A once-weekly oral methadone for maintenance therapy for opioid use disorder

美沙酮是FDA批准的治疗阿片类药物使用障碍(OUD)的药物辅助疗法(MAT)。美沙酮 维持疗法已被证明可以促进康复和防止死亡。在美国的美沙酮 维持疗法目前包括在特别指定的治疗地点每天给药一次。 (“美沙酮诊所”)在直接监督下。每天一次的直接观察治疗对 许多患者和提供者，并促成了目前的治疗缺口，其中只有大约20% 患有尿毒症的患者正在接受垫子治疗。药物递送技术的最新创新，如长效 注射剂，还没有应用于美沙酮的释放，美沙酮药物产品基本上是 与几十年前推出的即刻释放产品完全相同。奈达已经表示需要 OUD的新治疗战略，以帮助解决目前的阿片类药物危机，包括新的 现有的药物，如美沙酮，以改善治疗的可及性和依从性，并减少转移。 这项建议是为了开发一种每周一次的口服美沙酮，用于OUD的维持治疗。Lyndra 已经开发出一种口服胃滞留剂型，已经证明至少提供了七种 连续几天提供多种不同的治疗药物，包括治疗阿尔茨海默氏症的药物 疾病、艾滋病毒和疟疾。Lyndra的技术已经在多个大型动物模型中得到验证，并正在 目前正在进行临床试验。每周一次的美沙酮口服产品可以(1)降低治疗的主要障碍。 对于许多患者来说，(2)减少MMT的耻辱和社会经济影响，以及(3)增加MMT的能力 美沙酮治疗中心通过减少患者就诊次数。 该提案的UG3阶段是为期两年的药物开发和药理学 每周一次口服美沙酮剂型的特征，导致临床候选药物的选择 进行首例人体试验并提交IND。在目标1中，剂型开发和优化将是 追求达到药物载量、释放动力学和PK曲线的目标值。Aim 2将专注于Ind- 支持导致提交IND进行首例人类临床试验的活动。每周一次美沙酮 剂型工艺开发和放大、货架期研究、临床制造和GLP毒性 我们会进行研究。该提案的UH3阶段包括评估安全性和PK的临床试验 每周一次的口服美沙酮剂型在患有OUD的受试者中的应用，这些受试者目前正在维持一次- 每日服用美沙酮。过渡到UH3阶段的门槛里程碑是FDA接受IND。 Lyndra Inc.保密第1页

Methadone is an FDA-approved medication-assisted therapy (MAT) for opioid use disorder (OUD). Methadone maintenance therapy has been shown to facilitate recovery and prevent deaths. In the US methadone maintenance therapy currently involves once-daily drug administration at specially designated treatment sites (“methadone clinics”) under direct observation. Once-daily directly observed therapy presents difficulties for many patients and providers and contributes to the current treatment gap wherein only approximately 20% of patients with OUD are receiving MATs. Recent innovations in drug delivery technology, such as long-acting injectables, have not been applied to methadone delivery and methadone drug products are essentially identical to the immediate release products introduced several decades ago. NIDA has expressed a need for new treatment strategies for OUD to help address the current opioid crisis, including new formulations of existing medications such as methadone to improve treatment access and compliance and reduce diversion. This proposal is for development of a once-weekly oral methadone for maintenance therapy for OUD. Lyndra has developed an oral gastric residence dosage form that has been demonstrated to provide at least seven days of continuous delivery of many different therapeutic agents, including drugs for treatment of Alzheimer’s disease, HIV and malaria. Lyndra’s technology has been validated in multiple large animal models and is currently in clinical trials. A once-weekly oral methadone product could (1) lower a major barrier to treatment for many patients, (2) reduce the stigma and socioeconomic impact of MMT, and (3) increase the capacity of methadone treatment centers by reducing the number of patient visits. The UG3 phase of this proposal is for two years of pharmaceutical development and pharmacological characterization of a once-weekly oral methadone dosage form, leading to the selection of a clinical candidate for a first-in-human trial and submission of an IND. In Aim 1, dosage form development and optimization will be pursued to achieve target values for drug load, release kinetics and PK profile. Aim 2 will focus on IND- enabling activities leading to submission of an IND for a first-in-human clinical trial. Once-weekly methadone dosage form process development and scale-up, shelf life studies, clinical manufacturing and GLP toxicity studies will be performed. The UH3 phase of the proposal includes clinical trials to evaluate the safety and PK of the once-weekly oral methadone dosage form in subjects with OUD who are currently maintained on once- daily methadone. The gating milestone for transition to the UH3 phase is acceptance of the IND by the FDA. Lyndra Inc Confidential Page 1