale University, where he elucidated role of transforming growth factor-beta (TGF-beta) in T-cell regulation in autoimmunity and anti- tumor immune responses. Subsequently he moved to Biogen Idec where he worked on and led a number of drug discovery projects for treatment of autoimmune diseases.

Alice Hughes

Food and Drug Administration

Alice Hughes is the Deputy Director for Safety of the Division of Neurology at the Food and Drug Administration’s Center for Drug Evaluation and Research. She oversees the identification, assessment, and management of post-marketing safety issues for drugs for neurological indications. She joined the FDA six years ago as a medical officer safety reviewer and subsequently was the leader of the division’s safety group prior to assuming her current position. She has been extensively involved in the review of, and regulatory actions pertaining to, safety data for natalizumab (Tysabri), notably Tysabri-associated Progressive Multifocal Leukoencephalopathy. Dr. Hughes received a B.A. from Princeton University and an M.D. from the Mount Sinai School of Medicine prior to completing a residency in Internal Medicine at the Duke University Medical Center. She was a Morris Fishbein Fellow in Medical Editing at the Journal of the American Medical Association prior to joining the FDA.

Mariska Kooijmans-Coutinho 

Biogen Idec Inc.

Mariska Kooijmans-Coutinho is Senior Director of Clinical Trial Safety and Risk Management at Biogen Idec Inc., Cambridge (MA), USA. After receiving her M.D. in 1985 from Erasmus University Rotterdam, The Netherlands, Dr. Kooijmans-Coutinho trained and worked in internal medicine (1986-1991) and nephrology (1991-1995) at the Leiden University Medical Center, The Netherlands. She was awarded a Ph.D. in nephrology (renal transplantation immunology) in 1997. Dr. Kooijmans-Coutinho became Manager Medical Department at Excerpta Medica Medical Communications, The Netherlands, in 1995. She moved to Biogen in 1998 where she worked as Medical Manager Northern Europe at Biogen International B.V., The Netherlands, until 1999, when she transferred to Biogen’s clinical research department in Cambridge, MA. She was Director of Clinical Research until January 2003, when she was promoted to her current position, in which she initially was responsible for Global Clinical Trial Safety and Risk Management, and currently leads the group that is responsible for drug safety and risk management of marketed drugs. She also leads the cross-functional PML Mitigation Research Team. Dr. Kooijmans-Coutinho is a member of the American Academy of Neurology, the Dutch Association of Internal Medicine, the Dutch Society of Nephrology, the Dutch and the British Association of Pharmaceutical Physicians, and of DIA and ISoP.

Eugene O. Major

National Institute of Neurological Disorders and Stroke

Dr. Major is Senior Investigator at the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH). Dr. Major has developed a basic research laboratory, the Laboratory of Molecular Medicine and Neuroscience, focusing on mechanisms of viral pathogenesis in the human nervous system, which includes JC Virus-induced demyelination, Progressive Multifocal Leukoencephalopathy, and HIV-1 associated encephalopathy. As Chief of the Laboratory of Molecular Medicine and Neuroscience, Dr. Major’s investigations focus on the biology of virus infections in nervous system cells derived from human brain and the molecular regulation which controls cellular and viral gene expression.

Richard M. Ransohoff

Lerner Research Institute

He is the Director of the Neuroinflammation Research Center in the Department of Neurosciences of Lerner Research Institute and Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. He is also Staff Neurologist in the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Ohio. For the past decade, Dr. Ransohoff’s research has focused on the functions of chemokines and chemokine receptors in development and pathology of the nervous system. He also has a longstanding and continuing interest in the mechanisms of action of interferon-beta. Dr. Ransohoff has published more than 150 scientific reports, more than 50 reviews and book chapters, and edited three books. Among multiple honors and awards, Dr. Ransohoff was elected to the American Association of Physicians in 2006, he received the Cleveland Clinic Lerner Research Institute’s Award for Excellence in Science in 2006, and was elected a Fellow of the American Association for the Advancement of Science in 2007.

Christian K Schneider

Paul-Ehrlich-Institut Federal Agency for Sera and Vaccines

Christian K Schneider, MD, is Director and Professor and Head of Division “EU Co-operation/Microbiology” at the Paul-Ehrlich-Institut, the German Federal Institute for Vaccines and Biomedicines. He is the chairman of the EMEA’s Committee for Advanced Therapies (CAT), which started its work in January 2009. Further, he is co-opted member of the CHMP, the Committee for Medicinal Products for Human Use at the European Medicines Agency EMEA, for the area of “Quality and safety (biological), with expertise in Advanced Therapies – Gene, Cell and Tissue Therapies”. Further, he is chairman of the CHMP Working Party on Similar Biological Medicinal Products (BMWP). Christian Schneider is Rapporteur or Co-Rapporteur for the CHMP for more than 50 biological medicinal products, e.g. Tysabri (natalizumab), Herceptin (trastuzumab), or Remicade (infliximab). He has been actively involved in the drafting of several multidisciplinary guidelines, including the CHMP Guideline on Strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (the former “high-risk products guideline”), the CHMP Guideline on Comparability of Biotechnology-Derived Medicinal Products after a change in the Manufacturing Process - Non-Clinical and Clinical Issues, and CHMP Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins for which he acts as Rapporteur. Before he joined the Paul-Ehrlich-Institut, Christian K Schneider was working for more than two years as a postdoctoral researcher at the Max-Planck-Institute for Neurobiology, Department of Neuroimmunology (Martinsried, Germany), where he worked in experimental immunology in the field of T cell immunology of inflammatory myopathies and multiple sclerosis. During his clinical career, Christian K Schneider worked in clinical immunology and hemato-oncology (Department of Internal Medicine III, University Erlangen-Nuremberg, Germany).

David Yocum

Genentech

Dr. David Yocum is the US Head of Drug Safety and the Global Safety Cluster Head for Inflammation and Ophthalmology at Genentech. He is also Adjunct Clinical Professor of Medicine at Stanford School of Medicine in the Section of Rheumatology. Prior to coming to Genentech in 2005, he was Professor of Medicine and Director of the Arizona Arthritis Center at the University of Arizona where his primary research interests centered around the development of immunomodulatory and biologic therapies for the rheumatic diseases, new treatments for osteoarthritis and the development of new imaging techniques for musculoskeletal diseases. Dr. Yocum is a Fellow of the American College of Rheumatology. He has published widely in peer-reviewed journals in his area of research, written several book chapters and edited books in the field of Rheumatology.

Sponsors

For sponsorship opportunities please contact Sonya Dougal at sdougal@nyas.org or 212.298.8682.

Presented by

This activity is supported by an educational grant provided by Amgen

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Abstracts

Overview and Clinical Perspectives of PML

Joseph R. Berger, MD,University of Kentucky Medical Center

Progressive multifocal leukoencephalopathy (PML) was first described in 1958. From that time through the onset of the AIDS pandemic, this viral CNS demyelinating disorder was exceptionally rare, almost always affecting individuals with a recognized underlying immunological disorder. More recently, the disease has been seen with immunomodulatory therapies, including natalizumab, rituximab, efalizumab, and mycophenolate mofetil. The clinical manifestations of the disorder are diverse with weakness, gait disturbance, speech and language disorders, and visual field deficits among the most common features. A diagnosis can be comfortably established when both clinical features and MRI suggest the disorder and CSF polymerase chain reaction reveals the presence of the causative polyomavirus, JC virus. Otherwise, brain biopsy is necessary. Affected brain demonstrates a classic histopathological triad characterized by enlarged oligodendroglial nuclei, bizarre astrocytes, and demyelination. Until the recent past, the prognosis of PML has been regarded as poor, but reversal of the underlying immunosuppressive condition may be associated with long term survival. Several treatment strategies directed against JC viral replication have been proposed, but have not, as yet, been demonstrated to be effective.

Mechanistic association of immune modulatory therapies for autoimmune diseases and the occurrence of progressive multifocal leukoencephalopathy, PML.

Eugene Major, PhD, National Institutes of Health

The viral induced demyelinating disease, PML, is a rare occurrence of viral reactivation from sites of latency likely due to migration of infected cells from bone marrow or other lymphoid compartments. The combination of migration of cells like CD34+ progenitor and/or pre B cells into the periphery along with upregulation of host factors in these cells that augment viral multiplication provide an ideal environment for JCV. Once JCV traffics into the brain, it can initiate infection in its most favorable host cell, the oligodendrocyte, leading to cell necrosis and demyelination.

Immunomodulating Therapies and Progressive Multifocal Leukoencephalopathy

Richard M. Ransohoff, MD, Cleveland Clinic

Progressive multifocal leukoencephalopathy (PML) is a serious and frequently fatal opportunistic infection of the human central nervous system (CNS), caused by the JC polyomavirus (JCV). PML was rare (~1/106 per year) until the HIV-AIDS pandemic and remains distinctly uncommon among HIV-negative individuals. However, during recent therapeutic applications of power biological immunomodulators, PML has occurred in diverse settings: natalizumab treatment for multiple sclerosis; natalizumab/Crohn’s disease; rituximab/lymphoma and rituximab/systemic lupus erythematosus; efalizumab/psoriasis. In several cases, PML had not been reported in this disease association previously, while in other circumstances, the underlying disorder had been recognized as a PML-risk state. The potential underlying mechanisms, which may be as varied and intricate as the agents and disease associations, will be considered.

Being Proactive with PML: Investigating the role viral and host factors playin PML

Leonid Gorelik, PhD, Biogen IDEC

PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral and/or host specific factors in addition to the specific immune status must be at play to account for the very large discrepancy between viral prevalence and very low disease incidence. Current presentation will examine the role that some of such viral and host factors play in susceptibility to PML. Specific focus will be given to the role that some mutations in the viral capsid proteinVP1 might play in the development of PML.

The TYSABRI Risk Management Plan

Mariska Kooijmans-Coutinho, Biogen Idec, Inc.

Natalizumab is the first α4-integrin antagonist approved for the treatment of relapsing MS. Natalizumab monotherapy significantly reduced annualized relapse rate by 68%, and 12- and 24-week sustained disability progression by 42-54%, respectively, compared with placebo in the AFFIRM study. Due to the rare risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab, there are Risk Management plans in place in all geographies. In the US there are two ongoing risk management programs for patients with MS to further evaluate the safety of natalizumab: the TYSABRI Outreach: Unified Commitment to Health (TOUCH™) Prescribing Program and the TYSABRI Global ObseRvation Program In Safety (TYGRIS). For patients with Crohn’s Disease (CD) there are the TOUCH Prescribing Program, and INFORM (Investigating Natalizumab through Further Observational Research and Monitoring). The TOUCH Prescribing Program is a mandatory prescribing program in the United States into which all patients, physicians, and infusion centers must enroll prior to initializing natalizumab treatment. This program ensures appropriate and informed use of natalizumab. Physicians monitor patients for signs and symptoms of PML and report on serious opportunistic infections (SOIs), including PML, deaths and natalizumab discontinuations. TYGRIS is a voluntary global observation study investigating the long-term safety of natalizumab in MS patients the clinical practice setting. Approximately 5000 patients, including patients from TOUCH, are expected to enroll. Patients in TYGRIS are evaluated at baseline and every 6 months thereafter for 5 years, regardless of whether or not they continue natalizumab treatment. Information collected includes: medical/MS history; prior natalizumab use; prior immunomodulatory, antineoplastic, or immunosuppressive agent use; and all serious adverse events, including serious infections and malignancies. INFORM is a voluntary observational study investigating the long-term safety of natalizumab in CD patients the clinical practice setting, it is expected to enroll 2000 patients. This presentation will provide an update on the status of the programs and key learnings from TYSABRI associated PML cases.

 

PML in Patients Treated with Raptiva and Rituxan

David Yocum, Genentech

Until recently, the development of PML was primarily seen in severely immunosuppressed patients with HIV/AIDS or hematologic malignancies. It was rarely noted to occur in patients with severe autoimmune diseases such as systemic lupus erythematosus (SLE) and even rarer in rheumatoid arthritis (RA). Prior to Tsyabri, PML had never been seen in patients with multiple sclerosis (MS). More recently, a small number of cases of PML have been seen in association with Raptiva and Rituxan. For Raptiva, the cases were seen in patients with psoriasis with no background association with PML while for Rituxan, they were seen in autoimmune diseases such as SLE, Vasculitis and RA, where there is a background association with PML.

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