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.

Project Narrative The withdrawal symptoms associated with initiating naltrexone (an opioid blocker) or buprenorphine (a partial opioid agonist) in patients with opioid use disorder can be serious obstacles to successful treatment. BioXcel has developed the alpha-2-adrenergic agonist dexmedetomidine as a sublingual film (BXCL501), which has shown preliminary efficacy in humans in reducing opioid withdrawal symptoms at doses that produce minimal adverse effects on respiration, hypotension, hypertension, bradycardia, and sedation. The purpose of these inpatient (UG3) and outpatient (UH3) multi-site randomized, double-blind, placebo-controlled studies is to test the safety and preliminary efficacy of BXCL501 for treating opioid withdrawal.