乌鸦传媒

BALTIMORE -- Once-weekly injectable human growth hormone (hGH) products appeared effective in treating prepubertal children with growth hormone deficiency, according to two studies presented here at the .

In the , treatment-naive, prepubertal children that received once-weekly hGH (TransCon) had significantly improved height velocity at 52 weeks versus those who received a once-daily formation (Genotropin) (difference 0.86 cm, 95% CI 0.22-1.50, P=0.009), reported Aristides Maniatis, of Rocky Mountain Pediatric Endocrinology, and colleagues.

Not only did TransCon -- hGH bound weakly to a carrier molecule aimed at extending the protein's lifetime in circulation -- show non-inferiority to the daily version, it was statistically superior, Maniatis told 乌鸦传媒.

"I think the reason it worked even better was because the [insulin-like growth factor 1 (IGF-1)], which is the balancing marker for growth hormone, was a little bit higher compared to the daily growth hormone, but not so high to where it would be concerning," he said.

Another trial reported here, the , yielded similar results with a different hGH-based product called somapacitan, with no significant difference observed in height velocity at 26 weeks between standard daily hGH replacement and once-weekly somapacitan at both 0.08 mg/kg per week (estimated treatment difference -0.55 cm/year, 95% CI -2.41 to 1.32) and 0.16 mg/kg per week (difference 1.67 cm/year, 95% CI -0.22 to 3.56), reported Paul Saenger, MD, of Winthrop University Hospital in Mineola, New York, and colleagues.

Somapacitan, under development by Novo Nordisk, is an hGH derivative designed to increase binding to albumin in circulation, thus extending its activity following injection and making it suitable for weekly administration.

Current hGH replacement therapies must be given daily.

"Studies have shown that when you give a daily growth hormone, up to 25% of kids miss at least one injection per week," Saenger told 乌鸦传媒. "The burden of daily treatment is large, and people are upset about it. ... If we can reduce [the burden] and get better adherence, you may get better results in the end."

In both double-blind trials, growth hormone deficiency was defined as a "standard deviation score" (SDS) -- the number of standard deviations above or below the mean for chronological age and gender -- of -2 or less for height and -1 or less for IGF-1.

Robert Rapaport, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who was not involved with this study, agreed that a weekly growth hormone would be more desirable than a daily formation for many patients. However, avoiding missed doses would also be particularly critical with the weekly formation, he added.

Rapaport noted that although this new advancement does not have the extensive long-term safety data that the daily formulation has, the overall results from these short-term studies seem to be positive.

He cautioned that it will be important to ensure that IGF-1 levels are not raised to supraphysiological doses with the weekly formation, but said the results thus far show the weekly formation seems to be safe.

"The reality is we don't really know what the effects of long-term, high-dose IGF-1 levels are," he told 乌鸦传媒. "But in the studies that have been shown so far, while the IGF-1 increases, it doesn't go, roughly, two standard deviations above the mean."

heiGHt Trial

In this study, the IGF-1 levels remained approximately in the normal range (<2 SDS) for both groups across the treatment period, with the mean IGF-1 SDS increasing from -2.08 to -0.7 for the once-weekly, and the scores hovering around 0 for the once-daily, Maniatis and colleagues reported.

Adverse events were common in both groups, with 11.4% of events deemed related to the once-weekly versus 17.9% related to the once-daily. Two significant adverse events occurred during the conduct of the study, but neither were related to treatment, researchers reported.

Low titer, non-neutralizing, anti-hGH binding antibodies were detected in less than 10% of subjects in both groups, but all of them resolved over time. Additionally, fasting glucose and hemoglobin A1c levels remained in the normal range across the study period for both forms.

In the heiGHt trial, treatment-naive males from 3 and 12 years and females from 3 and 11 years diagnosed with growth hormone deficiency were included from 54 sites. Participants were required to have two growth hormone stimulation tests showing growth hormone ≤10 ng/mL and a bone age at least 6 months behind their chronological age.

Patients were randomized 2:1 to the weekly and daily formations, which were administered at 0.24 mg/kg per week and 0.034 mg/kg per day, respectively. In both arms, treatment was delivered subcutaneously through the thigh, buttocks, or abdomen.

In total, 161 patients -- mostly male (82%) and Caucasian (94.4%) -- were included with a mean age of 8.5 years. Between groups, adolescents included in the trial did not differ significantly across baseline characteristics and overall, they had a mean height SDS of -2.93, a mean IGF-1 SDS of -2.04, and a mean bone age of 5.88 years, the authors reported.

REAL 3 Trial

Although the weekly somapacitan was effective in the higher two doses, it was significantly less effective than the daily formation at 0.04 mg/kg per week (difference -3.66 cm/year, 95% CI -5.57 to -1.75), Saenger reported.

Further, somapacitan seemed to have a dose-dependent effect, since the mean annualized height velocity increased by 8.0 cm/year in the 0.04 mg/kg per week group, 10.9 cm/year with 0.08 mg/kg per week, and 12.9 cm/year with 0.16 mg/kg per week. Height velocity averaged 11.4 cm/year in the daily growth hormone group.

Increases in IGF-1 also seemed to be dose-dependent, with the mean change from baseline for the somapacitan 0.16 mg/kg per week group reaching 3.21 standard deviations. One patient receiving this higher dose also had generalized edema and vomiting that were "probably related" to somapacitan.

Other adverse events were mild to moderate, but one patient in the 0.04 mg/kg per week arm had lipoatrophy. In terms of antibodies, one patient in each somapacitan group had a sample with transient anti-somapacitan antibodies, but these appeared not to be neutralizing.

REAL 3 excluded children born small for gestational age or who were diagnosed with diabetes. In total, 58 males from 2.5 and 10 years and females 9 years or younger were randomized 1:1:1:1 to three different doses of somapacitan weekly and daily growth hormone.

The mean age of this group was around 6 years and the average height SDS was from -3 to -4, approximately. The mean IGF-1 SDS was -2 for the somapacitan 0.16 mg/kg per week and the daily growth hormone group, whereas it was -2.5 for the two lower dose somapacitan groups.

Since both trials focused exclusively on treatment-naive prepubertal patients, the results might not be generalizable to pubertal adolescents who have had previous treatment. Additionally, neither trial reported data on outcomes beyond 52 weeks.