Mecasermin (Increlex)

Number: 0711

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Criteria for Initial Approval

   Aetna considers mecasermin (Increlex) medically necessary for members with severe primary insulin-like growth factor-1 (IGF-1) deficiency or GH gene deletion with neutralizing antibodies to growth hormone (GH) when all of the following criteria are met:

   1. Pretreatment height is greater than or equal to 3 standard deviations (SD) below the mean for age and gender; and
   2. Pretreatment basal insulin-like growth factor-1 (IGF-1) level is greater than or equal to 3 SD below the mean for age and gender; and
   3. Pediatric GH deficiency has been ruled out with a provocative GH test (i.e., peak GH level greater than or equal to 10 nanograms per milliliter (ng/ml)); and
   4. Epiphyses are open.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational or Not Medically Necessary, and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of mecasermin therapy medically necessary for severe primary IGF-1 deficiency or GH gene deletion with neutralizing antibodies to GH when all of the following criteria are met:

   1. The member's growth rate is greater than 2 cm per year or there is a documented clinical reason for lack of efficacy (e.g., on treatment less than 1 year, nearing final adult height/late stages of puberty); and
   2. The epiphyses are open (confirmed by X-ray or X-ray is not available).

3. Note: Persons with severe primary insulin-like growth factor-1 (IGF-1) deficiency include those with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects. 

4. Related Policies

   1. CPB 0170 - Growth Hormone (GH) and Growth Hormone Antagonists

Dosage and Administration

Increlex (mecasermin) is available as a sterile solution supplied in a multiple dose glass vial at a concentration of 10 mg per mL (40 mg per vial) for subcutaneous use.

Growth failure in pediatrics 2 years of age and older with severe primary IGF1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH: The recommended starting dose: 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily.

Source: Ipsen Biopharmaceuticals, 2019

Experimental and Investigational or Not Medically Necessary

Note: IGF-1 analogue therapy is no longer considered medically necessary once fusion of the epiphysis has occurred. Treatment is also considered not medically necessary if there is evidence of neoplasia or intra-cranial hypertension.

Note: Aetna does not consider idiopathic short stature a disease or injury. Accordingly, coverage of treatments for idiopathic short stature would not be available under most plans, which provide coverage only for treatment of injury or disease. Please check benefit plan descriptions for details. For other plans, Aetna considers mecasermin (Increlex) experimental and investigational for idiopathic short stature because there is inadequate evidence of effectiveness for this indication.

Aetna considers mecasermin (Increlex) experimental and investigational for the following indications (not an all-inclusive list):

1. Cardiovascular protection
2. Prevention of hearing loss
3. Prevention of retinopathy of prematurity
4. Treatment of AIDS muscle wasting
5. Treatment of autism spectrum disorders
6. Treatment of amyotrophic lateral sclerosis
7. Treatment of Alzheimer's disease
8. Treatment of anorexia nervosa
9. Treatment of burns
10. Treatment of chronic liver disease
11. Treatment of Crohn's disease
12. Treatment of cystic fibrosis
13. Treatment of extreme insulin resistance
14. Treatment of HIV-associated adipose redistribution syndrome (HARS)
15. Treatment of HIV-associated lipodystrophy
16. Treatment of ischemic heart disease
17. Treatment of melanoma
18. Treatment of myotonic muscular dystrophy
19. Treatment of neurodevelopmental disorders (e.g., Fragile X syndrome, Phelan McDermid syndrome, Rett syndrome, and SCHANK3 gene deficiency syndrome)
20. Treatment of osteoporosis
21. Treatment of partial GH resistance
22. Treatment of spinal and bulbar muscular atrophy
23. Treatment of spinal cord injury
24. Treatment of X-linked severe combined immunodeficiency
25. Treatment of Werner syndrome
26. Wound healing.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
80428 - 80430	Growth hormone stimulation panel (e.g., arginine infusion, l-dopa administration) or growth hormone suppression panel (glucose administration)
83003	Growth hormone, human (HGH) (somatotropin)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
99506	Home visit for intramuscular injections
HCPCS codes covered if selection criteria are met:
J2170	Injection, mecasermin, 1 mg
ICD-10 codes covered if criteria are met:
E34.30 - E34.39	Short stature due to endocrine disorder
R62.52	Short stature (child) [severe primary insulin-like growth factor-1 deficiency (IGFD) or growth hormone gene deletion with neutralizing antibodies]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B20	Human immunodeficiency virus [HIV] disease [AIDS muscle wasting]
C43.0 - C43.9	Malignant melanoma of skin
D03.0 - D03.9	Melanoma in situ
D80.0	Hereditary hypogammaglobulinemia [X-linked severe combined immunodeficiency]
D80.5	Immunodeficiency with increased immunoglobulin M (IgM) [X-linked severe combined immunodeficiency]
D81.0 - D81.2 D81.6 - D81.7 D81.89 - D81.9	Combined immunodeficiencies [X-linked severe combined immunodeficiency]
E34.8	Other specified endocrine disorders [Werner's syndrome]
E84.0 - E84.9	Cystic fibrosis
E88.1	Lipodystrophy, not elsewhere classified
E88.81	Metabolic syndrome [extreme insulin resistance]
F50.00 - F50.02	Anorexia nervosa
F84.0 – F84.9	Pervasive developmental disorders
G12.0 - G12.9	Spinal muscular atrophy and related syndromes
G30.0 - G30.9	Alzheimer's disease
G60.0	Hereditary motor and sensory neuropathy
G71.11	Myotonic muscular dystrophy
H35.101 - H35.179	Retinopathy of prematurity
H90.0 - H91.09 H91.3 - H91.93	Hearing loss
I20.0 - I22.9 I24.0 - I25.9	Ischemic heart disease
K50.00 - K50.919	Crohn's disease
K70.0 - K70.9 K73.0 - K74.69 K75.4 K76.0 K76.81 - K76.9	Chronic liver disease and cirrhosis
M62.50 - M62.59, M62.5A0 - M62.5A9	Muscle wasting and atrophy, not elsewhere classified [due to AIDS]
M80.00X+ - M81.8	Osteoporosis
M89.121 - M89.18	Physeal arrest [epiphyseal closure]
Q93.5	Other deletions of part of a chromosome [SCHANK3 gene deficiency syndrome, Phelan-McDermid syndrome]
Q99.2	Fragile X syndrome
Numerous options	Open wounds
S12.000+ - S12.9XX+ S22.000+ - S22.089+ S32.000+ - S32.2xx+	Fracture of vertebral column
S14.0XX+ - S14.9XX+ S24.0XX+ - S24.9XX+ S34.01x+ - S34.139+ S34.3XX+	Spinal cord injury [code also any associated fracture of vertebra]
T07.xxxA - T07.xxxS	Unspecified multiple injuries
T20.00x+ - T32.99	Burns and corrosions
T79.8xx+	Other early complications of trauma
T81.30x+ - T81.33x+	Disruption of wound, not elsewhere classified
T81.40xA - T81.49xS	Infection following a procedure
T81.89X+	Other complications of procedures, not elsewhere classified

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Increlex is indicated for the treatment of growth failure in children with severe primary insulin-like growth factor-1 (IGF-1) deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.
• Severe primary IGF-1 deficiency is defined by:
  
  
  • Height standard deviation (SD) score ≤ –3.0; and
  • Basal IGF-1 SD score ≤ –3.0; and
  • Normal or elevated GH.
    
    
• Limitations of use: Increlex is not a substitute to GH for approved GH indications. Increlex is not indicated for use in patients with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory corticosteroids.

Mecasermin is available as Increlex (Ipsen Biopharmaceuticals, Inc). Mecasermin is an aqueous solution for injection containing human insulin‐like growth factor‐1 (rhIGF‐1) produced by recombinant DNA technology. Insulin‐like growth factor‐1 (IGF‐1) is the principal hormonal mediator of statural growth. IGF‐1 must be present in order for children's bones, cartilage, and organs to grow normally. Under typical 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 signaling 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. Primary IGF‐1 deficiency (IGFD) is a distinct diagnosis of short stature. These patients are not GH deficient and therefore cannot be expected to response to exogenous GH treatment.

Per the label, Increlex carries the following warnings and precautions:

• Hypoglycemia, in which Increlex should be administered shortly before or after a meal or snack because it has insulin-like hypoglycemic effects.
• Hypersensitivity and allergic reactions, including anaphylaxis: A low number of cases indicative of anaphylaxis requiring hospitalization have been reported. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought. 
• Intracranial hypertension: Funduscopic examination is recommended at the initiation and periodically during the course of therapy.
• Lymphoid tissue hypertrophy (tonsillar/adenoidal hypertrophy)
• Slipped capital femoral epiphysis (SCFE)
• Progression of scoliosis
• Malignant neoplasia: Several cases of malignant neoplasia have been observed in pediatric patients treated with Increlex. Therapy should be discontinued if evidence of malignant neoplasia develops and appropriate expert medical care sought. 
• Risk of serious adverse reactions in infants due to benzyl alcohol preserved solution: Benzyl alcohol, a preservative in Increlex, has been associated with serious adverse reactions, including death, in neonates and infants. Use of Increlex in infants is not recommended.

Contraindications include known hypersensitivity to mecasermin, intravenous administration, closed epiphyses, and malignant neoplasia. The most common adverse reactions in clinical trials include hypoglycemia, local and systemic hypersensitivity, and tonsillar hypertrophy.

Primary Insulin Growth Factor Deficiency

Primary insulin growth factor deficiency (IGFD) afflicts an estimated 30,000 children evaluated for short stature in the United States.  Primary IGFD is a growth hormone (GH)-resistant state characterized by lack of insulin-like growth factor-1 (IGF-1) production in the presence of normal or elevated levels of endogenous GH.  Approximately 6,000 children suffer from a more severe form of this condition, called severe primary IGFD (Tercica, Inc., 2005).  Severe primary IGFD includes persons with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; these persons are not GH deficient, and therefore, they can not be expected to respond adequately to exogenous GH treatment.

The U.S. Food and Drug Administration (FDA) approved 2 injectable drugs for the treatment of growth failure in children with severe primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH.  Both mecasermin (Increlex) and mecasermin rinfabate (Iplex) were approved as part of the FDA’s orphan drug program in which drugs designed to treat rare conditions or those with few available therapies are given expedited approval.  Both drugs contain recombinant human IGF-1 (rhIGF-1), which is identical to the natural hormone, IGF-1.  In humans, IGF-1 is released in response to stimulation by GH, and has a broad range of activity central to growth and metabolism.  Increlex and Iplex seek to replicate the naturally occurring form of IGF-1, providing patients who are IGF-1 deficient with a viable replacement source for the protein.  Under normal circumstances, GH binds to its receptor in the liver and other tissues and stimulates the synthesis 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 intra-cellular signaling, thus stimulating statural growth.  The metabolic actions of IGF-1 stimulate the uptake of glucose, fatty acids, and amino acids, which lead to cell, tissue, organ, and skeletal growth.  In addition to having IGF-1 activity, Iplex contains a binding protein, binding protein-3 (rhIGFBP-3), which seeks to maintain equilibrium of these proteins in the blood.

The FDA’s approval of Increlex was based upon the results of 5 phase III clinical studies (4 open-label and 1 double-blind, placebo-controlled), with subcutaneous doses of Increlex generally ranging from 0.06 to 0.12 mg/kg administered twice-daily for the treatment of short stature caused by severe primary IGFD (n = 71).  Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal GH secretion.  In clinical studies, normal GH was defined as serum GH level (peak level) of greater than 10 nanograms per milliliter (ng/ml) (20 mU/liter), after stimulation with insulin, levodopa, arginine, propranolol, clonidine, or glucagons, or an unstimulated (basal) serum GH level of greater than 5 ng/ml.  Data from these 5 clinical studies were pooled for global efficacy and safety analysis.  Of these children, 61 completed at least 1 year of rhIGF-1 replacement therapy, which is the generally accepted minimum length of time required to adequately measure growth responses to drug therapy.  Fifty-three (87 %) had Laron syndrome; 7 (11 %) had GH gene deletion, and 1 (2 %) had neutralizing antibodies to GH.  Data from the study, presented during the 86th Annual Meeting of The Endocrine Society (June 2004), demonstrated a statistically significant increase (p < 0.001) in growth rate over an 8-year period in response to therapy.  Compared to pre-treatment growth patterns, on average, children gained an additional inch per year for each year of therapy over the course of 8 years.  Patients were treated for an average of 3.9 years, with some patients being treated up to 11.5 years.  An analysis of safety in the study concluded that long-term treatment with rhIGF-1 appears to be well-tolerated.  Side effects were mild-to-moderate in nature and included hypoglycemia (42 %), injection site lipohypertrophy, and tonsillar hypertrophy (15 %).  Intra-cranial hypertension occurred in 3 subjects.  Funduscopic examination is recommended at the initiation and periodically during the course of Increlex therapy.  Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly before (i.e., 20 mins) or after the administration of Increlex.  

According to the FDA-approved product labeling, Increlex is indicated for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (primary IGFD) or with GH gene deletion who have developed neutralizing antibodies to GH.  Increlex is not intended for use in individuals with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.  Thyroid and nutritional deficiencies should be corrected before initiating Increlex treatment.  Increlex is not a substitute for GH treatment (Tercica, Inc., 2005). 

Children with primary IGF‐1 deficiency have short stature, slow growth rates, low IGF‐1 serum concentrations, and normal GH secretion. These patients are not GH deficient and therefore cannot be expected to respond to exogenous GH treatment. Mutations in GH receptor, defects in post‐GHR signaling pathway, GH gene deletion, development of neutralizing GH antibodies and IGF‐1 gene defects can cause low IGF‐1 serum concentrations. The low serum levels of IGF‐1 prevent the normal growth of childrens’ bones, cartilage, and organs.

Severe primary IGF‐1 deficiency includes members with mutations in the GH receptor (GHR), post‐GHR signaling pathway, and IGF‐1 defects (e.g. primary GH insensitivity, Laron Syndrome)

Failure to increase height velocity during the first year of therapy by at least 2 cm/year suggests the need for assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under‐nutrition, and advanced bone age.

Iplex

Iplex contains rhIGF-1 and IGF binding protein-3 (rhIGFBP-3).  The primary effect of IGFBP-3 in humans is to regulate the release of IGF-1 to target tissues as needed.  Iplex has a longer half-life than Increlex and seeks to reduce the risk of short- and long-term adverse events that have been associated with unbound levels of free IGF-1.

The FDA's approval of Iplex was based upon 2 cohort studies in children and adolescents with primary IGFD who received up to 2 mg/kg mecasermin rinfabate administered once-daily by subcutaneous injection.  Subjects included primary IGFD due to GH receptor deficiency (Laron syndrome) (n = 32 or 89 %), GH gene deletion with neutralizing antibodies to GH (n = 3 or 8 %), and 1 primary IGFD of unknown etiology.  In the first cohort, subjects (n = 16) received up to 1 mg/kg daily for the first 12 months.  The mean height velocity reportedly increased from 3.4 cm/year pre-treatment to 6.4 cm/year at 12 months (p < 0.0001).  In the second cohort (n = 9), doses were titrated up to 2 mg/kg daily for 6 months.  The investigators reported that the mean height velocity increased from 2.0 cm/year pre-treatment to 8.3 cm/year at 6 months (p < 0.0001).  Children with genetic and acquired forms of GH insensitivity or IGFD appeared to respond equally well to treatment.  Patients were treated for an average of 10.4 months.  Safety information beyond 1 year of treatment is limited.  The most common treatment-related adverse advents were mild hypoglycemia (31 %), headaches (22 %), and tonsillar and/or adenoid hypertrophy (19 %).  As is common with protein therapeutics, antibodies to the protein complex were detected in most patients, but were not associated with growth attenuation or adverse effects.

According to the FDA-approved product labeling, Iplex is indicated for the treatment of growth failure in children with severe primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH.  Iplex is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.  Thyroid and nutritional deficiencies should be corrected before initiating Iplex treatment.  Iplex is not a substitute for GH treatment (Insmed, Inc., 2005).

Rosenbloom (2006) questioned the use of recombinant IGF-1 in the treatment of idiopathic short stature.  The author noted that there is no evidence that a substantial number of children with this condition are GH-insensitive, or that those who have lower concentrations of IGF-1 or GH-binding protein are less responsive to treatment with recombinant human GH than those with more normal baseline values.  A rationale for monotherapy with IGF-1 or IGF-1 plus IGF binding protein 3 (IGFBP3) for growth other than for the specific indications characterized by unquestioned GH unresponsiveness is lacking, and considerable evidence suggests that treatment with IGF-1 or IGF-1 plus IGFBP3 will be less effective than GH monotherapy in individuals with idiopathic short stature.

A Cochrane systematic evidence review of the effectiveness of recombinant IGF-1 in amyotrophic lateral sclerosis (ALS) found that the available randomized placebo controlled trials do not permit a definitive assessment of the clinical efficacy of recombinant IGF-1 on ALS (Mitchell et al, 2007).  Two randomized controlled trials involving 449 patients measured disease progression on a clinical rating scale of disease severity in amyotrophic lateral sclerosis.  The combined results showed a small significant benefit in favor of recombinant IGF-1, the clinical relevance of which is unclear.  The authors concluded that more research is needed, noting that one trial is in progress.  They recommended that future trials should include survival as an outcome measure.

Rosenbloom (2009) stated that although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications.  Promotion of rhIGF-I for the treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH.  Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, ALS, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity.  The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals.  Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies.  The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis – a concern for long-term therapy.   It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.

In summary, both Increlex and Iplex had been shown to be effective; however, there are no studies comparing the efficacy of Increlex with Iplex (Kemp and Thrailkill, 2006).  In addition; Increlex requires twice-daily injection, may cause hypoglycemia (42 %) and requires product refrigeration until use.  Iplex requires once-daily injection, may cause hypoglycemia (31 %), and must be kept frozen and thawed at room temperature for approximately 45 mins before use.

IGF-1 analogue therapy is no longer necessary once fusion of the epiphysis has occurred.  If growth in height velocity does not increase by 2 cm after 1 year of therapy, the physician should re-evaluate the cause of growth failure.

Kemp (2009) noted that mecasermin is approved by the U.S. FDA and the European Medicines Agency for the treatment of patients with severe primary IGFD or for patients with GH1 gene deletion who have developed neutralizing antibodies to GH.  Moreover, mecasermin rinfabate (Iplex), is not available in the U.S. or Europe for treating conditions involving short stature, because of a court order related to patent infringement.  Mecasermin has been shown to be effective in increasing height velocity and adult height in patients with severe GH resistance and in IGF-1 gene deletion.  There has been some interest in using mecasermin to treat patients with partial GH resistance or idiopathic short stature.  At the present time, the data are insufficient to make this recommendation.

On July 27, 2009, Insmed Inc (manufacturer of Iplex) announced that the Company will cease the supply of Iplex to any new patients.  In addition, the Company will not initiate further clinical trials with Iplex at this time.  The Company has determined that its limited inventory on hand must be conserved for the treatment of existing patients.  Furthermore, the FDA and Insmed have agreed that access to Iplex for investigational use in patients with ALS will occur in 2 ways under Investigational New Drug applications (INDs):

• Single-patient INDs requesting “compassionate use” of Iplex for treatment of named patients with ALS, received and date-stamped by FDA’s document room by close of business on March 6, 2009, will be allowed to proceed, and Insmed has agreed to supply Iplex to those patients; and
• The remaining supply of Iplex, which is very limited, will be used by Insmed to conduct a clinical trial under an IND in which other patients with ALS who are interested in receiving Iplex treatment will be randomly assigned to receive drug through a lottery system.

In a 1-year, randomized, open-label trial, Midyett et al (2010) examined the safety and effectiveness of rhIGF-I in short children with low IGF-I levels.  A total of 136 short, pre-pubertal subjects with low IGF-I (height and IGF-I sd scores less than -2, stimulated GH greater than or equal to 7 ng/ml); 124 completed the study, and 6 withdrew for adverse events and 6 for other reasons.  Recombinant human IGF-I was administered subcutaneously, twice-daily using weight-based dosing (40, 80, or 120 microg/kg; n = 111) or subjects were observed (n = 25).  First-year height velocity (centimeters per year, cm/yr), height SD score, IGF-I, and adverse events were pre-specified outcomes.  First-year height velocities for subjects completing the trial were increased for the 80- and 120-microg/kg twice-daily versus the untreated group (7.0 +/- 1.0, 7.9 +/- 1.4, and 5.2 +/- 1.0 cm/yr, respectively; all p < 0.0001) and for the 120- versus 80-microg/kg group (p = 0.0002) and were inversely related to age.  They were not predicted by GH stimulation or IGF-I generation test results and were not correlated with IGF-I antibody status.  The most commonly reported adverse events of special interest during treatment were headache (38 % of subjects), vomiting (25 %), and hypoglycemia (14 %).  The authors concluded that rhIGF-I treatment was associated with age- and dose-dependent increases in first-year height velocity.  Adverse events during treatment were less common than in previous studies and were generally transient, easily managed, and without known sequelae.  However, the authors noted that it is premature to state whether or not rhIGF-I treatment may alter adult height.  A long-term extension trial is currently underway, which may provide some insight on this issue.

In a review on the potential of cytokines and growth factors in the treatment of ischemic heart disease, Beohar et al (2010) stated that the effect of GH on myocardial growth, cardiac function, and IGF-1 levels in patients with non-ischemic as well as ischemic cardiomyopathy, and in mixed patient populations, has been examined in several small studies.  The authors concluded that available evidence suggested that more investigations with GH or IGF-1 are needed, despite concerns regarding retinopathy and other potential long-term side effects.

The European Federation of Neurological Societies’ guidelines on “The clinical management of amyotrophic lateral sclerosis” (EFNS, 2012) noted that “Currently, there is insufficient evidence to recommend treatment with vitamins, testosterone, antioxidants such as co-enzyme Q-10 and gingko biloba, intravenous immunoglobulin therapy, cyclosporin, interferons, Copaxone, KDI tripeptide, neurotrophic factors (including brain-derived neurotrophic factor [BDNF], insulin-like growth factor-1 [IGF-1], and mecasermin rinfabate), ceftriaxone, creatine, gabapentin, minocycline, stem cells, or lithium”.

Rinaldi et al (2012) noted that spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by poly-glutamine expansion in the androgen receptor.  Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations.  Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity.  No effective disease-modifying therapy is currently available for this disease.  Recent studies by these investigators have demonstrated that IGF-1 reduces the mutant androgen receptor toxicity through activation of Akt in-vitro, and spinal and bulbar muscular atrophy transgenic mice that also over-express a non-circulating muscle isoform of IGF-1 have a less severe phenotype.  These researchers sought to establish the effectiveness of daily intra-peritoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract.  The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations.  The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle.  In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival.  The authors concluded that these findings suggested that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicated that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.

Kim and colleagues (2013) examined the effects of recombinant IGF-I in an adipocyte model of HIV lipodystrophy and in an open label study on body composition and metabolism in patients with HIV-associated lipodystrophy.  The effects of IGF-I on ritonavir-induced adipocyte cell death were studied in-vitro.  These researchers assessed lipid accumulation, IGF signaling, apoptosis, and gene expression.  They conducted a 24-week open label trial of recombinant IGF-I in 10 adults with HIV-associated lipoatrophy.  Laboratory assessments included glucose, insulin, lipids, and IGF-I.  At weeks 0 and 24, body composition studies were performed including skinfold measurement, dual-energy x-ray absorptiometry, and computed tomography of the abdomen and thigh.  In-vitro, ritonavir increased delipidation and apoptosis of adipocytes, whereas co-treatment with IGF-I attenuated the effect.  In the clinical study, subcutaneous adipose tissue did not increase in patients after treatment with IGF-I; however, there was a decrease in the proportion of abdominal fat (39.8 ± 7 % versus 34.6 ± 7 %, p = 0.007).  IGF-I levels increased with treatment (143 ± 28 μg/L at week 0 versus 453 ± 212 μg/L at week 24, p = 0.002), whereas IGFBP-3 levels declined (3.554 ± 1.146 mg/L versus 3.235 ± 1.151 mg/L, p = 0.02).  Insulin at week 12 week decreased significantly (90.1 ± 39.8 pmol/L versus 33.2 ± 19.6 pmol/L, p = 0.002).  There was a non-significant decrease in visceral adipose tissue (155.2 ± 68 cm2 at week 0 versus 140.6 ± 70 cm2 at week 24, p = 0.08).  The authors concluded that use of recombinant IGF-I may lower fasting insulin and abdominal fat in patients with lipoatrophy associated with HIV infection.  Moreover, they stated that further evaluation of this agent for treatment of HIV-associated lipodystrophy may be warranted.

Autism Spectrum Disorders and Childhood-Onset Neurodevelopmental Disorders

Costales and Kolevzon (2016) stated that central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity.  Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning.  Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for IGF-1 in normal CNS development.  Work in model systems has shown rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of effectiveness in CNS disorders, including autism spectrum disorder (ASD).  The authors examined the molecular pathways and down-stream effects of IGF-1 and summarized the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders.  This aim of this review was to provide evidence for the potential of IGF-1 as a treatment for ASD and neurodevelopmental disorders.

Riikonen (2016) noted that there are no treatments for the core symptoms of ASD, but there is now more knowledge on emerging mechanisms and on mechanism-based therapies.  In autism there are altered synapses: genes affected are commonly related to synaptic and immune function.  Dysregulation of activity-dependent signaling networks may have a key role the etiology of autism.  There is an over-activation of IGF-AKT-mTor in ASDs.  Morphological and electro-physiological defects of the cerebellum are linked to system-wide ASD-like behavior defects.  The molecular basis for a cerebellar contribution has been demonstrated in a mouse model.  These have led to a potential mechanism-based use of drug targets and mouse models.  Neurotrophic factors are potential candidates for the treatment.  Insulin-like growth factor-1 is altered in autism.  It reduces neuro-inflammation: by causing changes of cytokines such as IL-6 and microglial function; IGF-1 reduces the defects in the synapse.  It alleviates NMDA-induced neurotoxicity via the IGF-AKT-mTor pathway in microglia; IGF-1 may rescue function in Rett syndrome and ASD caused by changes of the SCHANK3 gene.  There are recently pilot studies of the treatment of Rett syndrome and of SCHANK3 gene deficiency syndromes.  The FDA has granted orphan drug designations for Fragile X syndrome, SCHANK3 gene deficiency syndrome and Rett syndrome.

Vahdatpour and colleagues (2016) stated that IGF-1 is a neurotrophic polypeptide with crucial roles to play in CNS growth, development and maturation.  Following interrogation of the neurobiology underlying several neurodevelopmental disorders and ASD, both recombinant IGF-1 (mecasermin) and related derivatives, such as (1-3)IGF-1, have emerged as potential therapeutic approaches.  Clinical pilot studies and early reports have supported the safety/preliminary effectiveness of IGF-1 and related compounds in the treatment of Rett Syndrome, with evidence mounting for its use in Phelan McDermid syndrome and Fragile X syndrome.  In ASD, clinical trials are ongoing.

Rett Syndrome

Khwaja et al (2014) noted that Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2.  Mouse models suggested that mecasermin may improve many clinical features.  In a phase I clinical trial, these researchers evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT).  In addition, they performed a preliminary assessment of efficacy using automated cardio-respiratory measures, EEG, a set of RTT-oriented clinical assessments, and 2 standardized behavioral questionnaires.  This study included a 4-week multiple ascending dose (MAD) (40 to 120 μg/kg twice-daily) period and a 20-week open-label extension (OLE) at the maximum dose.  Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events.  Mecasermin reached the central nervous system compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD.  The drug followed non-linear kinetics, with greater distribution in the peripheral compartment.  Cardio-respiratory measures showed that apnea improved during the OLE.  Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE.  These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression.  The authors concluded that these findings indicated that IGF-1 is safe and well-tolerated in girls with RTT and, as demonstrated in pre-clinical studies, ameliorated certain breathing and behavioral abnormalities.  These preliminary findings need to be validated by well-designed studies.

Pini and colleagues (2016) examined the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by 2 blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of 10 patients with classic RTT and 10 untreated patients matched for age and clinical severity.  Significant improvement in both the ISS (p = 0.0106) and RSS (p = 0.0274) was found in patients treated with IGF1 in comparison to untreated patients.  Analysis of the novel RSS also suggested that patients treated with IGF1 have a greater endurance to social and cognitive testing.  The authors concluded that the present clinical study added significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum. 

The main drawback of this study was its open-label design.  While the ISS was not fully blinded, the RSS was assessed by blinded assessors.  Notably, the strongest results in the present study were observed for the RSS.  When interpreting the results of this study a key aspect was the sample size, which is a common factor of rare diseases and in this case was also affected by limited availability of IGF1; hence this study should be considered a presentation of clinical cases rather than a clinical trial.  Several statistical tests failed to reach significance because of the limited sample size and the statistic test used; hence the replication of study results by additional clinical studies and trials is particularly important. 

In a double-blind, cross-over study, O'Leary and colleagues (2018) measured the efficacy of mecasermin (rhIGF-1) for treating symptoms of Rett syndrome (RTT) in a pediatric population.  A total of 30 girls with classic RTT in post-regression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed-over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week wash-out period.  The primary end-points were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behavior Questionnaire (RSBQ) Fear/Anxiety sub-scale, Parent Target Symptom Visual Analog Scale (PTSVAS) top 3 concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale.  Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed.  There were no significant differences between randomization groups.  The majority of adverse events (AEs) were mild-to-moderate, although 12 episodes of serious AEs occurred.  The Kerr severity scale, ADAMS Depressed Mood subscale, VAS- Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms; EEG parameters also deteriorated.  A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings.  However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.  The authors concluded that as in the phase-I clinical trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

Severe Insulin Resistance Syndromes

Plamper and colleagues (2018) stated that mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson-Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first 2 years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. These investigators presented a case involving a male patient with DS, harboring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice-daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6 %). However, this patient died at 22 months of age during the course of a respiratory infection. Currently available data in the literature comprising more than 30 treated patients worldwide appeared to support a trial of rhIGF-I in SIR. The authors concluded that rhIGF-I represents a therapeutic option for challenging SIR cases, however, careful consideration of the therapeutic benefits and the burden of the disease is needed.

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Appendix

Basal serum IGF-1 reference ranges: Normal serum IGF-1 values vary by age, sex, and pubertal status.  Reference ranges for serum IGF-1 vary among laboratories.  The reference range for the laboratory performing the test should be used to determine whether the member’s basal serum IGF-1 level meets criteria. 

Height standard deviation score: The following website includes growth charts for children indicating heights (lengths) with curves down to 2 standard deviations (approximately third percentile).

Centers for Disease Control and Prevention: Growth Charts-Homepage

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References