SKYTROFA Powder for solution for injection Ref.[28361] Active ingredients: Lonapegsomatropin

Somatropin released from SKYTROFA produces a dose linear IGF-1 response, with a change of 0.02 mg/kg on average resulting in a change in IGF-1 standard deviation score (SDS) of 0.17.

At steady-state, IGF-1 levels peak approximately 2 days post-dose, with the average weekly IGF-1 occurring approximately 4.5 days post-dose. IGF-1 levels are in the normal range for GHD patients for the majority of the week, similar to daily somatropin.

Absorption

Following subcutaneous dose administration, SKYTROFA releases fully active somatropin via autocleavage of the TransCon linker that follows first-order kinetics.

In pediatric patients with GHD, following subcutaneous dose administration of 0.24 mg/kg/week SKYTROFA, the observed mean (CV%) steady state peak serum concentration (C_max) of lonapegsomatropin-tcgd was 1230 (86.3) ng hGH/mL, and the median time to reach maximum concentrations (T_max) was 25 hours. For released somatropin, C_max was 15.2 (83.4) ng/mL with a median T_max of 12 hours. The mean (CV%) somatropin exposure over the one-week dose interval (area under the curve) was 500 (83.8) h*ng/mL. No significant accumulation of lonapegsomatropin-tcgd and somatropin following repeat dose administration was observed.

C_max of the methoxypolyethylene glycol carrier was 13.1 (28.1) µg /mL with a median T_max of 36 hours.

In healthy adults, following single subcutaneous dose administration in the range of 0.24 to 0.42 mg/kg of SKYTROFA, exposure of released somatropin increased greater than proportional to dose.

Distribution

In pediatric patients with GHD, the mean (CV%) steady state apparent volume of distribution of lonapegsomatropin-tcgd after subcutaneous administration of 0.24 mg/kg/week SKYTROFA was 0.13 (109) L/kg. A similar distribution pattern as observed for daily somatropin is expected once somatropin is released from lonapegsomatropin-tcgd.

Elimination

Metabolism

The metabolism of somatropin involves protein catabolism in both the liver and kidneys. The methoxypolyethylene glycol carrier is cleared by the kidneys.

Excretion

In pediatric patients with GHD, the mean (CV%) lonapegsomatropin-tcgd apparent clearance at steady state was 3.2 (67) mL/h/kg following subcutaneous administration of 0.24 mg/kg/week SKYTROFA with a mean (±SD) observed half-life of 30.7 (±12.7) hours. The apparent half-life of somatropin released from lonapegsomatropin-tcgd was approximately 25 hours.

Specific Populations

Based on a population pharmacokinetic analysis, age, sex, race, and body weight do not have clinically meaningful effects on pharmacokinetics.

Male and Female Patients

No sex-specific pharmacokinetic studies have been performed with SKYTROFA. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.

Patients with Renal or Hepatic Impairment

No specific studies have been performed with SKYTROFA.

Carcinogenicity studies have not been conducted with lonapegsomatropin-tcgd.

Lonapegsomatropin-tcgd was not mutagenic in the Ames test, in the human chromosomal aberration assay or in the rat bone marrow micronucleus test.

In an animal fertility study, lonapegsomatropin-tcgd was administered via subcutaneous injection to male and female rats before cohabitation, through mating to implantation.

Lonapegsomatropin-tcgd did not affect fertility or early embryo-fetal development at doses up to 20-fold the clinical dose of 0.24 mg/kg/week.

14.1 Treatment-Naïve Pediatric Patients with Growth Hormone Deficiency (NCT02781727)

A multi-center randomized, open-label, active-controlled, parallel-group phase 3 study was conducted in 161 treatment-naïve, prepubertal pediatric subjects with growth hormone deficiency (GHD); 105 subjects received once-weekly SKYTROFA, and 56 received daily somatropin. The dose in both arms was 0.24 mg/kg/week. The primary efficacy endpoint was annualized height velocity at Week 52.

The subjects ranged in age from 3.2 to 13.1 years with a mean of 8.5 years. One hundred thirty-two (82%) subjects were male and 29 (18%) were female. One subject was Asian, three were Black or African American, 152 were Caucasian, and five were categorized as “other.” The subjects had a mean baseline height SDS (standard deviation score) of -2.9.

Treatment with once-weekly SKYTROFA for 52 weeks resulted in an annualized height velocity of 11.2 cm/year. Subjects treated with daily somatropin achieved an annualized height velocity of 10.3 cm/year after 52 weeks of treatment. Refer to Table 4.

Table 4. Annualized Height Velocity at Week 52 in Pediatric Treatment-Naïve Subjects with Growth Hormone Deficiency:

^*6 The estimates of least square (LS) means and 95% confidence interval (CI) are from an ANCOVA model that included baseline age, peak GH levels (log transformed) at stimulation test, baseline height SDS – average SDS of parental height as covariates, and treatment and sex as factors. Missing data were imputed with multiple imputation method.

Height SDS (change from baseline) was 1.1 in the SKYTROFA arm and 0.96 in the daily somatropin arm at Week 52. Refer to Table 5.

Table 5. Height SDS over 52 Weeks in Pediatric Treatment-Naïve Subjects with Growth Hormone Deficiency:

Abbreviations: SDS: Standard deviation score.
^* Height SDS, change from baseline: The estimates of LS means are from an ANCOVA model that included baseline age, peak GH levels (log transformed) at stimulation test and baseline height SDS as covariates, and treatment and sex as factors.