An ultra-long-acting oral treatment for opioid use disorder

丁丙诺啡（BUP）是一种FDA批准的药物辅助治疗（MAT），可改善预后， 挽救阿片类药物使用障碍（OUD）患者的生命。它有多种剂型和给药途径， 给药，包括每日舌下（SL）和口腔片剂和薄膜，每月皮下（SC） 注射和6个月SC植入;然而，这些形式使许多患者未经治疗或治疗不足。 目前没有口服BUP产品，也没有非胃肠外BUP产品， 频率低于每天一次。NIDA和联邦政府都呼吁采取新的治疗方法 OUD帮助解决当前阿片类药物危机的战略，包括现有药物的新配方 改善获取和遵守情况并减少转用。该提案旨在开发每周一次的 用于OUD维持治疗的口服BUP剂型。长效口服BUP可解决重要的 当前MAT的局限性，通过提供改善的PK和比SL更少的欣快，SL是一种患者和提供者， 优选的给药途径，以及用于改善患者依从性的最佳给药间隔。 具有成本效益的直接观察治疗的潜力。BUP的口服生物利用度低于SL，但可能 如果连续递送至上胃肠道，则足够高以达到治疗血浆浓度。 Lyndra开发了一种口服胃驻留剂型，可提供至少7天的连续药物 交付. Lyndra的技术已在多个大型动物模型中得到验证，并通过临床试验。 与爱力根合作治疗阿尔茨海默病Lyndra的主要产品已在cGMP下生产 并获得严格的监管机构批准用于正在进行的I期试验。UG 3阶段 建议是两年的药理学表征的连续胃输送的BUP， 临床候选剂型的药物开发，以及首次临床试验IND的提交。 人体试验目的1评价持续口服布吡格雷的药理学作用， 在充分表征的恒河猴模型中的胃递送。在目标2中，剂型开发和 将进行优化以实现药物负荷、释放动力学和PK特征的目标值。Naloxone (NAL)将通过热熔挤出与BUP共包封在聚合物基质中以阻止转移， 误用目标2最终选择了一种用于临床开发的主要制剂。目标3将侧重于 导致提交IND用于每周一次BUP/NAL剂量的首次人体临床试验的活动 包括工艺开发和规模扩大、有效期研究、临床生产和GLP毒性 问题研究该提案的UH 3阶段包括一项首次人体临床试验，以评估以下药物的安全性和PK OUD患者每周一次口服BUP/NAL剂型，以及POC单次递增剂量 和多次给药研究，证明了治疗性BUP血浆浓度的安全和一致的递送。 进入UH 3阶段的门控里程碑是FDA接受IND。 Lyndra Inc机密第1页

Buprenorphine (BUP) is an FDA-approved medication-assisted therapy (MAT) for that improves outcomes and saves lives in patients with opioid use disorder (OUD). It is available in multiple dosage forms and routes of administration, including daily sublingual (SL) and buccal tablets and films, a monthly subcutaneous (SC) injectable, and a 6-month SC implant; however, these forms leave many patients untreated or undertreated. No oral BUP product is currently available, nor do non-parenteral BUP products exist that are administered less frequently than once per day. NIDA, as well as the federal government, have called for new treatment strategies for OUD to help address the current opioid crisis, including new formulations of existing medications to improve access and compliance and reduce diversion. This proposal is for development of a once-weekly oral BUP dosage form for maintenance therapy for OUD. A long-acting oral BUP may address important limitations of current MATs by providing improved PK with less euphoria than SL, a patient- and provider- preferred route of administration, and an optimal dosing interval for improved patient adherence with the potential for cost-effective direct observed therapy. The oral bioavailability of BUP is lower than SL but may be high enough to achieve therapeutic plasma concentrations if delivered continuously to the upper GI tract. Lyndra has developed an oral gastric residence dosage form that provides at least 7 days of continuous drug delivery. Lyndra's technology has been validated in multiple large animal models and through a clinical partnership with Allergan for Alzheimer's Disease. Lyndra's lead product has been manufactured under cGMP and approved by a stringent regulatory authority for Phase 1 trials which are ongoing. The UG3 phase of this proposal is for two years of pharmacological characterization of continuous gastric delivery of BUP, pharmaceutical development of a clinical candidate dosage form, and submission of an IND for a first-in- human trial. Aim 1 will evaluate the pharmacology of continuous oral administration of BUP and feasibility of gastric delivery in a well-characterized rhesus monkey model. In Aim 2, dosage form development and optimization will be pursued to achieve target values for drug load, release kinetics and PK profile. Naloxone (NAL) will be co-encapsulated with BUP in a polymer matrix via hot melt extrusion to deter diversion and misuse. Aim 2 culminates in the election of a lead formulation for clinical development. Aim 3 will focus on activities leading to submission of an IND for a first-in-human clinical trial of a once-weekly BUP/NAL dosage form, including process development and scale-up, shelf life studies, clinical manufacturing and GLP toxicity studies. The UH3 phase of the proposal includes a first-in-human clinical trial to evaluate the safety and PK of a once-weekly oral BUP/NAL dosage form in individuals with OUD, as well as a POC single ascending dose and multiple dose study demonstrating safe and consistent delivery of therapeutic BUP plasma concentrations. The gating milestone for advancement to the UH3 phase is acceptance of the IND by the FDA. Lyndra Inc Confidential Page 1