Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and somatropin agonists, ATC code: H01AC08.

Mechanism of action

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.

Pharmacodynamic effects

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.

Water and mineral metabolism
Somatrogon induces the retention of phosphorus.

Clinical efficacy and safety
The safety and efficacy of somatrogon for the treatment of children and adolescents from 3 years of age with GHD were evaluated in two multi-centre randomised, open-label controlled clinical studies.
Both studies included a 12-month main study period that compared once weekly somatrogon to somatropin administered once daily followed by a single arm OLE period during which all patients were administered somatrogon once weekly. The primary efficacy endpoint for both studies was annualised height velocity (HV) following 12 months of treatment. Other endpoints reflective of catch-up growth such as change in height SDS from baseline and height SDS were also evaluated in both studies.

The pivotal phase 3 multi-centre non-inferiority study evaluated the safety and efficacy of 0.66 mg/kg/week dose of somatrogon compared to 0.034 mg/kg/day of somatropin in 224 pre-pubertal paediatric patients with GHD. The mean age across the treatment groups was 7.7 years (min 3.01, max 11.96), 40.2% of patients were > 3 years to ≤ 7 years, 59.8% were > 7 years. 71.9% of patients were male and 28.1% were female. In this study, 74.6% of patients were White, 20.1% were Asian; 0.9% were Black. Baseline disease characteristics were balanced across both treatment groups.
Approximately 68% of patients had peak plasma GH levels of ≤ 7 ng/mL, and the mean height was below -2 SDS.

Once weekly somatrogon was non-inferior based on HV at 12 months compared to somatropin administered once daily (see Table 2). Once weekly somatrogon also produced an increase in IGF-1 SDS values, from a mean of -1.95 at baseline to a mean of 0.65 at 12 months.

Table 2. Efficacy of somatrogon compared to somatropin in paediatric patients with GHD at month 12
Treatment group
Treatment                                                           LSM difference parameter         Somatrogon (N=109) Somatropin (N=115)                (95% CI) LSM estimate         LSM estimate
Height velocity              10.10                 9.78                0.33 (-0.24, 0.89) (cm/yr)

Height standard                  -1.94                    -1.99                0.05 (-0.06, 0.16) deviation score

Change in height                 0.92                     0.87                 0.05 (-0.06, 0.16) standard deviation score from baseline
Abbreviations: CI=confidence interval; GHD=growth hormone deficiency; LSM=least square mean; N=number of patients randomised and treated.

In the open-label extension of the pivotal phase 3 study, 91 patients received 0.66 mg/kg/week of somatrogon for at least 2 years and provided height data. A progressive gain in height SDS from baseline was observed at 2 years [cumulative change in height SDS mean (SD) = 1.38 (0.78), median = 1.19 (range: 0.2, 4.9)].

In the phase 2, multi-centre safety and dose-finding study, 31 patients received up to 0.66 mg/kg/week of somatrogon for up to 7.7 years. At the last assessment, height SDS [mean (SD)] was -0.39 (0.95) and cumulative change in height SDS [mean (SD)] from baseline was 3.37 (1.27).

Treatment burden
In a phase 3 randomised, open-label, crossover study in 87 paediatric patients with GHD, the impact of somatrogon administered once weekly (0.66 mg/kg/week) on treatment burden was compared to daily somatropin. Somatrogon administered once weekly demonstrated significant improvement (reduction) in treatment burden for the patient, improved (reduced) treatment burden for the caregiver, greater patient convenience, greater intent to comply and greater patient preference.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Somatrogon pharmacokinetics (PK) was assessed using a population PK approach for somatrogon in 42 paediatric patients (age range 3-15.5 years) with GHD.

Absorption

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.

Distribution

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.

Biotransformation

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.

Elimination

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.

Special populations

Age, race, gender, body weight
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.