The program outlined in this Fast Track application has been designed to accelerate the development and commercialization of the DiazePen(tm) for the treatment of uncontrolled seizures in persons with epilepsy. The envisioned product would replace the current standard of care, diazepam rectal gel (DiaStat(r)), with a novel formulation fo rapid delivery via subcutaneous injection. For this effort, Xeris will use its proprietary formulaton platform (XeriSol(tm)), which has already demonstrated feasibility of a very-low volume, stable diazepam with pharmacokinetics similar to DiaStat(r). Successful completion of the aims will advance development of the DiazePen(tm) through the formulation optimization and nonclinical phase, IND application and manufacture of clinical supplies for a future Phase 1 clinical trial tha will be sponsored by Xeris Pharmaceuticals. This research is directly relevant to the NINDS which is explicitly interested in the development of innovative therapeutics for neurological disorders, including therapeutics (drugs, biologics, and/or devices) for treatment of neurological disorders, and technologies/methodologies to deliver therapeutics to the central nervous system. This proposal envisions six main objectives to significantly advance development of an auto-injectable diazepam as a first-line, at-home treatment for uncontrolled seizures. 1. Optimize XeriSol(tm) non-aqueous, soluble, stable diazepam formulations to provide the desired pharmacokinetic (PK) profile and confirm container-closure compatibility. 2. Manufacture at least three (3) GLP batches of non-clinical supplies of the optimized formulations and place these supplies on a short term stability study (real-time and accelerated). 3. Conduct IND-enabling animal studies: a. A 14-day safety-tolerability study in rats evaluating three (3) XeriSol diazepam formulations by daily subcutaneous and intradermal routes of injection. b. A comparative GLP PK study in mini pigs with Xeris' non-aqueous diazepam and DiaStat(r). This study will seek to demonstrate pharmacological comparability between the two products administered via intradermal and subcutaneous injection with respect to tolerability various PK parameters including Cmax, Tmax, and AUC compared to DiaStat(r) rectal gel. 4. Manufacture two (2) cGMP clinical batches of the drug product formulation in vials for the first clinical trialand place this batch on an ICH-compliant long-term stability study. 5. Conduct a comprehensive risk analysis and formative comparative human factors study with a DiazePen(tm) auto-injector and the commercial rectal gel applicator (Diastat(r) AcuDial). 6. Prepare and submit an amended IND application to the FDA seeking clearance for a Phase 1 clinical study.
The program outlined in this Fast Track application has been designed to accelerate the development and commercialization of the DiazePen(tm), an ultra-low volume, auto-injectable diazepam formulation for the rapid treatment of uncontrolled seizures in persons with epilepsy.