A Phase 1b/2a Study of a New Long-acting Growth Hormone (VRS-317) in Pre-pubertal Children with Growth Hormone Deficiency (GHD)

Program: Late-Breaking Abstracts
Session: SUN-LB-Late-Breaking Poster Session 2
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-LB-06
George M Bright*1, Teresa Quattrin2, Gad Benjamin Kletter3, Paul Michael Desrosiers4, Wayne V Moore5, Eric Humphriss6 and Jeffrey Lynn Cleland7
1Versartis, Inc., Redwood City, CA, 2University at Buffalo, State University of New York and Women and Children's Hospital of Buffalo, Buffalo, NY, 3Swedish Physician Division, Seattle, WA, 4Orlando Healthcare/Arnold Palmer, Orlando, FL, 5Children's Mercy Hosp, Kansas City, MO, 6Versartis, Inc, Redwood City, CA, 7Versartis Inc., Redwood City, CA
Background: VRS-317 is a novel fusion protein produced in E. coli and consisting of rhGH with amino acid sequences (XTEN) added to the C- and N-termini. In GHD adults, single SC doses of VRS-317 were safe, well tolerated and increased IGF-I levels in a dose-dependent manner. At the highest dose tested (0.80 mg/kg, equivalent by rhGH mass to  0.15 mg rhGH/kg), the mean VRS-317 t1/2 was 131 hrs and mean IGF-I SDS was maintained above -1.5 for three weeks after a single SC dose.

Objectives: Determine the safety, tolerability, PK and IGF-I responses to VRS-317 (Phase 1b) and 6 month height velocity (Phase 2a) using VRS-317 dosing regimens that normalize IGF-I SDS in prepubertal children with GHD.

Methods: GHD was documented by auxologic criteria and two GH stimulation tests. Subjects were naïve to rhGH treatment. Phase 1b uses an ascending dose format to study four dose levels (0.8, 1.2, 1.8 and 2.7 mg/kg VRS-317) as a single SC dose in up to 12 subjects per dosing cohort (48 total patients). By rhGH content, these doses are 0.15, 0.22, 0.33 and 0.50 mg/kg. Patients are monitored for safety and PK/PD for 30 days post-dose with continued safety assessment up to 60 days. Safety and PD data from a minimum of 8 subjects are reviewed by a Safety Review Committee (SRC) before each dose escalation. In Phase 2a, subjects will be randomized into treatment groups and treated for 6 months with dose regimens selected from Phase 1b.

Results: To date, 24 subjects (15M, 9F) with mean (SD) age 7.2 (2.0) yrs have been studied in the first three dose cohorts (8 per cohort). At screening, mean (SD) HT-SDS was -2.7 (0.6), weight was 18.3 (4.5) kg and IGF-I SDS was -1.77 (0.6). VRS-317 concentrations generally peak at 3 to 5 days, are proportional to dose and remain detectable for a minimum of 21 days in all subjects tested. Maximal changes in IGF-I SDS occur at Days 3 to 8. The amplitude and duration of IGF-I responses increase with increasing VRS-317 dose. At both 1.2 mg/kg and 1.8 mg/kg, mean change in IGF-I SDS remains > 1.0 for one week and > 0.5 for at least two weeks. Only a single value of IGF-I SDS in one patient has exceeded +2 (2.11).  Adverse events have been reported in 8 subjects to date and all have been mild and transient with no serious or unexpected adverse events reported.  The SRC has approved dose escalation to the highest proposed dose, 2.7 mg/kg VRS-317.

Conclusions: The data through a single dose of 1.8 mg/kg VRS-317 from prepubertal GHD children demonstrate that VRS-317 is safe, well tolerated and drug levels and IGF-I responses increase in intensity and duration with increasing dose.  Given the demonstrated duration of VRS-317 exposure and IGF-I responses, repeat dosing in Phase 2a is expected to cause progressive increase in IGF-I responses to enable dose frequency up to once per month.

Disclosure: GMB: Employee, Versartis, Inc.. TQ: Investigator, Versartis, Inc. GBK: Investigator, Versartis, Inc. PMD: Investigator, VErsartis, Inc. WVM: Investigator, Versartis, Inc. EH: Employee, Versartis, Inc. JLC: Management Position, Versartis, Inc.

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm