Endocrine Abstracts

Introduction: A 24-week, PhIII, randomised study (PAOLA) demonstrated superior efficacy of pasireotide long-acting release (PAS-LAR; 40 and 60 mg) vs continued treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (15.4%, 20.0% vs 0%) at providing biochemical control (GH<2.5 μg/l and normalized IGF-1) in patients with acromegaly inadequately controlled on first-generation somatostatin analogues. Results from PK/PD analyses of PAS-LAR are reported here.

Methods: Relationship between PAS plasma concentration/efficacy endpoints (GH and IGF-1) and PAS exposure/safety (FPG, ECG, and liver function tests) were analysed. Dose-proportionality was explored and possible covariate effects were determined using linear mixed-effects models.

Results: A steady-state PAS concentration was achieved following three consecutive monthly injections. PAS exposures were approximately dose proportional for the tested dose range (40–60 mg). Gender, age, and baseline total bilirubin levels were statistically significant PK covariates for PAS concentration but without clinically significant impact. A clear exposure-response relationship was observed between PAS concentration and efficacy endpoints. Estimated maximum GH and IGF-1 suppression (mean±S.E.M.) was 83.0±6.5% and 67.1±5.8%, respectively. Estimated effective concentration of PAS to suppress GH to 2.5 μg/l was 12.3±3.3 ng/ml; to suppress IGF-1 to 1×ULN required higher PAS concentration (42.3±16.6 ng/ml). These results were aligned with clinical finding of higher response rate for GH vs. IGF-1 with 40 and 60 mg (40 mg: 35.4% vs 24.6%; 60 mg: 43.1% vs 26.2%). A 1.5-fold increase in PAS trough concentration (40–60 mg dose) was associated with a 54, 44, and 51% increase in the odds of GH+IGF-1, GH and IGF-1 responses, respectively; corresponding increase in the odds of having hyperglycaemia was only 36%.

Conclusions: A positive relationship between PAS exposure and efficacy supported the clinical observations of higher GH and IGF-1 response rates with higher dose (60 mg vs 40 mg). These results are aligned with the clinical findings of a positive benefit/risk profile for PAS-LAR treatment in this patient population.

Disclosure: This work was supported by Novartis.