Increlex (mecasermin) contains recombinant-DNA-engineered human insulin-like growth factor-1 (rhIGF-1). It is designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized statural growth. Patients with severe primary IGF-1 deficiency (Primary IGFD) fail to produce adequate levels of IGF-1, due to disruption of the growth hormone (GH) pathway used to promote IGF-1 release (possible GH pathway disruptions include mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects).

Increlex is specifically indicated for the long-term treatment of growth failure in pediatric patients with Primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. It is not indicated to treat Secondary IGFD resulting from GH deficiency, malnutrition, hypothyroidism or other causes; it is not a substitute for GH therapy.

Increlex is supplied as a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Dosing should be titrated on a per-patient basis: the recommended initial dose is 40-80 mcg/kg twice daily. The dose can be increased in 40 mcg/kg/dose increments if well tolerated for one week, to a maximum dose of 120 mcg/kg twice daily.

FDA Approval
Approval of Increlex was based on five clinical trials of the drug: four were open-label studies, and one was double-blind and placebo-controlled. The studies enrolled a total of 71 children suffering from extreme short stature; all children exhibited symptoms of Primary IGFD, including slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Pooled results from these studies indicated that administration of Increlex increased height velocity significantly compared to baseline for years 1 through 6:

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• Year 1: + 5.2 cm/year, n=58, p<0.0001
• Year 2: + 2.9 cm/year, n=48, p<0.0001
• Year 3: + 2.3 cm/year, n=38, p<0.0001
• Year 4: + 1.5 cm/year, n=23, p=0.0045
• Year 5: + 1.5 cm/year, n=21, p=0.0015
• Year 6: + 1.5 cm/year, n=20, p=0.0009

Increlex was also shown to increase bone maturation rate in 49 subjects, with bone age increasing 8.1% faster than chronological age (+5.3 years vs. +4.9 years).

Adverse events associated with the use of Symlin may include, but are not limited to, the following:

• Bruising
• Lipohypertrophy
• Otitis Media
• Snoring
• Headache
• Dizziness
• Convulsions
• Vomiting
• Ear pain
• Hypoacusis
• Cardiac Murmur
• Arthralgia

Hypoglycemia, thought to be related to the drug's insulin-like activities, occurred in a significant portion of patients (42%) during their course of therapy. While most cases were mild or moderate, 5 subjects had severe hypoglycemia on one or more occasions, and 4 subjects experienced hypoglycemic seizures/loss of consciousness. Risk of hypoglycemia was generally mediated when a meal or snack was consumed 20 minutes prior to Increlex administration.

Also, as the drug is a pharmaceutical protein, anti-Increlex/anti-IGF-1 antibody formation can occur. 14 of 23 subjects treated for 2 years with the drug experienced some degree of anti-IGF-1 antibody formation, though no clinical consequences (allergic reaction or loss of efficacy) were observed.

Increlex supplies recombinant-DNA-origin IGF-1, which binds to the Type I IGF-1 receptor. This receptor exerts intra-cellular signaling activity in a number of processes involved in statural growth, including mitogenesis in multiple tissue types, chondrocyte growth and division along cartilage growth plates, and increases in organ growth.

Rosenfeld RG. The IGF system: new developments relevant to pediatric practice. Endocrine Development 2005;9:1-10

Clark RG. Recombinant human insulin-like growth factor I (IGF-I): risks and benefits of normalizing blood IGF-I concentrations. Frontiers of Hormone Research 2004; 62 Suppl 1:93-100

Roelfsema V, Clark RG. The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. Journal of the American Society of Nephrology 2001 Jun;12(6):1297-306

For additional information regarding Increlex or growth failure due to Primary IGFD, please visit the Increlex web page.