Somatrogon is a glycoprotein comprised of the amino acid sequence of hGH with one copy of the of C-terminal peptide (CTP) from the beta chain of human chorionic gonadotropin (hCG) at the N-terminus and two copies of CTP (in tandem) at the C-terminus. The glycosylation and CTP domains account for the half-life of somatrogon, which allows for weekly dosing.
Somatrogon binds to the GH receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism. Consistent with GH signalling, somatrogon binding leads to activation of the STAT5b signalling pathway and increases the serum concentration of IGF-1. IGF-1 was found to increase in a dose-dependent manner during treatment with somatrogon partially mediating the clinical effect. As a result, GH and IGF-1 stimulate metabolic changes, linear growth and enhance growth velocity in paediatric patients with GHD.
In clinical studies, somatrogon increases IGF-1. Pharmacodynamic evaluations performed approximately 96 hours after dose administration in order to assess the mean IGF-1 standard deviation score (SDS) over the dosing interval showed IGF-1 values normalised in treated subjects at one month of treatment.
Somatrogon induces the retention of phosphorous.
Somatrogon pharmacokinetics (PK) was assessed using a population PK approach for somatrogon in 42 paediatric patients (age range 3-15.5 years) with GHD.
Following subcutaneous injection, serum concentrations increased slowly, peaking 6 to 18 hours after dosing.
In paediatric patients with GHD, somatrogon exposure increases in a dose-proportional manner for doses of 0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week. There is no accumulation of somatrogon after once weekly administration. In paediatric patients with GHD, the population PK estimated steady-state peak concentrations following 0.66 mg/kg/week was 636 ng/mL. Patients who tested positive for ADA had an approximately 45% higher steady-state average concentration.
In paediatric patients with GHD, the population PK estimated apparent central volume of distribution was 0.728 L/kg and apparent peripheral volume of distribution was 0.165 L/kg.
The metabolic fate of somatrogon is believed to be classical protein catabolism, with subsequent reclamation of the amino acids and return to the systemic circulation.
In paediatric patients with GHD, the population PK estimated apparent clearance was 0.0317 L/h/kg. Patients who tested positive for ADA had an approximately 25.8% decrease in apparent clearance. With a population PK estimated effective half-life of 28.2 hours, somatrogon will be present in the circulation for about 6 days after the last dose.
Based on population PK analyses, age, sex, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of somatrogon in paediatric patients with GHD. The exposure of somatrogon decreases with an increase in body weight. However, the somatrogon dose of 0.66 mg/kg/week provides adequate systemic exposure to safely achieve efficacy over the weight range evaluated in the clinical studies.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeat-dose toxicity.
Reproductive and developmental toxicity studies were conducted in rats with somatrogon administered subcutaneously at doses up to 30 mg/kg (associated with exposures levels approximately 14 times the maximum recommended human dose based on AUC).
Somatrogon induced an increase in oestrous cycle length, copulatory interval, and number of corpora lutea in female rats but no effects on mating indices, fertility or early embryonic development.
No effects of somatrogon were observed on embryo-foetal development.
In a pre-postnatal development study somatrogon elicited an increase in first generation (F1) mean body weights (both sexes) as well as an increase in the mean copulatory interval in F1 females at the highest dose (30 mg/kg), which was consistent with a longer oestrous cycle length; however, there were no associated effects on mating indices.
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