Safety and Pharmacokinetic Profile of BTA585, a Novel Fusion Inhibitor of Respiratory Syncytial Virus, in Single and Multiple-ascending Dose Healthy Volunteer Studies

Background: Respiratory Syncytial Virus (RSV) is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. BTA585 is an oral, selective F-protein inhibitor of RSV A and B infection in development for the treatment of RSV infections.

Methods: A single ascending dose (SAD) study evaluated the safety and pharmacokinetics (PK) of single oral doses of BTA585. The starting dose was 50 mg with escalating dose level cohorts of 100 mg (both fed and fasted to assess food effect), 200 mg, 400 mg, 500 mg, and 800 mg. Following the SAD study, a multiple-ascending dose (MAD) study evaluated the safety and PK profile of BID doses 100 mg, 400 mg, and 600 mg over 7 consecutive days of fasted dosing. BTA585 was also measured in nasal wash fluid in the MAD study.

Results:

BTA585 was well-tolerated in both single and multiple dose trials. The most common adverse events (>1 one treated subject in both studies) were chromaturia, headache, and nausea. There were no SAEs or drug-related, clinically-significant adverse changes in ECGs or clinical lab values in either the SAD or MAD. High precision exposure response assessment of ECG data from all SAD cohorts was conducted. The relationship between BTA585 and change from baseline in QTcF was not statistically significant and an exposure-dependent effect of BTA585 on QTcF was not observed. BTA585 was rapidly absorbed, with median T_max of ~ 1 hour with an estimated t_1/2 ranging from 5 to 6 hours among all single doses. A significant food effect on PK was not observed. In both SAD and MAD studies, C_max and AUC increased dose-proportionally with single and multiple doses. In the MAD study, plasma levels of BTA585 sufficient to be viricidal were rapidly achieved and maintained with no significant accumulation. BTA585 levels in nasal wash fluid increased with exposure and were present as early as 3 hours post first dose and still detectable 24 hours after the last dose in all MAD groups.

Conclusion: BTA585 demonstrated a favorable safety and PK profile across all dose cohorts in the Phase 1 trials. Antiviral levels of BTA585 in the plasma and nasal wash fluid were reached rapidly and exceeded the EC₅₀ for RSV clinical isolates. Taken together, these data support further clinical evaluation of BTA585.