Dexmedetomidine Sublingual Film for the Ambulatory Treatment of Hyperadrenergic Autonomic Crisis in Patients with Familial Dysautonomia

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ABSTRACT This proposal tests a novel approach to treating hyperadrenergic autonomic crises in patients with a rare ge- netic disease – familial dysautonomia (FD). FD is caused by an autosomal recessive mutation in the ELP1 gene and manifests in developmental delay, musculoskeletal abnormalities, labile blood pressure, chronic lung infections, difficulty swallowing, and optic nerve atrophy. There are no disease-modifying therapies for FD. Hy- peradrenergic autonomic crises are the most frequent and severe symptoms of FD, occurring as often as once per day, with a median occurrence of once per month, are triggered by either physical illness or emotional exci- tation, and entail acute elevation in blood pressure and heart rate, accompanied by continuous vomiting and retching. Autonomic crises can be deadly or lead to secondary complications (i.e., bronchoaspiration; infec- tions). Current approaches towards autonomic crisis resolution at home involve non-pharmacologic treatments to decrease the sympathetic surge followed by benzodiazepines and clonidine, which may produce sedation and carry severe side effects, such as hypotension and respiratory depression. Effective and safe therapies that could abort or prevent autonomic crises in the at-home setting are desperately needed. This study will test a novel approach toward autonomic crisis resolution at home. At the core of this approach is the administration of sublingual dexmedetomidine (IGALMI™; BioExcel Therapeutics, Inc). IV dexmedetomi- dine is the standard of care for aborting refractory autonomic crises when delivered intravenously (IV) but can only administered in the ICU. The innovation of this new presentation lies in its mode of drug delivery, a sublin- gual fast-absorbing film that can circumvent a patient’s swallowing difficulties and vomiting episodes, allow for easy administration of the medication at home, and prevent hospitalizations. This study hypothesizes that IGALMI™ film is more effective than placebo and non-pharmacologic treatments in terminating autonomic cri- ses at home. Concurrently with IGALMI™ treatment, FD patients will undergo non-pharmacological interven- tion via telemedicine and help manage symptoms and vital signs monitoring. An exploratory aim of this study is the development of a methodology for predicting autonomic crisis onset 24 hours before the event to prevent the crisis through early intervention. This will be achieved by collecting continuous data on patients’ trend changes in vital signs through wearable device and AI analytics. In Aim 1 of this clinical trial, fifteen FD patients will be randomized 2:1 into active treatment (IGALMI™) and placebo groups to receive medication/placebo at the onset of the autonomic crisis in addition to non-pharmacological assistance through video. In Aim 2, we will evaluate if patients had fewer hospital stays than the previous year by using IGALMI™ at home for crisis man- agement. In Aim 3 of this study, data collected through a wearable Biobeat® device will be analyzed to identify early signs of AC for each patient.