Source: Health Products and Food Branch (CA) Revision Year: 2015
In vitro, tesamorelin binds and stimulates human Growth Hormone-Releasing Factor (hGRF) receptors with similar potency as the natural GRF. Tesamorelin mimics the pharmacology of GRF in vitro as well as in animals and humans (see Pharmacodynamics).
Growth Hormone-Releasing Factor, also known as Growth Hormone-Releasing Hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous Growth Hormone (GH). Growth hormone has been shown to be anabolic and lipolytic. It exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.
Increases in GH secretion were observed in two Phase 1 studies wherein 2 mg EGRIFTA was administered daily for 14 consecutive days. A Phase 1, randomized, 2-way cross-over study showed that treatment with 2 mg EGRIFTA increased mean GH secretion in a pulsatile fashion.
During the clinical trials, patients were monitored every three months. Among patients who received EGRIFTA for 26 weeks, 47.4% had IGF-1 levels greater than 2 standard deviation scores (SDS), and 35.6% had SDS >3, with this effect seen as early as 13 weeks of treatment. Among those patients who remained on EGRIFTA for a total of 52 weeks, at the end of treatment 33.7% had IGF-1 SDS >2 and 22.6% had IGF-1 SDS >3.
Administration of EGRIFTA was also associated with significant increases in insulin-like growth factor binding protein-3 (IGFBP-3) levels in clinical studies. No clinically significant changes in the levels of other pituitary hormones, including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), prolactin and adrenocorticotropic hormone (ACTH) were observed in subjects receiving EGRIFTA.
Treatment of HIV-infected patients with excess abdominal fat with 2 mg EGRIFTA daily resulted in a significant and selective reduction in visceral adipose tissue (VAT), as no clinically significant changes were observed in abdominal subcutaneous adipose tissue (SAT). EGRIFTA may decrease fat depots through GH-stimulated intracellular lipolysis. Treatment with EGRIFTA was also associated with improvements in triglyceride levels, while the other lipid parameters remained within the normal range.
Treatment of type 2 diabetic patients with daily doses of 1 or 2 mg EGRIFTA for 12 weeks did not interfere with insulin response or glycemic control.
Mean levels of fasting blood glucose and fasting insulin were not significantly different between EGRIFTA-treated and placebo-treated patients after 26 weeks of treatment in the Phase 3 clinical trials of EGRIFTA in HIV-infected patients with excess abdominal fat. Mean baseline (Week 0) HbA1c was 5.26% among patients in the EGRIFTA group and 5.28% among those in the placebo group. At Week 26, mean HbA1c was higher among patients treated with EGRIFTA compared with placebo (5.39% vs. 5.28% for the EGRIFTA and placebo groups, respectively, mean treatment difference of 0.12%, p=0.0004). Patients receiving EGRIFTA had an increased risk of developing diabetes (HbA1c level ≥6.5%) compared with placebo (4.5% vs. 1.3%), with a hazard ratio of 3.3 (CI 1.4, 9.6).
Treatment with 2 mg EGRIFTA daily for up to 52 weeks increased osteocalcin levels, a marker of bone formation, in HIV-infected patients with excess abdominal fat. Endogenous GH has been shown to increase long bone growth and to stimulate bone turnover.
The pharmacokinetics of a one-way multiple-dose study in which 18 HIV-positive patients received a daily sc injection of 2 mg tesamorelin (2 mL of tesamorelin 1 mg/mL injectable solution) during 14 consecutive days are presented in Table 7 below.
Table 7. Summary of Tesamorelin Pharmacokinetic Parameters in an HIV-infected Patient Population:
| Parameters | Day 1 (N=17) | Day 14 (N=15) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Mean | SD (±) | CV (%) | Geo. Mean | Geo. Mean CV (%) | Mean | SD (±) | CV (%) | Geo. Mean | Geo. Mean CV (%) | |
| AUC0-t (pg·h/mL) | 1149.5 | 1008. | 87.75 | 852.8 | 91.87 | 1117.23 | 953.4 | 85.34 | 794.6 | 108.59 |
| AUC0-inf (pg·h/mL) | 1255.4 | 1104. | 87.98 | 933.3 | 90.94 | 1312.60 | 1124. | 85.65 | 940.4 | 104.73 |
| AUCt/inf (%) | 91.44 | 3.62 | 3.96 | - | - | 84.73 | 6.39 | 7.54 | - | - |
| Cmax (pg/mL) | 3106.4 | 1375. | 44.27 | 2822. | 48.89 | 2333.3 | 1185. | 50.78 | 2013. | 66.52 |
| Tmax (h) | 0.162 | 0.060 | 37.23 | - | - | 0.157 | 0.042 | 26.61 | - | - |
| Tmax* (h) | 0.150 | 0.000 | - | - | - | 0.150 | 0.025 | - | - | - |
| Kel (h-1) | 4.3214 | 2.719 | 62.93 | - | - | 2.5071 | 1.969 | 78.54 | - | - |
| T½ el (h) | 0.31 | 0.32 | 104.7 | - | - | 0.63 | 0.61 | 96.54 | - | - |
| Cl/F (L/(hr·kg)) | 38.71 | 26.85 | 69.38 | - | - | 40.97 | 31.15 | 76.04 | - | - |
| Vd/F (L/kg) | 10.48 | 6.10 | 58.25 | - | - | 20.19 | 9.87 | 48.90 | - | - |
* Median and interquartile ranges are also presented.
“-” = Not applicable.
The absolute bioavailability of EGRIFTA after subcutaneous administration of a 2 mg dose was determined to be less than 4% in healthy adult subjects. Single and multiple dose pharmacokinetics of EGRIFTA have been characterized in healthy subjects and HIV-infected patients without lipodystrophy following 2 mg subcutaneous administration.
The mean values [coefficient of variation (CV)] of the extent of absorption (AUC) for tesamorelin were 634.6 (72.4) and 852.8 (91.9) pg·h/mL in healthy subjects and HIV-infected patients, respectively, after a single subcutaneous administration of a 2 mg EGRIFTA dose. The mean (CV) peak tesamorelin concentration (Cmax) values were 2874.6 (43.9) pg/mL in healthy subjects and 2822.3 (48.9) pg/mL in HIV-infected patients. The median peak plasma tesamorelin concentration (Tmax) was 0.15 h in both populations.
The mean volume of distribution (±SD) of EGRIFTA following a single subcutaneous administration was 9.4±3.1 L/kg in healthy subjects and 10.5±6.1 L/kg in HIVinfected patients.
No formal metabolism studies were performed in humans.
Mean elimination half-life (T1/2) of EGRIFTA was 26 and 38 minutes in healthy subjects and HIV-infected patients, respectively, after subcutaneous administration for 14 consecutive days.
The pharmacokinetic profile of EGRIFTA has not been evaluated in the pediatric population.
The pharmacokinetic profile of EGRIFTA has not been evaluated in the geriatric population.
Gender-related differences in the pharmacokinetics of EGRIFTA have not been assessed.
Race-related differences in the pharmacokinetics of EGRIFTA have not been assessed.
The pharmacokinetic profile of EGRIFTA has not been evaluated in patients with hepatic insufficiency.
The pharmacokinetic profile of EGRIFTA has not been evaluated in patients with renal insufficiency.
In vitro pharmacology studies demonstrated that tesamorelin did not act as a prodrug in porcine anterior pituitary cells in either the presence or absence of a source of proteolytic enzymes (i.e. fetal calf serum) and using GH-releasing activity as a pharmacodynamic marker.
In vivo pharmacodynamic studies were conducted in Landrace x Yorkshire barrow pigs dosed with tesamorelin to demonstrate the resultant GH release and IGF-1 production. Tesamorelin stimulated GH release for up to 8 hours after intravenous (IV) or SC administration in barrow pigs and produced, on average, 2-3 peaks of GH during this period, simulating the pulsatile nature of GH release resulting from endogenous hGRF. Tesamorelin produced greater increases in serum IGF-1 concentrations than hGRF in barrow pigs.
Safety pharmacology studies evaluated the effect of tesamorelin on the cardiovascular system, the central nervous system (CNS), and the respiratory system.
Cardiovascular system:
The potential for tesamorelin to inhibit hERG currents was assessed in Chinese hamster ovary (CHO) cells modified to stably express the human ERG gene at escalating concentrations of 0, 80, 400 or 800 ng/mL. There were no tesamorelin related effects on hERG current amplitude or density.
The in vivo cardiovascular effect of tesamorelin was assessed in male dogs administered a single SC injection of 0 (vehicle), 0.6, 6 or 50 mg/kg. There were no tesamorelin-related changes in blood pressure, body temperature, heart rate or ECG parameters and the NOAEL was considered to be 50 mg/kg.
CNS:
A Functional Observational Battery (FOB) was performed in male Sprague-Dawley rats administered a single SC dose of tesamorelin at 0 (vehicle), 0.6, 6 or 50 mg/kg. There were no tesamorelin-related effects and the NOAEL was considered to be 50 mg/kg.
Respiratory system:
Tesamorelin was administered by single SC injection to male SpragueDawley rats at doses of 0 (vehicle), 0.6, 6 or 50 mg/kg. There were no tesamorelin-related effects on the measured respiratory parameters and the NOAEL was considered to be 50 mg/kg.
In vitro biodegradation studies have demonstrated that tesamorelin is more stable than its endogenous counterpart, hGRF, in human plasma. Tesamorelin appears to be primarily biodegraded via cleavage from the C-terminal as opposed to DPP IV-mediated catalysis.
Single and multiple dose pharmacokinectics of EGRIFTA have been characterized in several studies involving healthy subjects and HIV-infected patients. Mean Cmax ranged across studies from 1843 to 4278 pg/mL for the 2 mg tesamorelin dose and was always higher than the corresponding Cmax following 1 mg doses. Mean Tmax ranged across studies from 0.119 to 0.162 hours (7 to 10 minutes). There was no difference between the 1 mg and the 2 mg EGRIFTA doses, and/or between single and multiple dosing. The rate of absorption was rapid and there was no difference in the rate of absorption between healthy volunteers and HIV-infected patients. Mean AUC0-inf ranged across studies from 829 to 1514 pg·h/mL for the 2 mg tesamorelin dose and was always higher than AUC0-inf following 1 mg doses. Elimination (T½ el) of EGRIFTA was rapid and essentially similar between healthy volunteers and HIV-infected patients following subcutaneous administration. Following a 2 mg single-dose, the mean T½ el varied between studies from 0.21 h (13 min) to 0.31 h (19 min), was highly variable between individuals and appeared to increase after 14 consecutive days of daily EGRIFTA administration.
This section is not applicable.
Single-dose intravenous toxicity studies were conducted in mice, rats and dogs. The maximum tolerated dose was <100 mg/kg in mice (due to mortality at 100 and 200 mg/kg), between 100 to 200 mg/kg in rats (due to mortality at 200 mg/kg), and <5 mg/kg in dogs (due to dose-limiting clinical signs at 5 and 25 mg/kg).
Repeat-dose toxicity studies were conducted in rats (up to 26 weeks of duration) and dogs (up to 52 weeks of duration).
In the subcutaneous 13-week study (doses of 0.1, 0.3 and 0.6 mg/kg/day) and 26-week study (doses of 0.1, 0.6 and 1.2 mg/kg/day), treatment-related findings included increased body weight and food consumption, injection site irritation, increased GH levels, and hepatocellular vacuolation. Additional findings in the 26-week study included increased liver weights, increased cholesterol, serum glucose and increased incidence of diestrus. With the exception of injection site irritation, all findings were considered to be a result of the pharmacological activity of tesamorelin. The NOAEL was considered to be 0.6 mg/kg/day in the 13-week study and 1.2 mg/kg/day in the 26-week study. Antibodies against tesamorelin were observed in both studies, however, the immunogenic response was low and considered to be non-neutralizing since tesamorelin-induced increases in GH were not affected.
In the subcutaneous 16-week (doses of 0.1, 0.3 and 0.6 mg/kg/day), numerous findings were observed at all dose levels including increased body weights and food consumption, decreased red blood cell count (RBC), hemoglobin and hematocrit, increased reticulocytes and platelets (all dose levels), increased cholesterol/triglycerides, increased serum phosphorus, increased serum protein and globulin, increased cIGF-1, increased liver and pituitary weights, decreased spleen weights, injection site irritation, renal tubular basophilia, and centrilobular hepatocellular vacuolation. The NOAEL was considered to be 0.6 mg/kg/day as the noted alterations were not considered adverse (>500x clinical exposure, based on AUC).
Similar results were observed in the 52-week study (doses of 0.1, 0.6 and 1.2 mg/kg/day). Additional findings included the development of a condition sharing many of the characteristics of canine acromegaly, including morphological changes and development of insulin resistance and/or diabetes. One female dosed at 0.6 mg/kg was euthanized due to a suspected case of diabetes. Although most of the findings were attributable to the pharmacological activity of tesamorelin or secondary to insulin resistance, a NOAEL was not established (<0.1 mg/kg/day) due to histopathological findings of unknown etiology in the kidney (vacuolar degeneration of the collecting ducts), exocrine pancreas (microcytic degeneration), and gallbladder (epithelial vacuolar degeneration).
Antibodies against tesamorelin were observed in both toxicity studies; however, the presence of anti-tesamorelin antibodies did not have an impact on the increase in cIGF-1 levels over the course of the studies and were considered non-neutralizing.
The carcinogenic potential of tesamorelin was not evaluated.
Tesamorelin does not exhibit genotoxic (mutagenic or clastogenic) potential. Specifically, tesamorelin was negative in the bacterial reverse mutation assay, in vitro chromosome aberration assay in CHO cells (with or without metabolic activation) and in vivo mouse micronucleus assay.
Male and female rats were dosed with tesamorelin at 0.1, 0.3 and 0.6 mg/kg by SC injection. Males were administered the test compound at least 28 days prior to mating, whereas females were administered the test compound at least 14 days prior to mating and up to Day 17 of gestation. There were no tesamorelin-related effects on male or female reproductive performance. Increases in body weight and food consumption in the F0 generation were attributed to the pharmacological properties of tesamorelin. Effects on the fetal skeleton were indicative of advanced ossification, which, along with increased fetal weight, was considered attributable to the maternal effects on body weight and food intake. The NOAEL was considered to be 0.6 mg/kg (approximately 1x the clinical dose, based on AUC).
An embryo-fetal development study was also conducted in rabbits wherein pregnant females were dosed with tesamorelin by SC injection at 2.0 mg/kg from Gestation Day 7 to 19. There was no evidence of embryolethality, fetotoxicity, or teratogenicity in F1 animals and the NOAEL was considered to be 2.0 mg/kg (approximately 362x the clinical dose, based on AUC).
In a pre- and post-natal toxicity study, pregnant female rats were dosed with 0.1, 0.6 and 1.2 mg/kg/day by SC injection from Gestation Day 6 to Lactation Day 21. In F0 females, an increase in maternal body weight was observed and was considered to be related to the pharmacology of tesamorelin. There was a slight increase in the incidence of F1 litters developing hydrocephaly during the lactation period following administration of 1.2 mg/kg/day to the F0 dams. Behavioural and reproductive development of the F1 adult generation and the viability and growth of the F2 generation pups were unaffected by tesamorelin. The NOAEL for the F0 and F2 generations was considered to be 1.2 mg/kg/day. The NOAEL for the F1 generation was considered to be 0.6 mg/kg/day.
The potential for tesamorelin to cross the placenta was not evaluated.
The effects of tesamorelin on immune function were investigated in rats in the T-cell dependent antibody response (TDAR) assay at doses of 0.1, 0.6 and 1.2 mg/kg/day for 4 weeks. There were no adverse effects on immune function at any dose level tested.
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