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)正在支持治疗OUD的创新药物的开发。 与停止使用阿片类药物有关的戒断症状是启动阿片类药物的严重障碍。 阻滞剂(纳曲酮)，并可能造成患者过渡到其他药物治疗阿片类药物的困难 使用精神障碍(Moud)，如丁丙诺啡。FDA批准α-2-肾上腺素能激动剂洛非西定 为改善戒断做出了重大贡献，但只有40%的受试者成为阿片类药物 在一项关键的研究中免费。这项研究是在强效合成药物广泛上市之前进行的 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是 不清楚。BioXcel已经开发出另一种α-2-肾上腺素能激动剂右美托咪定作为舌下(SL)膜 (BXCL501)。BXCL501可能优于阿片类药物，因为它是一种非阿片类药物 在最小的滥用可能性下，在减少阿片类药物戒断症状的剂量下，它的不良影响最小 呼吸、低血压、高血压、心动过缓和镇静。此外，它还避免了潜在的肝脏 旁路首过代谢引起的并发症。在最近完成的多项测试中收集的数据 递增剂量安全性和初步疗效研究表明，BXCL501测试的最高剂量 减少焦虑和改善睡眠障碍，这些症状通常没有得到很好的治疗 洛非西定。在拟议的研究中，BXCL501将被测试其减少体征和症状的能力 通过两个具体目标在多个地点控制阿片类药物戒断：1(UG3)。A阶段1b随机，双重- 盲法、安慰剂对照的安全性、最佳剂量发现和初步疗效住院研究(n=160)和2 (UH3)。一项2b期随机、双盲、安慰剂对照的门诊研究，比较了 BXCL501对安慰剂和洛非西定的疗效(n=300)。从UG3迁移到UG3的两个通过/不通过标准 UH3阶段为：1)BXCL501可减少30%以上的戒断症状(母猪总分) 与接受安慰剂的受试者母猪得分相比。2)严重不良事件不超过一次 在接受活性BXCL的受试者中，被归因于BXCL501，其最小剂量被确定为表现为 戒断症状至少减少30%。我们使用BXCL501和Strong的阳性临床结果 研究小组承诺，将这种新疗法推向市场将取得巨大成功。

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.