Background: The event-driven BEAT study evaluated the addition of esuberaprost compared to placebo in patients receiving ITRE alone or in combination with one or two additional PAH therapies. Addition of esuberaprost did not demonstrate a clinically significant benefit in delaying time to clinical worsening. The purpose of this exploratory analysis is to further evaluate the effect of ITRE on endpoints in the BEAT study.
Methods: Patients were experienced or naïve to ITRE at screening. Naïve patients were treated with ITRE for 90-days prior to randomization. Patients were randomized to esuberaprost or placebo, stratified by ITRE experience. Clinical worsening (CW), exercise capacity (measured by six-minute walk distance [6MWD]) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assessed. Mixed model repeated measurement was performed to estimate mean treatment change in 6MWD from screening and median ratio of NT-proBNP values to screening (ratio <1 indicates a decrease).
Results: 271 functional class III/IV patients were included in the analysis: n=73 ITRE-naïve/placebo, n=78 ITRE-naïve/esuberaprost, n=62 ITRE-experienced/placebo, and n=58 ITRE-experienced/esuberaprost. Baseline 6MWD and NT-proBNP were not statistically different between groups. Median duration of ITRE treatment prior to randomization in experienced patients was 375 days. 31.37% of patients achieved >9 breaths/session ITRE at WK24. Time from screening to CW was statistically different when comparing ITRE-experienced versus ITRE-naïve patients (log rank p=0.0469; HR [95% CI] 0.673 [0.454, 0.997], p=0.0483). Mean 6MWD changes at WK24 were 39.36 m ITRE-naïve/placebo, 25.01 m ITRE-naïve/esuberaprost, 11.16 m ITRE-experienced/placebo, and 19.12 m ITRE-experienced/esuberaprost. Median NT-proBNP WK24 to screening ratio were 0.65 ITRE-naïve/placebo, 0.66 ITRE-naïve/esuberaprost, 1.09 ITRE-experienced/placebo, and 1.05 ITRE-experienced/esuberaprost.
Conclusions: Patients newly initiated on ITRE demonstrated a more robust response than experienced patients. Improvements resulting from ITRE in all groups overshadow any comparison of esuberaprost to placebo, further supporting evidence of the long-term safety and efficacy of ITRE.