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7 HD Insights, Vol. 12 Dr. Maurice Zauderer is the founder, president, and CEO of the privately held biotechnology company Vaccinex Inc., headquartered in Rochester, NY. Vaccinex focuses on the development of new human antibodies to combat a variety of conditions, including multiple sclerosis, cancer, and more recently, HD. Vaccinex's VX15/2503 monoclonal antibody has recently been evaluated in Phase I trials for safety in multiple sclerosis and solid tumors, and the company has initiated a Phase II study to evaluate the safety, tolerability, and efficacy of VX15/2503 in HD. Dr. Zauderer recently shared his thoughts with HD Insights on VX15/2503 and its potential use in HD. The following is an edited transcript of the conversation. HD INSIGHTS: Dr. Zauderer, can you describe the mechanism of action of VX15/2503 in HD? ZAUDERER: VX15/2503 is a monoclonal antibody to semaphorin 4D, which is a member of the semaphorin family of proteins. Semaphorins direct the movement of cells in the body. They play a very important role during embryonic development, where cells move to shape different tissues and organs, and they continue to be important in the adult, because the adult continues to generate a variety of cells that are required to migrate to different locations in the body. For example, immune cells are generated in one location, but they must migrate to the site of an infection. Semaphorins play an important role in guiding that migration, and we have shown that semaphorin 4D plays a particularly important role in guiding the migration of cells that are relevant to neuroinflammatory and neurodegenerative diseases. Microglia and astrocytes are two important inflammatory cells in the central nervous system that are activated by semaphorin 4D. They are beneficial in an acute situation, but they can both contribute to neurodegenerative processes if they are chronically activated. They produce biological modifier molecules such as cytokines that can cause damage to neural tissue. It is important to be able to regulate their activation and to minimize their effect on these neuroinflammatory and neurodegenerative processes. Vaccinex's new therapy, VX15/2503, is a humanized antibody that is specific for semaphorin 4D, which it neutralizes, and thereby inhibits chronic activation of microglia and astrocytes and prevents some of the deleterious consequences that are associated with neuroinflammatory and neurodegenerative disease. HD INSIGHTS: You have studied VX15/2503 for use in multiple sclerosis (MS) and in solid tumors with Phase I trials. Why have you proposed it for use in HD? ZAUDERER: In both progressive MS and HD, microglia and astrocytes contribute to the slow, but progressive, neurodegenerative process. HD INSIGHTS: You recently collaborated with Dr. Amber Southwell and colleagues on a study of VX15/2503 in the YAC128 mouse model of HD. 1 Can you tell us about that study? ZAUDERER: That was a very exciting collaboration. The YAC128 mouse model expresses a fully human mutant huntingtin gene that leads to neuroinflammation and neurodegeneration. The mice typically develop HD-like symptoms between six and 12 months of age with a variety of cognitive and behavioral deficits, and with neuropathology such as decreased brain volume. Our goal was to see whether VX15/2503 could prevent the development of these deficits. We tested it as a preventive therapy, by treating YAC128 mice starting at around six weeks of age. It was very gratifying to see that at least in some areas, we saw a marked amelioration of the disease process. Meet the CEO VITAL SIGNS NAME: Maurice Zauderer, PhD CURRENT POSITION: President and CEO, Vaccinex Inc. EDUCATION: BS, Physics, Yeshiva University, New York, NY; PhD, Cell Biology, Massachusetts Institute of Technology, Cambridge, MA HOBBIES: Listening to music (particularly Mozart), and golf (continued on Page 8...) Copyright © Huntington Study Group 2015. All rights reserved. H D I N S I G H T S Dr. Maurice Zauderer