Abstracts

Rationale: USL261 is a proprietary intranasal (IN) formulation of midazolam (MZ) in development for the orphan indication of rescue treatment of seizures in patients who require control of intermittent bouts of increased seizure activity, often referred to as seizure clusters or acute repetitive seizures. MZ for injection (MZ-inj) given IN has been reported in the literature to be a safe and effective treatment for this use. USL261 has been formulated for easy and rapid administration of MZ by healthcare providers and in an outpatient setting. This study was conducted to assess the degree and duration of sedation, impairment of psychomotor performance, and safety of USL261 in healthy volunteers and compare the results with MZ-inj dosed IN and by IV infusion. Methods: This single-dose, open-label, 5-way crossover study randomly assigned healthy adult subjects (N=25) to 1 of 5 sequences of MZ with 5 subjects per dosing sequence. The dosing regimens included 2.5, 5.0, and 7.5 mg USL261 delivered by a single actuation of a unit-dose nasal spray device; 2.5 mg MZ-inj (5 mg/mL) administered via 15-min IV infusion; and 5.0 mg MZ-inj administered IN (0.5 mL in each nostril given by needleless syringe). The interval between dose regimens was ≥3 days. Pharmacodynamic assessments of sedation (Stanford Sleepiness Scale [SSS] and Observer's Assessment of Alertness/Sedation Scale [OAA/S]) and psychomotor performance (Digit-Symbol Substitution Test [DSST]) were conducted at predetermined times before and after study drug administration. Safety was assessed by the incidence of treatment-emergent adverse events (TEAEs) and by monitoring respiratory rate (RR) and pulse oximetry. Results: Sedation (SSS, OAA/S) and psychomotor impairment (DSST) increased with increasing doses of USL261. Mean peak changes from baseline scores occurred 30 to 75 min after dosing for SSS and OAA/S and 10 to 20 min after dosing for the DSST. MZ-inj (5 mg) dosed IN resulted in similar times to peak response for each of the assessments with peak changes from baseline similar to USL261 5 mg. Mean peak changes from baseline in the SSS were 5.1 vs 5.3 units (on a 7-point scale) for MZ-inj (5 mg) dosed IN and USL261 5 mg, respectively. In all groups, scores for each assessment returned to near baseline values by 4 hr. All subjects reported at least one TEAE; all were mild in severity and occurred only in the IN dosing groups. Nearly all were considered probably related to treatment and occurred with similar frequency in the 4 IN dosing groups. The most common (reported by >20% of subjects) TEAEs were dysgeusia, increased lacrimation, nasal discomfort, and throat irritation. No subjects had RR <8 breaths/min or O₂ saturation <90%. Conclusions: USL261 dosed up to 7.5 mg in healthy volunteers was well-tolerated and did not result in excessive or prolonged sedation or psychomotor impairment. The safety profile of USL261 was consistent with literature reports of MZ-inj dosed IN. These results support the further development of USL261 for the rescue treatment of patients with intermittent bouts of increased seizure activity.