Mecasermin was safe, protective against hypoglycemia for pediatric growth failure

Patients treated with mecasermin for use in pediatric growth failure had significant height increases and reduced incidence of hypoglycemic events, according to data presented at the 13th International Congress of Endocrinology in Rio de Janeiro, Brazil.

Mecasermin (Increlex, Tercica) is an injectable recombinant human insulin-like growth factor-1 and was approved in 2006 for the treatment of growth failure in children with severe primary IGF-I deficiency. Severe primary IGF-I deficiency is defined as height and IGF-I SDS <-3 and normal/elevated growth hormone level; children with less severe disease may also benefit from treatment with mecasermin.

Alan D. Rogol, MD, PhD, professor of pediatrics, University of Virginia Health System, and colleagues announced the results of the 12-month, multicenter, open-label, parallel-dose comparison MS301 clinical trial examining the incidence of hypoglycemic events with mecasermin. The researchers randomly assigned 124 prepubertal children with primary IGF-I deficiency to twice-daily mecasermin (weight-based dosing: 40 mcg/kg; 80 mcg/kg; or 120 mcg/kg).

The incidence of hypoglycemic events was not dose-related, according to the researchers. Mecasermin-treated patients experienced a 14% incidence of hypoglycemia compared with 8% among untreated patients. The majority of patients in both the treated (86%) and untreated (92%) groups did not experience any hypoglycemia.

Hypoglycemia was more likely to occur early in the course of treatment. According to the researchers, the incidence of hypoglycemia during the first year of treatment was lower (14%) than similarly treated patients with severe primary IGF-I deficiency in a previous study (42%; J Clin Endocrinol Metab. 2007;92:902-910).

Safety and efficacy

In another poster presentation at the meeting, George M. Bright, MD, vice president and medical director of endocrinology at Tercica, reported the safety and efficacy of once-daily mecasermin in prepubertal children with primary IGF-I deficiency. Forty-five patients were assigned to mecasermin 60 mcg/kg; the dose was titrated after each study visit until and IGF-I target equivalent to a mean IGF-I SDS of +2 was reached.

The 20-month, single-arm, open-label MS308 clinical trial is ongoing. The data reported were collected up to Aug. 31, 2008.

Once-daily mecasermin up to 240 mcg/kg was safe and well-tolerated in this pediatric population, according to the researchers. Therapy was associated with significant increases in first-year height velocities in a dose-dependent fashion, according to the researchers. The effect was similar to first-year height velocities achieved with twice-daily mecasermin in children with primary IGF-I deficiency.

Adverse events were reported in 98% of the patients; more than half (56%) were considered possibly drug-related. The most commonly reported adverse events were headache (40%), vomiting (40%), pyrexia (31%) and upper respiratory infection (29%). Most adverse events were mild, transient and resolved without reducing the mecasermin dose.

“For children with GH deficiency, GH is the obvious choice to help them achieve normal growth. These results, however, point to the potential that mecasermin may have to improve growth in patients that are insensitive to GH and would need more IGF-I to achieve normal growth. Further data will be required to better define the contribution IGF-I may have in the category of growth therapies,” Philippe F. Backeljauw, MD, professor of pediatrics at Cincinnati Children’s Hospital Medical Center, said in a press release.

Both studies were funded by Tercica. – by Katie Kalvaitis

Summarized in the current issue of Endocrine Today are the reports from two of three studies utilizing IGF-I. These reports focus on one group of short statured children and expand the definition of primary IGF disorder to include children who are less affected in terms of statural growth. In fact, by utilizing a different, albeit reasonable, standard of 7 ng/mL as the cutoff rather than 10 ng/mL, the authors increase the number of children who fit their definition of low IGF-I and normal GH concentrations after provocative testing. Using this parameter of >7 ng/mL as the cutoff for normal GH secretion as well as height and IGF-I SDS of <–2.0, they note a prevalence of 26% of short statured children in their patient population. This expands the potential treatment population because currently IGF-I is approved in the United States for treatment of severe primary IGF deficiency (classical GH insensitivity; height SD ≤3.0 normal or elevated GH levels, IGF-I SDS ≥–3.0).

A brief overview of growth and human GH treatment provides the clinical context regarding IGF-I therapy. Statural growth is a very complex process involving the neuroregulation of GH secretion and IGF-I. Short stature is caused by heterogeneous etiologies and in many children the etiology is unknown. In animal studies, 35% growth is regulated by IGF-I alone, 14% by GH alone, 34% by GH and IGF-I and 17% unrelated to either; thus in 69% of growth, IGF-I is the primary hormonal medication of statural growth because GH itself stimulates the production of IGF-I.

Currently, human GH is an effective and safe therapy in children with short stature due to GH deficiency, Turner syndrome, small for gestational age, chronic renal failure, Prader-Willi syndrome and the broad category of idiopathic short stature. In appropriately selected patients, human GH is very effective and safe, in fact; in both instances, it is superior to IGF-I. On the other hand, there are children who will not respond to human GH and can potentially benefit from IGF-I therapy.

Although there is a high incidence of side effects with IGF-I — especially in comparison with human GH — the most significant one of hypoglycemia is much less when compared to the original reports in children with severe primary IGF deficiency. Fortunately, many of these side effects are not dose dependent, thus allowing higher dosing schemes, which results in better growth. Currently, human GH is administered daily whereas IGF-I is given twice daily. The report using once-daily dosing demonstrated comparable efficacy and safety to twice-daily treatment; thus a once-daily dosing schedule will offer a superior and more practical alternative to twice-daily injections.

It is important for the reader to be aware that the definition of IGF deficiency and GH deficiency would be affected by a plan to introduce a new reference standard for GH measurement; this would likely require a downward adjustment of the lower limit of normal. Also, there is marked variability in current GH assays, thus causing inconsistencies in how short statured children are categorized. Such a correction in reference standard would be a welcome improvement to the field.

It remains very important that there be continued long-term investigation and reporting of the progress using IGF-I treatment. In idiopathic short stature children who do not respond to human GH, IGF-I therapy is a theoretical option; however, there are no published data regarding safety and efficacy in this population. Ultimately, as more is known from evidence-based research, the clinician will find the most suitable role for its use in the treatment of children with short stature.

– Barry B. Bercu, MD

Professor of Pediatrics, Molecular Pharmacology and Physiology
University of South Florida

For more information:

Bright GM, et al. P00719.

Rogol A, et al. P00716. Both presented at: 13th International Congress of Endocrinology; Nov. 8-12, 2008; Rio de Janeiro.