Ecopipam

Long-term safety data collected in pediatric patients treated with investigational drug ecopipam; durable treatment effect reported with no evidence of tachyphylaxis CHICAGO--(BUSINESS WIRE)-- An open-label extension study of 121 pediatric patients with Tourette syndrome evaluated the safety pro the investigational drug ecopipam for up to 12-months of treatment. No new safety concerns were identified based on an evaluation of adverse events, physical exams, vital signs, laboratory results and safety scales, according to Emalex Biosciences. A durable effect was also observed over the course of the study based on evaluation of the patients’ motor and vocal tics, which were assessed every three months. The findings were first presented at the International Congress of Parkinson’s Disease and Movement Disorder Society in Copenhagen and will be highlighted at the Child Neurology Society Annual Meeting this week in Vancouver. Patients in the open-label study previously completed a Phase 2b clinical trial involving more than 150 children and adolescents that found ecopipam significantly reduced the total number of motor and vocal tics compared to placebo, according to a study published in the journal Pediatrics. In this open-label study, ecopipam was generally well tolerated, with 33.1% (40/121) of patients reporting treatment-related adverse reactions (ARs). The most common ARs were anxiety (6.6%), insomnia (5.8%), and somnolence (5.8%). One patient experienced a serious adverse reaction (obsessive thoughts) and 11.6% (14/121) of patients discontinued the study due to adverse events. In addition, patients did not have observable evidence of excessive weight gain or metabolic side effects commonly reported with antipsychotic agents, which are often used to treat patients with Tourette syndrome. Ecopipam is a first-in-class dopamine-1 receptor antagonist. The antipsychotic agents currently approved to treat Tourette syndrome target the dopamine-2 receptor. Ecopipam is the lead candidate for Emalex Biosciences, a clinical-stage biopharmaceutical company founded by Paragon Biosciences. Emalex is currently conducting a Phase 3 clinical trial of ecopipam for the treatment of Tourette syndrome at more than 90 sites in North America and Europe. Tourette syndrome is a chronic, childhood-onset neurodevelopmental disorder characterized by motor and vocal tics. The condition is associated with both increased mortality and significant morbidity. In the majority of individuals, Tourette syndrome substantially impacts day-to-day physical and social function. “The fact that most patients who completed the Phase 2b study asked to participate in the open-label extension points to the unmet medical needs for people with Tourette syndrome. The 12-month data supports the continued development of ecopipam as a first-in-class novel therapy for children and adolescents with Tourette syndrome,” said Emalex Biosciences Chief Medical Officer Frederick Munschauer, MD. About Ecopipam Emalex’s first-in-class development candidate ecopipam, a novel investigational compound that is being studied as a potential treatment for certain central nervous system disorders, blocks the actions of the neurotransmitter dopamine at the D1 receptor. Dopamine is a neurotransmitter in the central nervous system, and its receptors have been classified into two “families” based on their genetic structure: “D1” (including subtypes D1 and D5) and “D2” (including subtypes D2, D3, and D4). D1 receptor super-sensitivity may be a mechanism for the repetitive and compulsive behaviors associated with Tourette syndrome. Currently approved therapies for the treatment of Tourette syndrome act at D2 receptors. Ecopipam has been shown to be generally well tolerated in clinical trials conducted to date and has received Orphan Drug and Fast Track designation from the FDA for the treatment of patients with Tourette syndrome. Adverse events affecting primarily the central nervous system have been reported in clinical trials conducted to date, including headache, fatigue, somnolence, insomnia, restlessness, anxiety, depression and rarely, suicidal ideation. About Emalex Biosciences Emalex Biosciences was created by Paragon Biosciences to develop new treatments for central nervous system disorders. Emalex is in late-stage development of a new class of drug targeting the D1 receptor for patients with Tourette syndrome and other conditions that have limited treatment options. Visit to learn more. About Paragon Biosciences, LLC Paragon Biosciences is a global life science leader that creates, builds and funds innovative biology-based companies in three key areas: cell and gene therapy, biology engineering and advanced biotechnology. Our portfolio companies use biology to accelerate scientific breakthroughs that solve some of society’s most challenging problems. Learn more at .

近日，美国西北大学的研究团队获得了精神病神经基础理解的里程碑式发现——与抗精神病药物相结合调控纹状体输出并不是D2R，而是D1R。 精神分裂症是一种严重的精神障碍，患者可能出现感知、思维和情感方面的严重紊乱，对日常生活产生十分恶劣的影响。 多巴胺假说是精神分裂症发病机制的重要假说之一。多巴胺假说认为，精神分裂症可能与大脑中多巴胺的过度活跃有关。过度活跃的神经递质导致特定神经回路的失衡，从而引发幻觉、妄想、思维紊乱、情感疏离等症状。抑制多巴胺活性被认为是抗精神病药物的主要作用机制之一。 大脑纹状体区域的棘状投射神经元（SPNs）分别表达多巴胺受体D1（D1R）和多巴胺受体D2（D2R），受体与Gαs偶联可以增加或降低SPN活动。通过调节SPN，可以达到平衡纹状体输出的目的。 以往科学家认为，抗精神病药物是通过与D2R结合来抑制多巴胺活性的。事实上，D2R在纹状体之外的脑细胞中也有表达，根据受体表达水平预测的药物治疗效果往往与实际存在误差甚至完全相反。 近日，美国西北大学的研究团队获得了精神病神经基础理解的里程碑式发现——与抗精神病药物相结合调控纹状体输出并不是D2R，而是D1R。 研究发现，有些药物虽然能够使D2-SPN动态正常化，但是却没有产生临床效果。药物的抗精神病功效与D1-SPN的动力学逆转有关。选择性抑制D1-SPN可以减弱安非他命驱动的过度运动、幻觉等症状。 研究发表在《自然·神经科学》上。 研究人员通过神经群体成像方法记录小鼠大脑D1-SPN和D2-SPN的活动。使用安非他命诱导多巴胺释放，神经元活动与之前观察的一致，D1-SPN活动水平增加，D2-SPN活动水平降低。 接下来，研究人员选择了4种抗精神病药物，评估其对神经元活动的影响。其中，氟哌啶醇有显著的运动障碍副作用，氯氮平和奥氮平运动障碍副作用较轻，MP-10为临床失败的精神分裂症候选药物。根据小鼠用药后的运动能力，设置高、低两种药物剂量。 结果显示，3种临床有效药物均可以减轻安非他命引起的D1-SPN神经元动态紊乱、过度运动和感觉运动门控异常（即感觉和运动之间的调节失常）。相比之下，MP-10虽然减轻了安非他命引起的D2-SPN活动水平降低，但是加剧了D1-SPN的过度活动，且并未纠正小鼠的感觉运动门控异常。 抗精神病药物改善小鼠的过度运动 这样的结果提示我们，是不是对D1-SPN活动的纠正，才是药物起效的关键呢？ 研究人员用其他新型抗精神病药物候选化合物进行了测试。虽然这些化合物的作用机制并不是与多巴胺受体结合，但所有产生临床疗效的化合物，都可以减轻安非他命引起的D1-SPN过度活动。而通过化学方法抑制D1-SPN活性，也可以减轻安非他命导致的小鼠幻听。 药物对D1-SPN的影响能更好地解释抗精神病药物的疗效 分别使用D1R部分激动剂SKF38393、D1R拮抗剂SCH23390/SCH39166处理小鼠，结果显示，3种化合物可以减轻安非他命引起的过度运动和感觉运动门控异常。其中，SKF38393在基线条件下促进D1-SPN活动，在多巴胺过度释放的条件下抑制D1-SPN活动，表现出多巴胺状态依赖性的D1-SPN选择性抑制。 总的来说，研究证明，抗精神病药物的疗效与其恢复D1-SPN的正常活动有关，为开发副作用更小的药物开辟了新的选择。研究人员表示，“这是一个里程碑式发现，彻底改变了我们对精神病神经基础的理解”。