Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Ipsen Pharma, 65, quai Georges Gorse, 92100, Boulogne-Billancourt, France
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and somatropin agonists
ATC code: H01AC03
Mecasermin is a human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesised in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.
Insulin-like growth factor-1 (IGF-1) is the principal hormonal mediator of statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver and other tissues and stimulates the synthesis/secretion of IGF-1. In target tissues the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signalling which stimulates multiple processes leading to statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.
The following actions have been demonstrated for endogenous human IGF-1:
Tissue Growth:
Skeletal growth is accomplished at the epiphyseal plates at the ends of a growing bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by GH and IGF-1. Organ growth: treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth. Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activity that leads to an increased number of cells in the body.
Carbohydrate Metabolism:
IGF-1 suppresses hepatic glucose production, stimulates peripheral glucose utilization, and can reduce blood glucose and cause hypoglycaemia. IGF-1 has inhibitory effects on insulin secretion.
Bone/Mineral Metabolism:
Circulating IGF-1 plays an important role in the acquisition and maintenance of bone mass. IGF-1 increases bone density.
Five clinical studies (4 open-label and 1 double-blind, placebo-controlled) were conducted with INCRELEX. Subcutaneous doses of mecasermin, generally ranging from 60 to 120 μg/kg given twice daily (BID), were administered to 92 paediatric subjects with severe Primary IGFD. Patients were enrolled in the studies on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations and normal GH secretion. Eighty-three (83) out of 92 patients were naïve to INCRELEX at baseline and 81 completed at least one year of INCRELEX treatment. Baseline characteristics for the 81 patients evaluated in the primary and secondary efficacy analyses from the combined studies were (mean ± SD): chronological age (years): 6.8 ± 3.8; age range (years): 1.7 to 17.5; height (cm): 84.1 ± 15.8; height standard deviation score (SDS): -6.9 ± 1.8; height velocity (cm/yr): 2.6 ± 1.7; height velocity SDS: -3.4 ± 1.6; IGF-1 (ng/ml): 24.5 ± 27.9; IGF-1 SDS: -4.2 ± 2.0; and bone age (years): 3.8 ± 2.8. Of these, 72 (89%) had Laron syndrome-like phenotype; 7 (9%) had GH gene deletion, 1 (1%) had neutralizing antibodies to GH and 1 (1%) had isolated genetic GH deficiency. Forty-six (57%) of the subjects were male; 66 (81%) were Caucasian. Seventy-four (91%) of the subjects were prepubertal at baseline.
Annual results for height velocity, height velocity SDS, and height SDS until year 8 are shown in Table 2. Pre-treatment height velocity data were available for 75 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year. The height velocities for years 2 through 8 remained statistically greater than baseline. For the 21 treatment naïve subjects with near-adult height, the mean (± SD) of the difference between observed increase in height versus that expected from Laron was approximately 13 cm (± 8 cm) after an average of 11 years of treatment.
Table 2. Annual Height Results by Number of Years Treated with INCRELEX:
| Pre-Tx | Year 1 | Year 2 | Year 3 | Year 4 | Year 5 | Year 6 | Year 7 | Year 8 | |
|---|---|---|---|---|---|---|---|---|---|
| Height Velocity (cm/yr) | |||||||||
| N | 75 | 75 | 63 | 62 | 60 | 53 | 39 | 25 | 19 |
| Mean (SD) | 2.6 (1.7) | 8.0 (2.3) | 5.9 (1.7) | 5.5 (1.8) | 5.2 (1.5) | 4.9 (1.5) | 4.8 (1.4) | 4.3 (1.5) | 4.4 (1.5) |
| Mean (SD) for change from pre-Tx | +5.4 (2.6) | +3.2 (2.6) | +2.8 (2.4) | +2.5 (2.5) | +2.1 (2.1) | +1.9 (2.1) | +1.4 (2.2) | +1.3 (2.8) | |
| P-value for change from pre-Tx 1 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | 0.0042 | 0.0486 | |
| Height Velocity SDS | |||||||||
| N | 75 | 75 | 62 | 62 | 58 | 50 | 37 | 22 | 15 |
| Mean (SD) | -3.4 (1.6) | 1.7 (2.8) | -0.0 (1.7) | -0.1 (1.9) | -0.2 (1.9) | -0.3 (1.7) | -0.2 (1.6) | -0.5 (1.7) | -0.2 (1.6) |
| Mean (SD) for change from pre-Tx | +5.2 (2.9) | +3.4 (2.4) | +3.3 (2.3) | +3.2 (2.1) | +3.2 (2.1) | +3.3 (2.0) | +3.0 (2.1) | +3.3 (2.7) | |
| P-value for change from pre-Tx 1 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | 0.0001 | <0.0001 | <0.0001 | 0.0003 | |
| Height SDS | |||||||||
| N | 81 | 81 | 67 | 66 | 64 | 57 | 41 | 26 | 19 |
| Mean (SD) | -6.9 (1.8) | -6.1 (1.8) | -5.6 (1.7) | -5.3 (1.7) | -5.1 (1.7) | -5.0 (1.7) | -4.9 (1.6) | -4.9 (1.7) | -5.1 (1.7) |
| Mean (SD) for change from pre-Tx | +0.8 (0.6) | +1.2 (0.9) | +1.4 (1.1) | +1.6 (1.2) | +1.7 (1.3) | +1.8 (1.1) | +1.7 (1.0) | +1.7 (1.0) | |
| P-value for change from pre-Tx 1 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | 0.0001 | <0.0001 | |
Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score
1 P-values for comparison versus pre-Tx values were computed using paired t-tests.
For subjects with bone age available for at least 6 years after treatment initiation, the mean increase in bone age was comparable to the mean increase in chronological age; for these subjects, there does not appear to be any clinically significant advance of bone age relative to chronological age.
Efficacy is dose dependent. The dose of 120 μg/kg given subcutaneously (SC) and twice daily (BID) was associated with the greatest growth responses.
Among all subjects included for safety evaluation (n=92), 83% of the subjects reported at least one adverse event during the course of the studies. There was no death during the studies. No subject discontinued the studies due to adverse events.
Hypoglycaemia was the most frequently reported adverse event and a proper attention has to be given to meals in relation to dosing.
This medicinal product has been authorised under “exceptional circumstances”.
This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The absolute subcutaneous bioavailability of mecasermin in severe Primary IGFD subjects has not been determined. The bioavailability of mecasermin after subcutaneous administration in healthy subjects has been reported to be approximately 100%.
In blood, IGF-1 is bound to six IGF binding proteins (IGFBPs), with ~80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution (mean ± SD) after subcutaneous administration of INCRELEX in 12 subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) l/kg at a mecasermin dose of 0.045 mg/kg, and is estimated to increase as the dose of mecasermin increases. Limited information is available on the concentration of unbound IGF-1 after the administration of INCRELEX.
Both the liver and the kidney have been shown to metabolise IGF-1.
The mean terminal t½ of total IGF-1 after single subcutaneous administration of 0.12 mg/kg in three paediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of total IGF-1 is inversely proportional to serum IGFBP-3 levels and total IGF-1 systemic clearance (CL/F) is estimated to be 0.04 l/hr/kg at 3 mg/l IGFBP-3 in 12 subjects.
The pharmacokinetics of INCRELEX have not been studied in subjects greater than 65 years of age.
The pharmacokinetics of INCRELEX have not been studied in subjects younger than 12 years of age.
In adolescents with Primary IGFD and in healthy adults there were no apparent differences between males and females in the pharmacokinetics of INCRELEX.
No information is available.
No studies have been conducted in children with renal impairment.
No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of mecasermin.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity or genotoxicity.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows.
In rats and rabbits reproductive toxicity was studied after intravenous but not after subcutaneous application (the normal clinical route). These studies did not indicate direct or indirect harmful effects with respect to fertility and pregnancy, but due to the different route of application the relevance of these findings is unclear. Placental transfer of mecasermin was not studied.
Mecasermin was administered subcutaneously to Sprague Dawley rats at doses of 0, 0.25, 1, 4, and 10 mg/kg/day for up to 2 years. An increased incidence of adrenal medullary hyperplasia and pheochromocytoma was observed in male rats at doses of 1 mg/kg/day and above (≥1 times the clinical exposure with the maximum recommended human dose [MRHD] based on AUC) and female rats at all dose levels (≥0.3 times the clinical exposure with the MRHD based on AUC).
An increased incidence of keratoacanthoma in the skin was observed in male rats at doses of 4 and 10 mg/kg/day (≥4 times the exposure with the MRHD based on AUC). An increased incidence of mammary gland carcinoma in both male and female rats was observed in animals treated with 10 mg/kg/day (7 times the exposure with the MRHD based on AUC). Excess mortality secondary to IGF-1 induced hypoglycaemia was observed in the carcinogenesis studies.
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