Phase 1 and 2 studies of sublingual dexmedetomidine, an alpha 2 adrenergic agonist, for treating opioid withdrawal

项目摘要 目前阿片类药物使用障碍（OUD）的流行是美国严重的公共卫生危机，作为回应， 美国国立卫生研究院（NIH）正在支持开发用于治疗OUD的创新药物。 与停止使用阿片类药物相关的戒断症状是启动阿片类药物的严重障碍 阻滞剂（纳洛酮），并可能给患者过渡到其他阿片类药物治疗带来困难 使用障碍（MOUD），如丁丙诺啡。FDA批准α-2-肾上腺素能激动剂洛非西定 对改善OUD戒断做出了重大贡献，但只有40%的受试者成为阿片类药物 在一项关键性研究中免费使用。这项研究是在有效的合成药物广泛使用之前进行的。 阿片类芬太尼，因此洛非西定治疗芬太尼依赖患者阿片类药物戒断的有效性 不清楚BioXcel开发了另一种α-2-肾上腺素能激动剂右美托咪定作为舌下（SL）薄膜 （BXCL501）。BXCL 501可能上级于阿片类药物减量等替代品，因为它是一种非阿片类药物 具有最小的滥用潜力，并且在减少阿片类药物戒断症状的剂量下，它具有最小的副作用 呼吸、低血压、高血压、心动过缓和镇静。此外，它避免了潜在的肝脏 绕过首过代谢引起的并发症。在最近完成的多次 递增剂量安全性和初步疗效研究显示，测试的最高剂量的BXCL 501 减少焦虑和改善睡眠障碍，这是通常不能很好地治疗的症状， 洛非西定。在拟议的研究中，将测试BXCL 501减少体征和症状的能力 通过两个特定目的在多个部位进行阿片类药物戒断：1（UG3）。一项1b期随机化、双- 设盲、安慰剂对照安全性、最佳剂量探索和初步疗效住院研究（n = 160），和2 （UH3）。一项2b期随机、双盲、安慰剂对照门诊研究，比较了 BXCL 501相对于安慰剂和洛非西定的疗效（n = 300）。从UG3移动到 UH3阶段是：1）BXCL 501显示出减少戒断症状（总SOWS评分）超过30% 与接受安慰剂的受试者的SOWS评分相比。2)不超过1起严重不良事件 在接受最小剂量活性BXCL的受试者中， 戒断症状减少30%我们对BXCL501的积极临床发现和强 研究小组保证将这种新疗法推向市场会取得很大成功。

Project Summary The current epidemic of Opioid Use Disorder (OUD) is a severe public health crisis in the US, and in response, the National Institutes of Health (NIH) is supporting development of innovative medications for treating OUD. The withdrawal symptoms associated with cessation of opioid use are serious obstacles to initiating opioid blockers (naltrexone) and may pose difficulties in transitioning patients to other medications for treating opioid use disorder (MOUD), such as buprenorphine. The FDA approval of the alpha-2-adrenergic agonist lofexidine has made a significant contribution to ameliorating OUD withdrawal, but only 40% of subjects became opioid free in a pivotal study. This study was conducted prior to the widespread availability of the potent synthetic opioid fentanyl, so the effectiveness of lofexidine in treating opioid withdrawal in fentanyl-dependent patients is unclear. BioXcel has developed another alpha-2-adrenergic agonist dexmedetomidine as a sublingual (SL) film (BXCL501). BXCL501 is potentially superior to alternatives such as opioid tapering because it is a non-opioid with minimal abuse potential, and at doses that reduce opioid withdrawal symptoms, it has minimal adverse effects on respiration, hypotension, hypertension, bradycardia, and sedation. Furthermore, it avoids potential liver complications due to bypassing first-pass metabolism. Data collected during a recently completed multiple ascending dose safety and preliminary efficacy study showed that the highest dose of BXCL501 tested reduced anxiety and improved sleep disturbances, which are symptoms that are typically not well treated with lofexidine. In the proposed studies, BXCL501 will be tested for its ability to decrease the signs and symptoms of opioid withdrawal across multiple sites through two Specific Aims: 1 (UG3). A Phase 1b randomized, double- blind, placebo-controlled safety, optimal dose finding, and preliminary efficacy inpatient study (n=160), and 2 (UH3). A Phase 2b randomized, double-blind, placebo-controlled outpatient study comparing the safety and efficacy of BXCL501 to placebo and lofexidine (n=300). Two Go/No-Go criteria for moving from the UG3 to the UH3 phases are: 1) BXCL501 is shown to reduce withdrawal symptoms (total SOWS score) more than 30% compared to the SOWS score of subjects receiving placebo. 2) No more than one serious adverse event attributed to BXCL501 among the subjects receiving active BXCL at the minimum dose identified to exhibit at least a 30% reduction in withdrawal symptoms. Our positive clinical findings with BXCL501 and strong investigative team promise high success for bringing this new treatment to market.