HD Insights™

H D I N S I G H T S Pfizer, cont... HD INSIGHTS: PDE10A levels are reduced in HD patients, so why would an enzyme inhibitor be beneficial? ZALESKA: PDE10A levels are most likely diminished by a compensatory biological response, an attempt to preserve cyclic nucleotide signaling at higher levels. Because PDE10A destroys cyclic nucleotide signaling, it diminishes with the disease. We know from animal models of HD that by inhibiting PDE10A, we can increase the level of cGMP and cAMP in the basal ganglia. Inhibition of PDE10A has been found to modulate striatal signaling in neuroprotective pathways, to decrease neurodegenerative changes in the striatum of animal models of HD, and to restore cAMP-dependent CREB signaling, which results in improved cortico-striatal communication. PAPAPETROPOULOS: The way that I see it as a physician scientist is we're basically helping nature. I know that is a paradox, but it has made a difference when it comes to electrophysiological signatures, especially improving the crosstalk between the cortex and the striatum which is so much affected in HD. I'll give you another example, which I borrow from my friend, Dr. Bernhard Landwehrmeyer. When I was first engaging with the program, I asked him, "Bernhard, what do you think we are doing here?" And he replied with a very simple analogy. "In HD the striatum is like a broken radio. No matter how much you try to crank up the volume, the radio can only produce a certain level of sound. What we're doing is amplifying this level of sound so the cortex can hear the basal ganglia better." HD INSIGHTS: You said that inhibition of PDE10A has a stimulating effect on the medium spiny neurons in the basal ganglia. Do PDE10A inhibitors prevent neuronal death of spiny neurons? ZALESKA: We do not have evidence of that. But, we have evidence that after dosing a transgenic mouse model of HD with PDE10A over four months, electrophysiological responses from medium spiny neurons following cortical stimulation are very significantly improved, compared with placebo-treated transgenic mice. We have evidence that the beneficial effects last beyond the presence of the drug in brain tissue, but we are very cautious about interpreting that as evidence of disease modification. At this moment we are focusing on potential treatment of symptoms, hoping that the improved cortico-striatal function will translate to clinically relevant effects in HD patients. HD INSIGHTS: Dr. Papapetropoulos, what are the plans for human clinical trials of phosphodiesterase inhibitors? PAPAPETROPOULOS: From a clinical perspective, we have multiple goals before we can safely move to a larger study. Our first goal is to answer the major question that Dr. Zaleska alluded to: Is PDE10A adequately expressed in HD? If the answer is yes, what areas are affected, and what are the clinical factors associated with different enzyme levels in HD? These are key questions in developing the right therapeutic approach for HD. The next question is: what are the treatment implications at the human brain circuit level? We have encouraging electrophysiological data that supports improved cortico-striatal connectivity, generated through our collaboration with CHDI. We want to replicate and sufficiently translate this dataset in a human cohort. We have established a collaborative study with the ICM at the Hôpital Salpétière in France, where we plan to dose early HD patients with our PDE10A inhibitor, and then scan these patients to detect PDE10A levels. This is a double blind, randomized, placebo controlled study with a sequential cohort design. It will be conducted at ICM in Paris, and we anticipate beginning to screen participants in the fall of 2013. We will use the monetary incentive delay task in an fMRI setting to look at potential differences between placebo and active drugs in brain activation. Abnormal activation in certain brain regions is known to occur starting in pre-symptomatic stages of HD with this task. This is work that was published by Enzi et al in 2012.5 We will also collect some additional endpoints. Although this study is not designed to answer any motor, behavioral, or cognitive questions, we have included a variety of exploratory endpoints that range from new innovative, objective measures of neuromotor function and tests of striatal activity to traditional endpoints, such as the UHDRS, apathy scales, both for safety purposes and also in the event that we can pick up signals of efficacy. (continued on Page 7..) Kleiman RJ, Kimmel LH, Bove SE, et al. Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington's disease. J Pharmacol Exp Ther. 2011 Jan;336(1):64-76. 1 Giampà C, Laurenti D, Anzilotti S, et al. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease. PLoS One. 2010 Oct 15;5(10):e13417. 3 4Strick Kleiman RJ, Schmidt CJ, Harms J et al. Phosphodiestrase inhibitors rescue deficits in synaptic plasticity and medium spiny neuron excitability in transgenic Huntington's Disease mouse model. Soc Neurosci. 2011 Abstract 148.15 2 6 CA, James LC, Fox CB, et al.Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A. Neuropharmacol. 2010 Feb;58(2): 444-51. 5 Enzi B, Edel MA, Lissek S, et al. Altered ventral striatal activation during reward and punishment processing in premanifest Huntington's disease: a functional magnetic resonance study. Exp Neurol. 2012 May;235(1):256-64. 6 clinicaltrials.gov/ct2/show/NCT01806896? term=PF-02545920&rank=8. Copyright © Huntington Study Group 2013. All rights reserved. HD Insights, Vol. 5

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