OR10-04 Interpretation of Insulin-like Growth Factor-1 (IGF-1) Levels Following Administration of Somatrogon (a Long-acting Human Growth Hormone - hGH-CTP)

Abstract IGF-1 is often used as a biomarker to evaluate the efficacy and safety of hGH replacement therapy. Typically, the mean IGF-1 SDS level during the dosing interval, rather than the peak value, guides clinical decision-making: sustained mean values > +2 may require hGH dose modifications. With long-acting formulations (administered weekly), the IGF-1 evaluation paradigm needs to take into account when the sample was obtained relative to the last administered dose. Previous studies with OPKO’s once weekly Somatrogon (hGH-CTP), demonstrated that IGF-1 SDS peaked ~ 48 hours post-dose and that values at ~ 96 hours best approximated the mean IGF-1 SDS throughout the dosing interval [1]. Data from the pivotal Phase 3 non-inferiority study comparing treatment with Somatrogon to Genotropin allowed further evaluation of the IGF-1 SDS analysis paradigm. Enrolled subjects were randomized to receive treatment with either once weekly Somatrogon (0.66 mg/kg; N=109) or once daily Genotropin (0.034 mg/kg; N=115). IGF1 was sampled ~ five times during 52 weeks of treatment with Somatrogon, providing a total of 557 samples obtained after the first dose of Somatrogon. IGF-1 SDS values were calculated using Bidlingmaier’s equations [2]. Analysis of IGF-I SDS data from the Phase 3 study showed that the previously-developed model, with adjustments to two parameters (baseline IGF-1, EC50) and adapted to fit IGF-1 values in the absence of Somatrogon concentration data, fit the IGF-1 data for Somatrogon with minimal bias. This allowed prediction of IGF-1 SDS values at timepoints throughout the dosing interval as well as calculation of the mean value during a dosing interval. Of the samples obtained between 48–72 hours post-dose (representing peak IGF-1 SDS), approximately 17% had an IGF1 SDS > +2. At 96 hours (corresponding to mean IFG-1 SDS), fewer than 2% of modeled values were > +2. Mean IGF-1 SDS over the dosing interval was between -1 and +1 for all subjects. These findings indicate that IGF-1 SDS values need to be interpreted in the context of when the sample was obtained relative to the last dose of Somatrogon. Our results indicate that samples obtained 96 hours post-dose best represent mean IGF-1 levels and that values obtained between 48–72 hours post-dose represent values closer to peak IGF-1 concentrations. In our Phase 3 study, of the 557 samples collected from 114 patients during the 12-month Somatrogon treatment period, fewer than 2% of the corresponding values at 96 hours postdose (estimated from a pharmacokinetic/pharmacodynamic model) had IGF-1 SDS levels > +2. 1. Fisher DM, et al. Horm Res Paediatr 2017;87:324. 2. Bidlingmaier M, et al. J Clin Endocrinol Metab 2014;99:1712

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