ORLANDO – An extended-release human growth hormone formulation proved safe and effective in both children and adults, offering the prospect of a less-rigorous dosing schedule and potentially better patient compliance with treatment.
The two phase II studies examined somavaratan, which is being developed by Versartis of Menlo Park, Calif. Kevin Yuen, MD, an endocrinologist at the Swedish Medical Center, Seattle, and Wayne V. Moore, MD, a pediatric endocrinologist at Children’s Mercy Hospital, Kansas City, Mo., presented the data at the annual meeting of the Endocrine Society.
“Despite the fact that human growth hormone is a proven treatment for growth hormone deficiency, daily use of our current formulations can be a factor that affects compliance,” said Dr. Yuen. He cited a 2008of 158 men taking growth hormone, which found that only one-third were highly compliant ( ). “And even among this group, there were 21 doses missed over just a 3-month period.”
The group of 55 international experts described several strategies for creating long-acting growth hormone formulations, including depot formulations, pegylation, prodrugs, noncovalent albumin binding growth hormone compounds, and growth hormone fusion proteins. These preparations are currently in various stages of development, with some already approved in Europe and Asia.
Somavaratan (VRS-317) is a fusion protein produced in Escherichia coli. The active portion is recombinant human growth hormone, which is bound to long chains of hydrophilic amino acids. This reduces renal filtration, Dr. Yuen said. The growth hormone loses some potency in this construct, but its delayed clearance, with a half-life 30-60 times longer than recombinant human growth hormone (rhGH) allows it to exert a prolonged effect in target tissue.
Of the two phase II studies of the molecule,was conducted in 64 prepubertal children who were naive to any growth hormone treatment, and in 36 adults with adult-onset growth hormone deficiency. The company also has made these presentations available online.
The pediatric study reported 3-year data on the cohort, which began treatment of children at a mean age of 7 years. At baseline, the children were about 2.6 standard deviations (SDs) below their expected height, and their mean IGF-1 levels, about 1.7 SDs below. They showed a mean maximum stimulated growth hormone level of 5.4 ng/mL. Although they were a mean of 7.8 years chronologically at the study’s outset, their mean bone age was 6.4 years.
The first 12 months of the study consisted of dose-ranging trials, with initial doses of 5 mg/kg each month, then 2.5 mg/kg twice a month, and then 1.15 mg/kg weekly. During the last 2 years of the study, all children were taking 3.5 mg/kg, once a month.
Within the first year, all children taking the 3.5-mg/kg dose had achieved normal IGF-1 levels, which were consistent with levels achieved in the ANSWERdataset of somatropin (rDNA origin) injection (Norditropin) recombinant human growth hormone (Clin Epidemiol. 2013;5:119-27).
Height velocity improved, as did height standard deviation. By year 3, patients were a mean of 1.25 SDs below expected height – a significant improvement over baseline. These findings were almost superimposable with those in the ANSWER registry. Bone age and chronological age came into alignment within the first year and that association was maintained throughout the study – again, in almost superimposable curves with the registry data.
Somavaratan exerted no untoward metabolic effects. There were no adverse changes in body mass index. At baseline, the mean hemoglobin A1c was 5.2%; this was unchanged at 3 years. No patient developed diabetes. The most commonly reported adverse event was injection site pain (48%). Injection site erythema was reported in 5% of patients, but no injection site nodules occurred.
Other adverse events were headache, extremity pain, arthralgia, and musculoskeletal pain. Although the numbers were small overall, reports did increase after all the children were switched to the 3.5-mg/kg dose. However, they occurred in 5% or less of the patient group. There were no withdrawals due to adverse events.
The second trial was a dose-ranging study conducted in 49 adults aged 23-70 years. They all had been diagnosed with adult-onset growth hormone deficiency, but had stable pituitary function. If they were on any growth hormone therapy, they underwent a 14-day washout period.
The subjects were divided and dosed by age and gender. All subjects received one injection per month for 5 months.
Cohort A comprised 21 men and women aged 35 years or older, who took 0.6 mg/kg per month. Cohort B comprised six men and women younger than 35 years, who took 0.8 mg/kg per month. Cohort C comprised eight women taking oral estrogen contraceptives. These women received 1 mg/kg per month.
The cohorts were similar in body mass index and weight, but they did differ significantly in baseline IGF-1 levels. In cohort A, the level was 0.52 SDs below normal. In cohort B, it was 2.89 SDs below normal, and in cohort C, it was 2.29 SDs below.
Overall, somavaratan induced a rapid and dramatic increase in IGF-1 that tailed off over 30 days. By day 8 after injection, IGF-1 had risen from a mean baseline of -1 SDs to more than 2 SDs above. By day 22, it had returned to baseline levels. The response to the fifth injection was identical to that of the first, Dr. Yuen said.
Response varied somewhat by cohort, with the younger, mixed-gender group responding the most dramatically, with a mean increase of about 4 SDs from baseline. This put the group above the maximum response target of 1.5 SDs.
The older, mixed-gender cohort experienced about a 3 SDs increase – also above the target level. The women taking estrogen experienced the flattest response, gaining about 2 SDs. However, the response curve was nearly identical, with a rapid, sharp increase in IGF-1 within the first week, followed by a gradual decline to baseline by 22 days.
The adverse event profile was not quite as benign as it was in the pediatric study. Virtually all patients experienced at least one adverse event. A third were mild and 58% moderate. The rest were serious, with one severe and one life-threatening event. Dr. Yuen did not discuss adverse events; these were, however, included in supplementary slides available on the Versartis Inc. slide set.
The finding of a predictable, 3-week tailing-off of efficacy, combined with the fact that patients responded so dramatically, exceeding the maximum target of a 1.5 SDs increase in IGF-1, has prompted a new dosing protocol for the somavaratan open-label extension, which includes all the phase II completers, plus an additional 40 adult patients.
Doses will be titrated to each subject’s individual IGF-1 responses, based on the IGF-I level 7 days post dose until a maintenance dose is reached. Subjects receiving somavaratan in a previous somavaratan study will have their dose decreased by half (minimum dose of 20 mg, or 40 mg for women on estrogen).
Dr. Yuen is a member of the Versartis advisory board. Dr. Moore has received research support from the company.