Children With Idiopathic Short Stature Respond Well to rhGH Plus rhIGF-1

Jill Stein

June 24, 2010

June 24, 2010 (San Diego, California — Researchers are reporting early favorable safety and efficacy results for the coadministration of recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor-1 (rhIGF-1) in children with idiopathic short stature.

Idiopathic short stature refers to low IGF-1 levels and short stature not associated with growth hormone (GH) deficiency.

The new data, released at ENDO 2010: The Endocrine Society 92nd Annual Meeting, show that rhGH/rhIGF-1 coadministration in 2 separate daily injections is generally well tolerated and is associated with first-year height gains that exceed those for rhGH alone.

"We noticed about an inch difference over the course of a year in the children who received GH alone and the children who received rhGH combined with the highest dose of rhIGF-1," L. Kurt Midyett, MD, chief of the Division of Pediatric Endocrinology at the University of Kansas School of Medicine in Kansas City, told Medscape Endocrinology. "This is a large difference in this population of children whose height is significantly below the norm for their age."

The investigators compared the effectiveness, measured by first-year height velocity (HV), and safety of 3 different rhGH/rhIGF-1 combinations with rhGH alone.

The study population included 106 treatment-naive prepubertal boys and girls with IGF-1 deficiency and short stature not associated with GH deficiency. Patients had a baseline mean height standard deviation score (SDS) of –2 or less, an IGF-1 SDS of –1 or less, and maximum stimulated GH of 10 ng/or more.

Both GH and IGF-1 are necessary for normal growth, Dr. Midyett explained. Studies have shown that short GH-sufficient children with low IGF-1 levels might require very high doses of rhGH (>100 µg/kg per day) to increase IGF-1 levels to the upper half of the normal range, and that twice-daily rhIGF-1 dosing can suppress nocturnal GH secretion. On the basis of these findings, his group hypothesized that rhGH/rhIGF-1 coadministration would be superior to both monotherapies.

Patients in the ongoing phase 2 study received morning injections of rhGH alone (45 µg/kg per day) or rhGH/rhIGF-1 coadministration (45 µg/kg rhGH plus 50, 100, or 150 µg/kg rhIGF-1 as 2 injections).

Data in 58 patients revealed that the first-year HV of patients assigned to coadministration generally exceeded those of rhGH patients. First-year HVs were 9.7 cm for the patients receiving rhGH alone and 10.6, 10.5, and 11.6 cm for the 3 rhGH/rhIGF-1 groups, respectively.

"If untreated, these children would have grown about 3 to 6 cm a year," Dr. Midyett said.

The mean changes in first-year height SDS were 0.76 cm for rhGH and 0.91, 0.90, and 1.07 cm for the 3 coadministration groups, respectively.

Safety data from 106 patients showed that the most common adverse events were headache (42% with rhGH and 50% with coadministration) and vomiting (27% and 15%, respectively).

Dr. Midyett was quick to emphasize that the combination might prove to not be the best choice for all patients. "There is going to be a group of children that will respond very well to rhGH monotherapy, another group that will respond very well to rhIGF-1, and still another group that will be better served by combination therapy," he said. "Future studies will help determine which patients are the best candidates for which therapy."

Jay Cohen, MD, medical director of the Endocrine Clinic, PC, in Memphis, Tennessee, said that the study has multiple take-home messages.

The study demonstrates that there is a dose-dependent linear increase in first-year growth with added rhIGF-1, compared with rhGH alone; that there was no increased incidence of hypoglycemia between combination and rhGH patients, and that the overall adverse effect profile was not significantly different in patients treated with the combination and those treated with rhGH alone.

Dr. Cohen also noted that the trial revealed that the first-year bone age advancement was less than the chronologic age advancement. "If this holds true in year 2 and 3 data, this would predict a potentially significant increase in final adult height when using combination therapy," he said.

The study was funded by Ipsen US and Genentech. Dr. Midyett reports being on the speakers bureau and advisory board at Ibsen and on the speakers bureau at Genentech. Dr. Cohen reports being on the advisory board and speakers bureau at Ibsen and Novo Nordisk, and being on the speakers bureau at Genentech, Serono, and Teva.

ENDO 2010: The Endocrine Society 92nd Annual Meeting. Abstract OR35-5. Presented June 22, 2010.