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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.
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.
PAPAPETROPOULOS: By combining ICM’s expertise with our medicinal chemistry and clinical experience, we are hoping to directly translate the circuitry level data acquired in our preclinical trials into HD patients. We are also looking at safety, because this will be the first time that our PDE10A inhibitor, or any PDE10A inhibitor, will be administered to HD patients. Details about the study are listed at www.clinicaltrials.gov 6. The design of the study was presented at the recent CHDI meeting in Venice, and there is a lot of enthusiasm at Pfizer for this study.
HD INSIGHTS: It sounds like you’re doing lots of novel things in this trial. The first is that you’re investigating a novel class of compounds for HD. And the second is that you’re including some novel techniques to measure connectivity, including functional MRI. I don’t believe fMRI has been used before as a technique in HD clinical trials.
PAPAPETROPOULOS: That is correct. This is our attempt to humanize clinical research and look at circuits rather than symptoms. We believe that circuits are more preserved than behaviors, so they are easier to translate. And when we see congruency between human clinical patients and animal models, our confidence increases. The question remains whether a signal in the circuit will translate into a clinical patient benefit, but that is still to be addressed in future trials.
HD INSIGHTS: Dr. Zaleska, Dr. Papapetropoulos, thank you for your contributions to HD research and for taking the time to share them with HD INSIGHTS.
Spyros Papapetropoulos, MD, PhD, is a neurologist and movement disorder specialist trained at the National Hospital for Neurology and Neurosurgery, Queen Square, London UK, who leads Pfizer’s HD clinical program. He holds an academic appointment with the University of Miami Miller School of Medicine. He has spent his entire academic career studying movement disorders, and since transitioning to industry, he has focused on migraine and pain, neurodegeneration, and neurorehabilitation. When Dr. Papapetropoulos is not working to develop drugs for HD, he focuses on medications for Parkinson disease. He is also an avid tennis player.
Margaret Zaleska, PhD is a neuroscientist who leads the PDE10 inhibitor for HD research project in the Pfizer Neuroscience division. She earned her PhD in Biochemistry at the Polish Academy of Science in Warsaw, Poland, and then completed post-doctoral programs focused on neuroscience research at SUNY in the Department of Pharmacology and Experimental Therapeutics, and at the Oklahoma Medical Research Foundation. She was a member of the research faculty of the Perelman School of Medicine at the University of Pennsylvania, then joined Wyeth Research’s Neuroscience Division in Princeton, NJ in 1993. When Pfizer acquired Wyeth in 2009, Dr. Zaleska became a member of the Pfizer Neuroscience team. In her spare time, Dr. Zaleska enjoys exploring Pfizer Neuroscience’s new hometown of Cambridge, Massachusetts.
1 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.
2 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
3 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.
4 Strick 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