Safety and Efficacy Results of a 6 Month, Randomized, Multi-Center Trial of a Novel Long-Acting Rhgh (VRS-317) in Na´ve to Treatment, Pre-Pubertal Children with Growth Hormone Deficiency (GHD)

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: MON 0136-0155-Growth and GH: Diagnostic Issues and Treatment
Monday, June 23, 2014: 1:00 PM-3:00 PM
Hall F (McCormick Place West Building)

Poster Board MON-0147
George M Bright, MD1, Wayne V Moore, MD, PHD2, H. Q. Nguyen, MD3, Gad B. Kletter, MD4, Bradley Miller, MD, PhD5, Douglas G. Rogers, MD6, Eric Humphriss, MBA7 and Jeffrey L Cleland, BS, PHD8
1Versartis, Inc., Redwood City, CA, 2Children's Mercy Hosp, Kansas City, MO, 3Sierra Medical Research, Clovis, CA, 4Swedish Physician Division, Seattle, WA, 5Univ of Minnesota Amplatz Childr, Minneapolis, MN, 6Cleveland Clin Fndn, Cleveland, OH, 7Versartis, Inc, Redwood City, CA, 8Versartis Inc., Redwood City, CA
Background: VRS-317 is a novel fusion protein (M.W. 119 kDa) consisting of rhGH with amino acid sequences (XTEN) attached at the N- and C-termini. In Phase 1 studies in GHD adults and children, VRS-317 concentrations, IGF-I and IGFBP-3 responses were proportional to dose, with drug concentrations and increases in IGF-I and IGFBP-3 still present 30 days after a single subcutaneous injection. Single dose VRS-317 administration has been safe and well tolerated, with minimal injection site discomfort; no new safety signals compared to daily rhGH products have emerged.

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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Sources of Research Support: This clinical trial was supported by Versartis, Inc.