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

舌下含服右美托咪定（一种 α2 肾上腺素能激动剂）用于治疗阿片类药物戒断的 1 期和 2 期研究

• 批准号: 10478324
• 负责人: SANDRA D COMER
• 金额: $ 331.22万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478324
• 关键词: Adrenergic Agonists; Adverse effects; Affinity; Agitation; Anxiety; Binding; Biological Assay; Blood Pressure; Bradycardia; Buprenorphine; Bypass; Clinical; Data; Development; Dexmedetomidine; Dose; Double-Blind Method; Dropout; Drops; Drug Metabolic Detoxication; Effectiveness; Exhibits; Fentanyl; Film; Future; Heart Rate; Human; Hypertension; Hypotension; Inpatients; Liver; Measures; Metabolism; Monitor; Naltrexone; Opiate Addiction; Opioid; Opioid agonist; Outpatients; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase; Phase II/III Trial; Physical Dependence; Placebo Control; Placebos; Play; Public Health; Randomized; Receptors, Adrenergic, alpha-2; Respiration; Role; Safety; Sedation procedure; Serious Adverse Event; Signs and Symptoms; Site; Sleep; Sleep disturbances; Suboxone; Substance Withdrawal Syndrome; Symptoms; Testing; Time; United States Food and Drug Administration; United States National Institutes of Health; Withdrawal; Withdrawal Symptom; abuse liability; associated symptom; clinically significant; compare effectiveness; craving; design; efficacy study; heroin use; illicit drug use; improved; innovation; lofexidine; non-opioid analgesic; opioid epidemic; opioid overdose; opioid tapering; opioid use; opioid use disorder; opioid withdrawal; overdose death; phase III trial; placebo controlled study; primary endpoint; response; safety testing; secondary endpoint; side effect; success; synthetic opioid

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.

项目概要 当前阿片类药物使用障碍 (OUD) 的流行是美国一场严重的公共卫生危机，为应对这一问题， 美国国立卫生研究院 (NIH) 正在支持开发治疗 OUD 的创新药物。 与停止使用阿片类药物相关的戒断症状是开始使用阿片类药物的严重障碍 阻滞剂（纳曲酮），可能会给患者过渡到其他药物治疗阿片类药物带来困难 使用障碍（MOUD），例如丁丙诺啡。 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% 的受试者使用阿片类药物 免费进行一项关键研究。这项研究是在有效的合成药物广泛使用之前进行的 阿片类药物芬太尼，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 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）。 BXCL501 可能优于阿片类药物逐渐减少等替代品，因为它是一种非阿片类药物 滥用可能性最小，并且在减少阿片类药物戒断症状的剂量下，其副作用也最小 关于呼吸、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 由于绕过首过代谢而引起的并发症。最近完成的多次收集的数据 递增剂量安全性和初步疗效研究表明，BXCL501测试的最高剂量 减少焦虑并改善睡眠障碍，这些症状通常无法通过以下方法得到很好的治疗 洛非西定。在拟议的研究中，将测试 BXCL501 减少体征和症状的能力 通过两个具体目标在多个站点减少阿片类药物戒断：1 (UG3)。 A 1b 期随机、双 盲法、安慰剂对照安全性、最佳剂量寻找和初步疗效住院研究 (n=160)，以及 2 （呃3）。一项 2b 期随机、双盲、安慰剂对照门诊研究，比较安全性和 BXCL501 相对于安慰剂和洛非西丁的疗效 (n=300)。从 UG3 转移到 UG3 的两个通过/不通过标准 UH3 阶段是：1) BXCL501 显示可减少戒断症状（总 SOWS 评分）30% 以上 与接受安慰剂的受试者的 SOWS 评分进行比较。 2) 不超过1次严重不良事件 归因于接受活性 BXCL 的受试者中的 BXCL501，该受试者以最小剂量确定表现出 戒断症状至少减少 30%。我们对 BXCL501 的积极临床发现和强大的 研究团队承诺将这种新疗法推向市场将取得巨大成功。