Team Asubio and Parkinson's Disease Team Asubio is working on an investigational drug that may improve the lives of patients suffering from the debilitating effects of motor complications associated with levodopa therapy for Parkinson's disease treatment. We want you to know about our progress. About Motor Complications in Parkinson's Disease As many as 6 million people worldwide suffer from Parkinson's disease including 1 million in the US alone, making it the 2nd most prevalent neuro-degenerative disease. The symptoms of Parkinson's disease may include tremor, slowness of movement, stiffness and rigidity of limbs and balance problems. Levodopa remains the gold standard therapy in the treatment of the symptoms of Parkinson's disease, and is used by nearly half of patients with early disease and up to 90% of patients with more advanced disease. While the beneficial effects of levodopa treatment are maintained throughout the entire course of the disease, chronic levodopa treatment is associated with the development of adverse events called motor complications (defined as motor fluctuations/increased OFF time also known as "wearing-off phenomenon" and dyskinesia) in most patients over time. Although the cause of motor complications is not completely clear, a relationship has been found between the occurrence of motor complications and unregulated dopamine concentrations in the brain. Motor fluctuations and increased OFF Time occur when the effect of levodopa is inadequate and Parkinson's disease symptoms are more prominent. This is thought to occur when dopamine concentrations in the brain are too low. Reduction in OFF Time is one of the key objectives of add-on therapy to levodopa treatment in Parkinson's disease. Dyskinesias are uncontrolled chaotic movements of the limbs, face, tongue and torso which seem to occur when dopamine levels in the brain are too high. Once a patient on levodopa develops dyskinesia, these abnormal movements usually occur soon after levodopa dosing and continue until the beneficial effects of the levodopa dose diminish. Dyskinesias can be extremely debilitating and are often the key complication that limits levodopa dose increases required to optimize the treatment of Parkinson's disease over the long term. Currently, no treatments exist that can adequately treat one element of levodopa-induced motor complications (dyskinesia and OFF Time) without potentially exacerbating the other. Pharmacologic advances that decrease both OFF Time and dyskinesia would be of benefit to Parkinson's disease patients as it would allow these patients to optimize their levodopa dose chronically to meet original treatment goals. BACK TO TOP New Developments in the Treatment of Motor Complications Associated with Parkinson's Therapy While the precise mechanisms underlying dyskinesias and increased OFF Time are not completely understood, emerging discoveries on levodopa-dependent dopamine release are offering hope for new treatment options for these devastating long-term side effects of levodopa therapy. Dopamine, a neurotransmitter that is essential for the healthy functioning of the central nervous system, affects emotion, perception and movement. Dopamine nerve cells are equipped with sensitive feedback mechanisms to control the amount of dopamine released and regulate body movement. Parkinson's disease is caused by the progressive destruction of these dopamine nerve cells. Levodopa therapy stimulates the release of dopamine from remaining dopamine neurons. Serotonin (5-HT1A) neurons also exist in the same area of the brain and in this specific area also play a role in motor functioning. The 5-HT1A receptor is a post-synaptic auto-receptor that reduces the firing of serotonin neurons when activated (Figure 1). Figure 1: Serotonin Innervation (click here to enlarge image)
		BACK TO TOP Levodopa is also known to stimulate dopamine neurotransmitter release from serotonin nerve cells located in this same area of the brain. Serotonin neurons are less likely to be damaged in Parkinson's disease, and may become a prime source of levodopa-derived dopamine as dopaminergic neurons are destroyed. These serotonin neurons lack the sensitive dopamine feedback mechanisms found on dopamine neurons, so the release of dopamine from serotonin neurons is poorly regulated, and this may result in uncontrolled, excessive swings in dopamine concentration in the brain. When serotonin neurons produce dopamine, they produce less serotonin, which causes the up-regulation of activity of serotonin neurons, which may in turn further exacerbate the excessive swings in dopamine release (Figure 2). Figure 2: Serotonin Innervation in Parkinson's Disease (click here to enlarge image)
		BACK TO TOP The integrity of the serotonin system may be an important determinant of both levodopa efficacy in advanced Parkinson's disease, and in the development of levodopa-induced dyskinesias and increased OFF Time. Piclozotan (SUN N4057) for the Treatment of Levodopa-induced Dyskinesia and Increased OFF Time Piclozotan (SUN N4057) is an investigational serotonin (5-HT1A) receptor agonist that originated in Asubio labs in Japan. By attaching itself to the 5-HT1A receptor and reducing neuronal firing, a 5-HT1A agonist would reduce the peaks of levodopa-derived dopamine in the brain while conserving remaining dopamine in storage sites in the synapse (Figure 3). Figure 3: 5-HT1A Agonists for Motor Complications in Parkinson's Disease (click here to enlarge image)
		BACK TO TOP Most 5-HT1A agonists that are commercially available or that are in development are also dopamine antagonists. Dopamine antagonists counteract the benefit of 5-HT1A agonists and worsen motor symptoms in Parkinson's disease. Piclozotan is different in that it has no dopamine antagonist activity, and is a functional agonist at dopamine D3 receptors. Asubio therefore believes that Piclozotan is uniquely suited to improve both dyskinesia and OFF Time associated with levodopa treatment in Parkinson's disease. Asubio evaluated Piclozotan for the treatment of levodopa-induced motor complications in Parkinson's disease in a recently completed placebo-controlled, Phase II, short duration proof-of-concept study. By the end of the trial, both ON time without dyskinesia and OFF time had improved with Piclozotan. The proportion of patients who were classified as dyskinesia responders also was higher in the Piclozotan group. Overall safety was consistent with known effects of 5-HT1A agonists. These results, which are consistent with the findings in animal models, support further clinical development in motor complications. Through our continued efforts, we hope to help Parkinson's disease patients optimize their levodopa treatment to control Parkinson's disease symptoms while minimizing the suffering from debilitating motor complications. BACK TO TOP DISCLAIMER: This website contains certain forward-looking statements about the potential of the investigational compound Piclozotan and reflect Asubio's current beliefs. However, as with any pharmaceutical compound under development, there are substantial risks and uncertainties in the process of development and regulatory review. All statements, facts, information, analyses, interpretations, and opinions contained in the report are provided "As Is" and are made without representation or warranty of any kind by Asubio, or their respective parents, affiliates, officers, employees, contractors or business partners as to accuracy, completeness, usefulness, merchantability, fitness for a particular purpose, or otherwise. There is no guarantee that later studies and patient experience with Piclozotan will be consistent with study findings to date. Asubio makes no guarantee, warranty, or assurances concerning the future financial return of an existing or proposed product or service related to the business alliance under evaluation. Asubio undertakes no duty to update forward-looking statements, and does not provide or act as a substitute for legal guidance and expertise. Piclozotan is being developed for the treatment of motor complications associated with Parkinson's disease. It has not been approved in any country by any regulatory authority for any indication.