HD Insights™

Vol. 5 - Fall 2013

Issue link: http://www.e-digitaleditions.com/i/164496

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H D I N S I G H T S Meet the Company VITAL SIGNS NAME: Pfizer, Inc. HEADQUARTERS: New York, NY STOCK PRICE AS OF 8/28/13: $28.00 52 WEEK RANGE: $23.55 - $31.15 MARKET CAPITALIZATION: $185 billion EMPLOYEES: 91,500 Pfizer, Inc. is a research oriented, global pharmaceutical company. In collaboration with CHDI and the ICM in Paris, Pfizer Neuroscience's HD team has been working to understand the role of phosphodiesterase 10A (PDE10A) inhibitors in the treatment of HD, and to develop clinical measures of their effectiveness and safety. Phosphodiesterase (PDE) inhibitors are a class of compounds currently being evaluated for a new use in HD therapy1. Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in medium spiny neurons of the striatum, and mouse models of HD and human HD patients demonstrate that PDE10A levels decline with progression of HD. However, promising preclinical studies on the use of PDE10A inhibitors for HD therapy are showing that paradoxically, PDE10A inhibition may represent an effective therapy.2-4 HD Insights spoke with Pfizer Global Clinical Lead Spyros Papapetropoulos, MD, PhD, and Pfizer Neuroscience HD Project Leader Margaret Zaleska, PhD, about the company's work with PDE10A inhibitors in HD. HD INSIGHTS: Can you tell us a little bit about Pfizer's interest in developing new treatments for HD? PAPAPETROPOULOS: HD research is supported across the Pfizer organization, as part of Pfizer's commitment to orphan indications. We are working with CHDI on many options for HD and scanning the landscape for opportunities at different levels of development. It's a very exciting time, for the clinical team, the research team, CHDI, and, I hope, the Huntington community. We have assembled an A-team of about 20 folks here, actively engaged in HD programs. ZALESKA: Our pursuit of phosphodiesterase inhibitors is in close collaboration with CHDI. This is a scientifically fulfilling and successful way of approaching this unmet medical need: combining Pfizer's expertise in medicinal chemistry and neuropharmacology with CHDI's focused efforts to apply the molecules that we make to HD. HD INSIGHTS: Dr. Zaleska, what is PDE10A? ZALESKA: PDE10A is a phosphodiesterase that catabolizes cyclic nucleotides. It is a dual substrate phosphodiesterase, meaning that the enzyme's substrates are both cyclic GMP (cGMP) and cyclic AMP (cAMP). The enzyme is important in cyclic nucleotide signaling cascades, which are involved in the functioning of many neuronal pathways. PDE10A is found almost exclusively in the medium spiny neurons of the striatum, the primary area of the brain affected in HD. Aggregates of mutated huntingtin have been found to impair cAMP signaling and cAMP responsive-element binding protein (CREB) mediated transcription of genes responsible for neurotransmitter synthesis, release and signaling pathways, as well as the production of brain derived neurotrophic factor (BDNF). The resulting degeneration affects many other areas of the brain, causing the behavioral, cognitive and motor impairments that are characteristic of HD. HD INSIGHTS: You say that PDE10A levels are reduced in individuals with HD. How do you measure that? ZALESKA: We measure that using imaging of the PDE10A selective PET ligand binding. We studied about ten individuals with different stages of HD in the pilot study. We found that their enzyme levels were between 50 and 55 percent of levels in controls. (continued on Page 6...) HD Insights, Vol. 5 Copyright © Huntington Study Group 2013. All rights reserved. 5

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