Session: MON 0136-0155-Growth and GH: Diagnostic Issues and Treatment
Poster Board MON-0147
Objectives: Conduct a repeat dosing study to determine the safety, tolerability, height velocity, IGF-I and IGFBP-3 responses after 6 months of VRS-317 treatment.
Methods: The primary endpoint is mean 6-month height velocity. Subjects were all pre-pubertal and naïve to rhGH treatment. GHD was diagnosed by short stature (HT-SDS < -2), delayed bone age, paired GH stimulation tests (GHmax ≤ 10 ng/mL), a low IGF-I (IGF-I SDS < -1) and absence of other conditions to cause poor growth. Initially, 48 subjects (8/dose cohort) received single doses at one of six VRS-317 dose levels (0.8 to 6.0 mg/kg; equivalent to 4.9 to 37 µg rhGH/kg/d taken for 30 d). Based on observed PK/PD results, 64 subjects were randomized into three dosing arms to evaluate 5.0 mg/kg monthly, 2.5 mg/kg semimonthly or 1.15 mg/kg weekly (cumulative dose of 30 mg/kg/6m for all). At the start of repeat dosing, the subjects (37M/27F) had a mean (SD) age of 7.8 (2.4) yrs, HT-SDS of -2.5 (0.5) and IGF-I SDS of -1.7 (0.8).
Results: With more than 465 injections administered to date, discomfort at injection sites has been mild (Grade 1), transient (generally < 30 min) and reported in only 22% of subjects. No nodule formation or lipoatrophy were noted at injection sites. There have been no related serious adverse events (SAEs) or unexpected AE. Other related AE have been mild and transient and of the type expected when rhGH is initiated in children naïve to rhGH treatment (e.g., musculoskeletal pain in 5 subjects, headache in 1 subject). Peak IGF-I SDS levels are greatest with monthly dosing but not > 3 and in only 2 cases transiently exceeded 2 (2.01 and 2.12). Mean trough IGF-I SDS levels remain above baseline at Day 30 in all dosing groups. After 2 months of dosing, peak IGF-I levels are generally higher than after the first dose, suggesting that repeat VRS-317 dosing may augment IGF-I responses.
Conclusion: At doses equivalent in rhGH mass to approximately 30 µg rhGH/kg/d, repeat dosing with VRS-317 were found to be safe and well tolerated in pre-pubertal GHD children and maintains mean IGF-I increases over baseline without IGF-I overexposure when given at weekly, semimonthly and monthly intervals. Repeat VRS-317 dosing may augment the IGF-I response seen with initial dosing. The mean 6 month height velocities and updated safety and PK/PD from each cohort in the study will be presented at the meeting.
Disclosure: GMB: Vice President, Versartis, Inc.. WVM: Investigator, Versartis, Inc. HQN: Investigator, Versartis, Inc.. GBK: Investigator, VErsartis, Inc. BM: Consultant, Sandoz, Principal Investigator, Sandoz, Consultant, Genentech, Inc., Consultant, Novo Nordisk, Principal Investigator, Novo Nordisk, Principal Investigator, Versartis. DGR: Investigator, Versartis, Inc. EH: Vice President, Versartis, Inc.. JLC: Chief Executive Officer, Versartis, Inc..
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