Medication Summary
Human IGF-I was synthesized by recombinant DNA techniques in 1986 and preparations of rhIGF-I for subcutaneous injection became available in 1990. The initial manufacturers in Japan (Fujisawa) and Sweden (Kabi) provided rhIGF-I for approximately 70 children with GHRD internationally and a handful of GH gene deletion patients with acquired GH insensitivity due to GH inactivating antibodies developing after treatment with rhGH.
Eventually, the 3 manufacturers stopped production of rhIGF-I because of the limited market. Subsequently, a company licensed by Genentech (Tercica Inc, Brisbane, California) obtained orphan drug approval of their rhIGF-I (mecasermin, [Increlex]) from the US Food and Drug Administration (FDA) in late 2005. Soon thereafter, an equimolar preparation of rhIGF-I and rhIGFBP3 (mecasermin rinfabate [Iplex], Insmed Inc, Glen Allen, Virginia) was approved by the FDA. In addition to the purported pharmacokinetic advantage permitting once daily injection for the latter preparation, a lower risk for hypoglycemia was proposed. [41] As a result of legal action, Iplex is no longer available for growth therapy; this is not a problem because the preparation was less effective than rhIGF-I alone. [42]
Pharmacokinetic profiles done at doses of 40, 80, and 120 mcg/kg suggested a plateau effect for circulating IGF-I concentrations between 80 and 120 mcg/kg per dose. It was considered that the carrying capacity of the IGFBPs was saturated at this level. [43] In a randomized, double-blind, placebo-controlled trial, 17 prepubertal Ecuadorian patients were given IGF-I at 120 mcg/kg SC bid for 6 months, following which all subjects received IGF-I. The 9 placebo-treated patients had a modest but not significant increase in height velocity from 2.8 ± 0.3 to 4.4 ± 0.7 cm/y, accounted for by 3 individuals with 6-month velocities of 6.6-8 cm/y. [40]
This response was attributed to improved nutritional status as noted with nutrition-induced catch up growth by Crosnier et al [39] in their GHRD patient with anorexia. For those receiving IGF-I, the height velocity increased from 2.9±0.6 to 8.8±0.6 cm/y and all 16 patients had accelerated velocities during the second 6-month period when all were receiving IGF-I.
Six-month, placebo-controlled, double-blind study of rhIGF-I in 16 Ecuadorian children with GHRD, followed by 6 months open label rhIGF-I therapy of the entire group.
In the comparison of growth response of the 22 Ecuadorian GHRD patients treated with rhIGF-I and 11 GHD patients treated with rhGH in the same setting and with comparable growth impairment, growth velocity increase in those with GHRD over the first year of treatment with IGF-I was 63% of that with GH treatment of GHD; in the second year the increment was less than 50% of that with GH-treated GHD. [43] The difference in growth response between GHRD treated with IGF-I and that treated with GHD was consistent with the hypothesis that 20% or more of GH-influenced growth is due to the direct effects of GH on growing bone. [44]
The collective experience of treating the rare conditions in which responsiveness to GH is severely impaired includes approximately 150 individuals, mostly with GHRD, and fewer than 10% with GH inactivating antibodies. The growth velocity increment in the first year was 4.3 cm in the European [45] and mecasermin (Genentech/Tercica) study populations, [46] and 5.6 cm in the Ecuadorian population, [43] all groups receiving comparable doses of rhIGF-I administered twice daily. In the Israeli population given a single injection of a comparable total daily dose, the increment was only 3.6 cm. [47]
Height SDS improvement in the first year of treatment paralleled these increments at 0.7, 0.8, and 0.6 for the twice daily rhIGF-I in the European, Ecuadorian, and International-mecasermin groups, respectively, and 0.2 for the Israeli population. The stimulatory effect on growth wanes rapidly after the first year, with only modest continued improvement. Among 76 patients treated for a mean 4.4 years, overall height SDS improvement was 1.4. [46]
Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
In a three-year study comparing 80 µg/kg rhIGF-I twice daily in 7 subjects to 120 µg/kg twice daily in 14 subjects, no differences in height velocity were seen, but osseous maturation increased rapidly in the higher dose and correlated with the increase in percentage of body fat and with adrenal size increase. Thus, the commonly used dosage of 120 µg/kg twice daily was considered excessive, disproportionately accelerating osseous maturation probably from the combined effects greater accumulation of body fat and inappropriate adrenal growth, compromising adult height potential. [48]
That growth failure due to GH insensitivity cannot be corrected with endocrine IGF-I replacement is not explained by concomitant IGFBP3 deficiency. Substantial tissue delivery is reflected in profound effects on adipose tissue, facies, and lymphoid tissue in treated patients (see below).
Four subjects with growth hormone (GH) receptor deficiency due to the E180 splice mutation on the GH receptor gene. From left to right, the first woman, age 22 years, was treated from age 4 years, when she had a height standard deviation score (SDS) of -8, to age 14 years with insulinlike growth factor-1 at a dose of 80 µg/kg body weight bid; adult height is -4.3 SDS and body fat percent is 39.8. The other 3 women were treated for 3 years with 120 µg/kg bid and are aged 30, 23, and 27 years with body fat content of 49.3%, 49%, and 54.6% and with heights of 120.7 cm, 120.8 cm, and 118.5 cm, respectively. Females with GH insufficiency who had comparable baseline characteristics and were treated with 120 µg/kg twice daily to adult height in the US trial only reached 112 cm, 121.2 cm, and 120.8 cm. These observations suggest no greater statural attainment with prolonged high-dose therapy than with short-term, high-dose treatment, consistent with the observation of disproportionate advancement of osseous maturation by the higher dose. Courtesy of The Journal of Clinical Endocrinology and Metabolism (Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab 98: 839–845, 2013).
Side effects include the following:
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Episodes of hypoglycemia, which may be severe, are common in infants and children with GHRD. In contrast to the hypoglycemia of GHD, which is corrected by GH replacement therapy, IGF-I treatment enhances the risk in children with GHRD. Hypoglycemia has been the most common early adverse event, reported in 49% of subjects in the largest series, including 5% with seizures. [46]
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In a 6-month placebo-controlled study, hypoglycemia was reported in 67% of those receiving placebo and 86% of those treated with rhIGF-I, an insignificant difference. [40] Fingerstick blood glucose measurements in 23 subjects residing on a research unit documented frequent hypoglycemia before breakfast and lunch, which did not increase in frequency with rhIGF-I administration. Five of the subjects participated in a crossover placebo-controlled study for 6 months with a 3-month washout period with fasting glucose determinations done thrice daily by caregivers for the entire 15-month study. The percentage of glucose values < 50 mg/dL was 2.6% on placebo and 5.5% on rhIGF-I—not a significant difference. [46] In practice, hypoglycemia appears reasonably controllable with adequate food intake.
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Pain at the injection site is common. Injection site lipohypertrophy is frequent, affecting at least one third of subjects; this is the result of failure to rotate injections, and injection into the lumps can attenuate growth response.
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The inotropic effect of IGF-I results in asymptomatic tachycardia in all treated patients, which clears after several months of continued use.
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Benign intracranial hypertension or papilledema has been noted in approximately 5% of IGF-treated subjects. While headache is frequent, the placebo-controlled study found no difference between those receiving placebo injections and those receiving IGF-I.
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Parotid swelling and facial nerve palsy have been described.
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Lymphoid tissue hypertrophy occurs in upwards of one fourth of patients, with hypoacusis, snoring, and tonsillar/adenoidal hypertrophy that required surgical intervention in more than 10% of patients. Thymic hypertrophy was noted in 35% of subjects having regular chest radiographs. Some of these side effects may be more frequent than reported because they take time to develop; for example, snoring incidence in the first year for the 25 subjects treated longest in the mecasermin study was only 4%, but increased to 65% for the entire period. [46]
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Transient elevation of liver enzymes has also been noted.
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Anaphylaxis has been reported. [49]
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Coarsening of facial features reminiscent of acromegaly has been noted in many patients, particularly those of pubertal age.
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In contrast to the increase in lean body mass and decreasing percentage of body fat that occurs with GH treatment of GHD, both lean and fat mass increase with rhIGF-I therapy, particularly at the higher dosages given. [43, 48] Mean body mass index (BMI) increased from +0.6 SDS to +1.8 SDS during 4-7 years of treatment with rhIGF-I in the European multicenter trial, and severe obesity has occasionally occurred. [45] BMI measurement may not accurately reflect the degree of obesity, which can be a doubling or tripling of body fat as demonstrated by dual energy x-ray absorptiometry. [9]
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Whether there might be long-term mitogenic effects of extended therapy with rhIGF-I in growing children is not known. The role of IGF-I in carcinogenesis as an anti-apoptotic agent favoring the survival of precancerous cells, increased cancer risk in hypersomatotropic states, and the evidence for aberrant tissue effects in patients treated with rhIGF-I dictate a need for long-term follow-up of these patients. [50, 51]
Peptide growth factors
Class Summary
rhIGF-I is a member of the somatomedin polypeptide hormones. IGF-I mediates the anabolic and growth-promoting effects of GH. Endogenous IGF-I is required for normal intrauterine growth and brain development. This intrauterine IGF-I is not GH dependent. GH dependent IGF-I is also required for normal extra uterine growth, but not brain development. GH stimulation of IGF-I production in liver (endocrine secretion) and peripheral tissues (autocrine/paracrine secretion) accounts for approximately 50% of normal growth. Mecasermin (Increlex) is the only rhIGF-I product available in the United States.
Mecasermin (Increlex)
Recombinant human insulinlike growth factor-I (rhIGF-I). Used to treat children with growth hormone insensitivity or resistance due to receptor deficiency (GHRD, Laron syndrome), in whom a GH receptor mutation results in inability to synthesize IGF-I in the liver or peripheral tissues or due to postreceptor genetic defects interfering with IGF-I synthesis and also for children with GH gene deletion who develop blocking antibodies against recombinant GH. Increlex has not been studied in children younger than 2 y.
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Diagram of the hypothalamic-pituitary-GH/IGF-I axis, showing mutational targets beginning with the GH-releasing hormone receptor (GHRHR), indicated in bold and italicized.
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A 50-year-old woman with GHRD (right) and her 75-year-old mother, indicating premature aging appearance. Photos were taken at the same distance, emphasizing the small size of the subject and relative foreshortening of the facies.
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A 10-year-old Ecuadorian girl with GHRD/Laron syndrome, who was performing at the top of the class, with her classmates.
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15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for the 11-year-old boy, 4th from the left, and his 8-year-old brother holding the ball who is almost the same height.
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A 21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, his IGF-I level is 4 times hers, and his IGFBP3 level is twice hers.
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Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Dr Frank Diamond) and the seated chief.
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Six-month, placebo-controlled, double-blind study of rhIGF-I in 16 Ecuadorian children with GHRD, followed by 6 months open label rhIGF-I therapy of the entire group.
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Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
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Four subjects with growth hormone (GH) receptor deficiency due to the E180 splice mutation on the GH receptor gene. From left to right, the first woman, age 22 years, was treated from age 4 years, when she had a height standard deviation score (SDS) of -8, to age 14 years with insulinlike growth factor-1 at a dose of 80 µg/kg body weight bid; adult height is -4.3 SDS and body fat percent is 39.8. The other 3 women were treated for 3 years with 120 µg/kg bid and are aged 30, 23, and 27 years with body fat content of 49.3%, 49%, and 54.6% and with heights of 120.7 cm, 120.8 cm, and 118.5 cm, respectively. Females with GH insufficiency who had comparable baseline characteristics and were treated with 120 µg/kg twice daily to adult height in the US trial only reached 112 cm, 121.2 cm, and 120.8 cm. These observations suggest no greater statural attainment with prolonged high-dose therapy than with short-term, high-dose treatment, consistent with the observation of disproportionate advancement of osseous maturation by the higher dose. Courtesy of The Journal of Clinical Endocrinology and Metabolism (Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab 98: 839–845, 2013).
Tables
Condition |
Growth failure |
GH |
GH binding protein |
IGF-I |
IGFBP3 |
Genetic |
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GHRD - Recessive forms |
Severe |
Elevated |
Absent-low* |
Very low |
Very low |
GHRD - Dominant negative forms |
Mild-moderate |
Elevated |
Increased |
Very low |
Low-normal |
STAT5b mutation |
Severe |
Elevated |
Normal |
Very low |
Very low |
ALS mutation |
None-moderate |
Normal |
Normal |
Very low |
Very low |
IGF-I gene mutation |
Severe |
Elevated |
Normal |
Absent-high** |
Low-normal |
IGF-I receptor mutation |
Mild-moderate |
Normal-elevated |
Normal |
Normal-elevated |
Normal-elevated |
Acquired |
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GH inhibiting antibodies |
Severe |
Absent |
Normal |
Very low |
Low |
Malnutrition |
None-mild |
Elevated |
Decreased |
Variable |
Variable |
Diabetes mellitus |
None-mild |
Elevated |
Decreased |
Decreased |
Increased |
Renal disease |
Mild-severe |
Normal |
Decreased |
Normal |
Increased |
Hepatic disease |
Mild-severe |
Elevated |
Normal-increased |
Decreased |
Normal |
*Increased in mutations of or near the transmembrane domain of the GH receptor**Absent with partial IGF1 gene deletion; very high with abnormal IGF-I |
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