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Somatrogon binds to the GH receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism. Consistent with GH signaling, somatrogon binding leads to activation of the STAT5b signaling 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 pediatric patients with GHD.
Pharmacodynamic effects: Somatrogon increases IGF-1. Pharmacodynamic evaluations were performed approximately 96 hours after dose administration in order to assess the mean IGF-1 SDS over the dosing interval (see Figure 1).
Click on icon to see table/diagram/imageClinical trials data on efficacy: The safety and efficacy of NGENLA for the treatment of pediatric patients with GHD were evaluated in two multi-center randomized, open-label controlled clinical studies. Both studies included a 12-month main study period that compared once weekly NGENLA to Genotropin administered once daily followed by a single arm open-label extension (OLE) period during which all patients were administered NGENLA once weekly. The primary efficacy endpoint for both studies was annualized 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.
In an initial safety and dose-finding study, 53 pediatric patients with GHD were randomized and treated with one of 3 doses of once weekly NGENLA [0.25 mg/kg/wk (N=13), 0.48 mg/kg/wk (N=15), 0.66 mg/kg/wk (N=14)] or Genotropin administered once daily [0.034 mg/kg/day (N=11)]. The annual HV of 0.66 mg/kg/wk of NGENLA was comparable to Genotropin administered once daily after 12 months of treatment (11.4 cm/yr [95% CI: 9.2, 13.7]); (12.5 cm/yr [95% CI: 11.0, 13.9]), respectively. During the OLE, 37 patients received 0.66 mg/kg/wk of NGENLA for at least 5 years. A progressive gain in height SDS from baseline was observed at 5 years (cumulative change in height SDS mean (SD)=3.11 (1.18), median=2.86).
The 0.66 mg/kg/wk dose of NGENLA was further evaluated in a definitive safety and efficacy study in 224 pre-pubertal pediatric patients with GHD. Patients were randomized and treated with once weekly NGENLA (N=109) or Genotropin administered once daily (N=115) at a dose of 0.034 mg/kg/day. Once weekly NGENLA resulted in a non-inferior HV at 12 months compared to Genotropin administered once daily. Catch-up growth as reflected by change in height SDS from baseline was numerically higher for NGENLA (see Table 2). Once weekly NGENLA 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. (See Table 2.)
Click on icon to see table/diagram/imageIn the definitive safety and efficacy study, 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 growth hormone (GH) levels of ≤7 ng/mL, and the mean height was below -2 standard deviation score (SDS).
The most frequently reported all-causality adverse events that occurred in ≥5% of subjects in any treatment group were injection site pain, nasopharyngitis, headache, pyrexia, cough, injection site erythema, vomiting, bronchitis, arthralgia, blood creatinine phosphokinase increased, anemia, pharyngitis, hypothyroidism, otitis media, ear pain, oropharyngeal pain, rhinitis, arthropod bite, injection site pruritus, abdominal pain upper, and tonsillitis.
Treatment burden: The impact of NGENLA administered once weekly (0.66 mg/kg/wk) on treatment burden was compared to daily Genotropin in a phase 3 randomized, open-label, crossover study in 87 pediatric patients with GHD. NGENLA administered once weekly demonstrated significantly lower treatment burden, assessed as the difference in mean overall Life Interference total score, compared to Genotropin administered once daily.
Treatment experience with NGENLA resulted in lower treatment burden for the caregiver, greater patient convenience, greater intent to comply, and patient preference for a once weekly administration regimen compared to Genotropin administered once daily.
Pharmacokinetics: Somatrogon pharmacokinetics (PK) was assessed using a population PK approach for NGENLA in 42 pediatric patients (age range 3-15.5 years) with GHD.
Absorption: Following SC injection, serum concentrations increased slowly, peaking 6 to 18 hours after dosing.
In pediatric patients with GHD, somatrogon exposure increases in a dose-proportional manner for doses of 0.25 mg/kg/wk, 0.48 mg/kg/wk and 0.66 mg/kg/wk. There is no accumulation of somatrogon after once weekly administration. In pediatric patients with GHD, the mean population PK estimated steady-state peak concentrations following 0.66 mg/kg/wk was 690 ng/mL.
Distribution: In pediatric patients with GHD, the mean population PK estimated apparent central volume of distribution was 0.812 L/kg and apparent peripheral volume of distribution was 0.169 L/kg.
Metabolism: 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 pediatric patients with GHD, the mean population PK estimated apparent clearance was 0.0336 L/h/kg. With a mean population PK estimated effective half-life of 28.3 hours, somatrogon will be present in the circulation for about 6 days after the last dose.
Excretion: Excretion was not evaluated in clinical studies.
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 pediatric patients with GHD. The exposure of somatrogon decreases with an increase in body weight. However the somatrogon dosing regimen of 0.66 mg/kg/wk provide adequate systemic exposure over the body weight range of 10 to 54 kg evaluated in the clinical studies. The effects of individual intrinsic factors on the pharmacokinetics of somatrogon are shown in Figure 2. (See Figure 2.)
Click on icon to see table/diagram/imagePatients with renal impairment: NGENLA has not been studied in patients with renal impairment.
Patients with hepatic impairment: NGENLA has not been studied in patients with hepatic impairment.
Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with NGENLA may develop antibodies to somatrogon.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to somatrogon in the studies described as follows with the incidence of antibodies in other studies or to other products may be misleading.
In the definitive safety and efficacy study, among 109 subjects treated with somatrogon, 84 (77.1%) tested positive for ADAs. There were no serious adverse drug reactions, or serious immune-related toxicities reported in patients with or without ADAs. In addition, annual height velocity, change in height SDS, height SDS, and IGF-1 response were similar in patients with or without treatment-emergent ADAs (see Pharmacology: Pharmacodynamics under Actions).
Toxicology: Preclinical safety data: Somatrogon has been evaluated in single- and repeat-dose toxicity studies in rats and rhesus monkeys. Based on the nonclinical studies conducted, injection site findings have been identified as the only target organ/effect. An anticipated increase in body weight was observed in rats since it is a primary pharmacodynamic effect of growth hormone and associated with secondary effects of increased IGF-1. Other findings related to the pharmacological activity of somatrogon occurred in mammary glands, liver, kidney, and spleen in rats.
Impairment of fertility: The potential for somatrogon to have effects on fertility and early embryonic development was evaluated in male and female rats. In an embryo-fetal development study in rats administered somatrogon via SC injection every 2 days from Gestation Day (GD) 6 to 18 at doses up to 30 mg/kg [45 times the maximum recommended human dose based on average concentration (Cave) exposure], there were no adverse maternal or embryo-fetal effects. Somatrogon elicited an increase in estrous cycle length, copulatory interval, and number of corpora lutea, but there was no impact on mating indices, fertility, number of viable embryos/early embryonic development (see Use in Pregnancy & Lactation).
Developmental toxicity: The potential for somatrogon to have effects on embryo-fetal development was also assessed in rats. Somatrogon elicited pharmacologically-mediated, nonadverse, increases in maternal body weights and body weight gain, but there were no corresponding embryo-fetal effects.
The potential for effects of somatrogon on prenatal and postnatal development was evaluated in rats. In a pre- and postnatal development study in rats, somatrogon was administered via SC injection to pregnant rats every 2 days from GD 6 to Lactation Day 20 at doses up to 30 mg/kg. There was no evidence of maternal toxicity and no adverse effects on the first generation (F1) offspring. Somatrogon elicited an increase in 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 estrous cycle length; however, there were no associated effects on mating indices.
Genotoxicity and carcinogenicity: Genotoxicity and carcinogenicity studies have not been performed. The potential for mitogenic activity of somatrogon was assessed in the 26-week repeat-dose toxicity study in rhesus monkeys. No mitogenicity was evident from macroscopic and microscopic tissue evaluations or from evaluation of organ weights in this study.
