Professor New York University, Langone Health, New York, NY, USA NEW YORK, New York
Rationale: The Staccato® inhaler is a device that aerosolizes a drug and, via inhalation with a normal breath, delivers it deep into the lung for rapid systemic exposure. A proof-of-concept study showed that Staccato alprazolam (STAP) rapidly suppressed epileptiform activity in photosensitive participants (ppts). Here we present the results from part 2 of a Phase 2b randomized, placebo (PBO)-controlled, double-blind study (NCT03478982) exploring the efficacy, feasibility, and safety of STAP treatment (tx) in ppts with predictable seizure patterns (PSPs) vs PBO. Methods: Adult ppts (≥18 y) with epilepsy and a documented history of predictable seizure episodes (i.e., clusters, prolonged focal seizures, or flurries of generalized seizures) entered a qualification period to confirm the frequency of PSPs. Prior to entering the inpatient unit for randomization and dosing, ppts must have experienced ≥4 seizure episodes with PSPs during the qualification period. Qualified ppts were randomized 1:1:1 to receive STAP 2 mg or 1 mg, or Staccato PBO (STPBO). Study tx was self-administered, if feasible, or given by a staff caregiver at the onset of clinical seizure activity. The primary endpoint was the proportion of ppts who achieved seizure cessation within 2 minutes of tx and no recurrence within 2 hours (responder). Other endpoints such as time to seizure cessation, time to next seizure event, and safety were assessed; sedation and somnolence were assessed using a visual analogue scale. All statistical tests were 2-sided with a significance value of 0.05, with no adjustments for multiple comparisons. Results: Of 116 enrolled ppts who completed the study, 57.8% were female with an age range of 18–66 years and duration of epilepsy range of 1.0–52.7 years; there were no notable differences in ppt characteristics between tx arms. The percentage of responders was 65.8% for both the STAP 2 mg and 1 mg arms vs 42.5% for STPBO (P=.039). The mean time to seizure cessation in ppts who received STPBO or STAP was 279 s and145 s, respectively, and in STAP- or STPBO-treated responders 34 s and 43 s respectively. Ppts treated with STAP 2 mg experienced significantly fewer seizure events vs STPBO up to 12 hours after tx (P=.027), and had a median time to next seizure event of 1509 minutes vs 670 minutes and 815 minutes for STAP 1 mg and STPBO, respectively. Adverse events (AEs) were mostly mild or moderate in intensity; no tx-related serious or severe AEs occurred. Cough and somnolence were the most common AEs (both 14.5%) in the STAP tx arms. Ppts treated with STAP experienced slightly higher sedation at earlier timepoints (< 1 hour); the effect diminished 2 hours after dosing. No clinically relevant changes in laboratory parameters and vital signs were observed. Conclusions: Tx with STAP 2 mg and 1 mg resulted in a significantly greater proportion of responders than STPBO. Tx was feasible in most ppts. Seizure cessation data support rapid systemic absorption and onset of clinical activity of STAP. The tx was generally well tolerated. These results support the efficacy and safety as well as feasibility of STAP as on-demand tx of acute seizure episodes and warrant further study. Funding: Please list any funding that was received in support of this abstract.: Engage Therapeutics, Inc.