Determination of Route of Administration and Cardiac Safety of a Novel Psychoplastogen for the treatment of SUDs

摘要 Delix治疗公司正在开发精神成形剂，这种化合物可以促进快速和持续的 神经可塑性。这类新化合物是由Delix创始人大卫·奥尔森教授(UC Davis)确定的。 DLX-007是一种新型的、有效的精神增塑剂，其设计和灵感来自于已知的精神增塑剂Ibogaine和 5-MeO-DMT。与这些临床有效化合物类似，DLX-007促进结构和功能神经 与物质使用障碍(SODS)治疗相关的回路的可塑性，显示出对 临床前模型中的各种物质，包括阿片使用障碍(OUD)。除了减少海洛因外- DLX-007在啮齿动物体内的消耗和产生抗抑郁药样作用避免了许多安全问题 丰富的伊波甘尼。 DLX-007已完成GLP IND启用研究，显示出良好的安全性和相关的预期效果 OUD的临床前模型。为了进一步推进DLX-007的研制，为其过渡做好准备 对于人体试验，Delix建议建立理想的给药概况，同时保持可接受的 心脏毒性安全，用于治疗人类。在这项建议中，我们将首先评估理想的路线 肌注给药的药代动力学(PK)参数测定 临床前物种，模拟预测的人类PK，并将这些结果与先前获得的PK进行比较 静脉和口服给药参数。其次，我们将使用最先进的心血管安全 验证和扩大我们的化合物相对于ibogaine的比较改进 臭名昭著的心脏安全档案。 这一建议引入了一种治疗SUD的新范式，即利用结构可塑性。Delix‘s DLX-007是一种高潜力的治疗OUD的药物，保留了其促进神经再生的特性和 伊波甘的行为功效，但没有致幻责任和减少的心脏毒性责任。DLX- 007治疗可能逆转阿片类药物诱导的结构变化，其临床发展可能增强 治疗OUD的治疗武器库，特别是因为它提供了一种非阿片受体为基础的治疗 从长远来看，这可能能够逆转潜在的疾病神经病理学。由于DLX-007，S的情况有所改善 相对于其母体化合物的安全性，我们预计DLX-007也可能具有广泛的治疗作用 除其他神经精神和神经退行性疾病外，治疗多发性肥厚症的潜力 以PFC及其下游靶点的树突棘和突触丢失为特征。

ABSTRACT Delix Therapeutics is developing psychoplastogens, compounds that promote rapid and sustained neuroplasticity. This new class of compounds was identified by Delix founder, Professor David Olson (UC Davis). DLX-007 is a novel, potent psychoplastogen designed and inspired by known psychoplastogens Ibogaine and 5-MeO-DMT. Similar to these clinically effective compounds, DLX-007 promotes structural and functional neural plasticity in circuits relevant for the treatment of substance use disorders (SUDs) with demonstrated efficacy for a variety of substances in preclinical models including opioid use disorder (OUD). In addition to reducing heroin- consumption and producing antidepressant-like effects in rodent, DLX-007 avoids many of the safety concerns abundant to ibogaine. DLX-007 has completed GLP IND-enabling studies, showing a good safety profile and desired effect in relevant preclinical models of OUD. In order to further advance the development of DLX-007 and position it for transition to human trials, Delix proposes to establish the ideal administration profile, while maintaining acceptable cardiotoxic safety, for the treatment of humans. In this proposal, we will first assess the ideal route of administration by establishing the pharmacokinetic (PK) parameters of intramuscular administration in three preclinical species, modelling the predicted human PK and comparing those results to previously obtained PK parameters for intravenous and oral administration. Secondly, we will use a state-of-the-art cardiovascular safety assay to validate and expand the comparative improvements our compound has in relation to ibogaine’s notorious cardio-safety profile. This proposal introduces a novel treatment paradigm for SUD, namely, leveraging structural plasticity. Delix’s DLX-007 is a high potential therapeutic for OUD, preserving its neuroplastic promoting characteristics and behavioral efficacy of ibogaine but without the hallucinogenic liabilities and reduced cardiotoxic liabilities. DLX- 007 treatment may reverse opioid-induced structural changes and its clinical development could enhance the therapeutic arsenal for treating OUD, in particular because it provides a non-opioid receptor-based therapeutic that might be capable of reversing the underlying disease neuropathology long-term. Due to DLX-007’s improved safety profile relative to its parent compound, we anticipate that DLX-007 may also have broad therapeutic potential for treating multiple SUDs in addition to other neuropsychiatric and neurodegenerative disorders characterized by dendritic spine and synapse loss in the PFC and its downstream targets.