Selective Adhesion Molecule Inhibitors and CNS Disease

July 26, 2005
Hotel Mandarin Oriental, Washington, D. C.

Table of Contents
Overview
Discussion
Agenda
Participant List

Overview

Inflammation is a necessary response to tissue injury and infection, but can be detrimental in clinical inflammatory/autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease and can contribute to the pathogenesis of central nervous system (CNS) disorders. Inflammation is characterized by a recruitment of leukocytes to the target tissue via chemo-attraction followed by interaction with cell adhesion molecules expressed on the surface of endothelial cells. For this reason, chemokine antagonists and selective inhibitors of adhesion molecules, both of which interfere with cell migration, appeared to have potential as novel therapeutics for immunomodulation. Natalizumab, an antibody which recognizes VLA-4 and which interferes with T cell trafficking into the CNS, was the first selective adhesion molecule inhibitor approved by the FDA for the therapy of relapsing-remitting multiple sclerosis. Shortly after approval the drug was withdrawn after three patients developed a rare condition termed progressive multifocal leukoencephalopathy (PML). PML is a rare condition typically only observed in immuno-compromised individuals such as AIDS patients or transplant recipients. It is caused by a ubiquitous virus termed JC virus which typically seems to persist in subjects without clinical manifestation.

The one-day Workshop on "Selective Adhesion Molecule Inhibitors and CNS Disease" aimed to discuss how inhibitors of immune cell migration might interfere with the immunological control of CNS infections such as presented by JC virus and whether cell migration inhibition therapies are viable in light of potential complications. Specifically, we intended to discuss 1) the mechanisms of action of therapies interfering with cell migration, 2) the biology of JC virus, 3) the potential existence of unknown co-factors that might contribute to the development of PML and 4) how such knowledge might affect the design and monitoring of future trials of CNS therapeutics.

Organized by Drs. Utz and Nunn from NINDS, NIH, the workshop included an international group of participants comprised of clinical and basic researchers with expertise in the areas of neurology, virology, immune cell trafficking and clinical trials design, representatives from industry involved in the development of these agents and NIH staff. A minimum of time was expended on presentations to allow for ample discussion of the outlined topics.

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Discussion

The workshop began with a presentation by Dr. Calabresi on two trials, SENTINEL and AFFIRM, which had led to the approval of Natalizumab for the therapy of relapsing-remitting multiple sclerosis. This was followed by two case studies of patients who had developed PML concomitant with therapy with this selective adhesion molecule inhibitor (by Drs. Langer-Gould and Kleinschmidt-DeMasters). Dr. Stueve presented his studies on the phenotypes and composition of immune cells present in the cerebrospinal fluid of multiple sclerosis patients treated with Natalizumab. These presentations were followed by three extended discussion sessions; each launched by a brief introduction into the topic. The three sessions explored 1) the biology of JC virus, 2) immune cell trafficking, and 3) considerations for therapeutic strategies involving selective adhesion molecule inhibition.

Session 1 led by Dr. Major discussed the cell types the virus might be able to infect, whether JC virus can persist in infected individuals in a latent state, the potential sites for latency and under what conditions dormant virus might get reactivated. We debated the origin of the virus inducing PML (CNS origin versus bone marrow versus new infection) and the relevant virus strains, viral receptors and tropisms which would contribute. Participants felt that unknown host factors might add to disease development and that the extent of viremia and immune surveillance may play a role in the disease process. A discussion ensued on how best to study PML. Differing opinions were voiced on which human tissue samples from brain, bone marrow or other tissues might be relevant and how to obtain these. Although the results of the serological survey being preformed by Dr. Major were not yet available the attendees looked forward to having this important data. Stored animal tissue obtained during toxicity studies which are a routine part of preclinical drug development might also provide research opportunities. It was felt that the existing viral animal models could be more thoroughly utilized, but that development of new improved models needs to be pursued. HIV cohorts or even the re-engagement in clinical trials of Natalizumab could provide other alternatives for the study of PML.

Session 2 led by Dr. Ransohoff explored the basic science of lymphocyte trafficking and of adhesion molecules. Questions discussed included 1) the types of adhesion molecules expressed on various cell types under certain conditions; 2) the role of adhesion molecules for CNS immuno surveillance; 3) the role of adhesion molecules in viral activation; and most important 4) whether ALL adhesion interventions would present with a similar risk for adverse events or similar types of adverse events. Would all inhibitors aiming at blood-brain-barrier blockade present with the same risk profile? General agreement was voiced on varying interventions likely presenting with specific sets of complications. Monitoring strategies however are hampered by a lack of knowledge about what intervention might trigger what types of adverse events.

In Session 3, led by Drs. Lublin and Calabresi, the participants discussed a variety of therapies currently under development which target immune cell migration. The panel explored what to consider before and during a clinical trial of selective adhesion inhibitors and how to deal with adverse event should they present. It was recommended that efforts be made to determine who would be at risk, how to assess risk and consequently who to enroll. The workshop debated whether monitoring for PML could be executed via frequent MRI imaging, PCR tests or serology testing for antiviral antibodies. Would a to-be-developed JC virus vaccine be able to prevent PML? How should PML be treated once diagnosed? The panel argued whether viruses other than JC could present problems or whether JC virus specifically interacts with VLA-4 the adhesion target molecule for Natalizumab. Did prior or concomitant treatments with immuno-suppressants or modulators play a role? Does JC viremia and clearance differ in patients with multiple sclerosis? How does virus enter the CNS? Why is PML so rare in light of the ever-presence of JC virus? The workshop presented a discussion forum for these questions, but most of them cannot be answered at the present time. The participants thought that more research in these areas is needed and that interdisciplinary collaboration between virologists and clinicians should be fostered.

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Agenda

Selective Adhesion Molecule Inhibitors and CNS Disease
July 26, 2005
Hotel Mandarin Oriental, Washington, D. C.

8:30am -- Welcome and Charge for the Day
Ursula Utz, Michael Nunn

8:50am -- The SENTINEL and AFFIRM Trials for MS
Peter Calabresi (15 min)

9:10am -- A Case Study of PML I
Annette Langer-Gould (15 min)

9:30am -- A Case Study of PML II
Betty Kleinschmidt-DeMasters (15 min)

9:50-10:10am -- Break

10:10am -- CSF Findings in Patients on Natalizumab
Olaf Stueve/Michael Racke (15 min)

10:30am -- Discussion Session I:
Biology of JC Virus
Gene Major (20 min)

12:00-1:30pm -- Lunch

1:30pm -- Discussion Session II:
Immune cell trafficking
Richard Ransohoff (30 min)

3:00pm -- Discussion Session III:
Therapeutic Strategies for Adhesion Molecule Inhibition
Peter Calabresi (20 min)
What to consider for future clinical trials?
Fred Lublin (15 min)

4:15pm -- Wrap up: Towards Successful Therapies for MS

5:00pm -- Adjourn

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Participant List

Walter J. Atwood, Ph.D.
Brown University

Peter A. Calabresi, M.D.
Johns Hopkins University

Robin Conwit, M.D.
NINDS, NIH

Thomas R. Esch, Ph.D.
NIAID, NIH

Robert S. Fujinami, Ph.D.
University of Utah

Brandy E. Fureman, Ph.D.
NINDS, NIH

William F. Hickey, M.D.
Dartmouth Medical School

Steven Jacobson, Ph.D.
NINDS, NIH

Kamel Khalili, Ph.D.
Temple University

Bette Kay Kleinschmidt-DeMasters, M.D.
University of Colorado Health Sciences Center

Igor J. Koralnik, M.D.
Beth Israel Deaconess Medical Center

Annette M. Langer-Gould, M.D.
Stanford University

Fred Lublin, M.D.
Mount Sinai Medical Center

Gene O. Major, Ph.D.
NINDS, NIH

Henry H. McFarland, M.D.
NINDS, NIH

Stephen D. Miller, Ph.D.
Northwestern University Medical School

Avindra Nath, M.D.
Johns Hopkins University

Michael Nunn, Ph.D.
NINDS, NIH

Michael A. Panzara, M.D., M.P.H.
Biogen Idec

Yuri Persidsky, M.D., Ph.D.
University of Nebraska

Michael K. Racke, M.D.
University of Texas Southwestern

Richard M. Ransohoff, M.D.
Cleveland Clinic Foundation

John R. Richert, M.D.
National Multiple Sclerosis Society

Gary J. Romano, M.D., Ph.D.
Merck Research Laboratories

Annette L. Rothermel, Ph.D.
NIAID, NIH

Alfred Sandrock, M.D., Ph.D.
Biogen Idec

Carlos Sanin,
GlaxoSmithKline

Keerti Shah
Johns Hopkins Univeristy

Olaf Stüve, M.D.
University of Texas Southwestern

Harry L. Ulrich, M.D.
Daiichi Medical Research, Inc.

Ursula Utz, Ph.D.
NINDS, NIH