Mecasermin (recombinant human insulin-like growth factor I)

Abstract

Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. 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 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, amyotrophic lateral sclerosis, 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.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

“…Several PK parameters in our study (e.g., C max , t 1/2 , t max ) and their changes with increasing doses of mecasermin (C max ) are comparable to those found in healthy volunteers and children with primary IGF-1 deficiency (39). As we observed, chronic treatment PK studies have suggested a plateau effect for doses between 160-240 μg·kg −1 ·d −1 , probably reflecting saturation of IGFBP3 (38). The nonlinear PK kinetics, greater volume distribution in the peripheral than the central compartment, and lack of change in IGFBP3 in serum and CSF suggest that serum levels of IGF-1 for may not be the best basis for dosing and that higher or chronic dosing in RTT may not necessarily result in higher exposures or a sustained exposure-response relationship.…”

“…This is not unexpected for a protein with complex regulation, mechanism of action, and pleiotropic effects (10,37,38). Recent data demonstrating activation of different signaling pathway by full length IGF-1 and its active breakdown product (29) highlights this issue.…”

Skin and brain age together: The role of hormones in the ageing process

“…(Rosenbloom, 2009). However, side effects such as hypoglycemia, hyperplasia of lymphoid tissue accumulation of body fat and coarsening of the face have been described after IGF-I application (Chernausek et al, 2007;Guevara-Aguirre et al, 1997;Guevara-Aguirre et al, 1995).…”

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials

“…It induces cell proliferation and differentiation (Rosenbloom, 2009). Whereas a first trial of IGF-1 in ALS patients reported a slower disease progression of functional impairment and a higher quality of life score (Lai et al, 1997), a subsequent study did not find beneficial effects after 9 months of treatment (Borasio et al, 1998).…”

“…Human growth hormone (hGH) stimulates the production and release of insulin-like growth factor I (IGF-1) which induces cell proliferation and differentiation (Rosenbloom, 2009). GH has evaluated in a phase II trial (NCT00635960) with no effects on disease progression (Sacca et al, 2011).…”