Reduced breakthrough symptom exacerbations in patients with biochemically controlled acromegaly switched from injected depot somatostatin receptor ligands to once-daily oral paltusotine in the PATHFNDR-1 clinical trial

PURPOSE: To evaluate the hypothesis that breakthrough acromegaly symptom exacerbation frequency would be reduced after switching biochemically controlled patients from depot somatostatin receptor ligand (SRL) injections to once-daily oral paltusotine. METHODS: Biochemical disease control (insulin-like growth factor 1 [IGF-I]) and Acromegaly Symptom Diary (ASD) data were analyzed from PATHFNDR-1, a 36-week, randomized, placebo-controlled, double-blind, phase 3 trial of paltusotine in patients with acromegaly biochemically controlled (IGF-I ≤ 1.0× ULN) with SRLs. The ASD measured the daily severity of 7 core and 2 exploratory acromegaly symptoms, each rated on a scale from 0 to 10 based on 24-hour recall. Breakthrough acromegaly symptom exacerbations were defined as ≥ 2-point increases for any individual symptom score, comparing a 2-day average with the prior 2-day average. RESULTS: Despite no significant changes in IGF-I levels or overall core symptom severity scores, mean (SE) symptom exacerbation frequencies declined progressively after switching to paltusotine, from 30.2% (5.6%) of days during screening (SRL treatment) to 6.2% (1.6%) of days (n = 22, p < 0.0001). The reduction in individual symptom exacerbation frequencies with paltusotine treatment was consistent across all acromegaly symptoms assessed. IGF-I levels did not correlate significantly with symptom severity scores or symptom variability. CONCLUSION: In patients with acromegaly biochemically controlled with injected SRLs, switching to once-daily oral paltusotine was associated with stable biochemical control, stable symptom severity, and a significantly reduced frequency of symptom exacerbations. A simple daily symptom assessment tool provided important information pertaining to acromegaly disease control that was not apparent from IGF-I measurements.