Background: Recombinant human growth hormone (rhGH) is the mainstay of treatment for children with GHD, but requirement for daily subcutaneous injections represents a treatment burden for patients and caregivers. Somavaratan is a novel, long-acting rhGH fusion protein with an extended half-life that allows less frequent dosing than daily rhGH. Somavaratan previously showed clinically meaningful improvements in height velocity (HV) and insulin-like growth factor (IGF)-I in children with GHD (VISTA Trial; NCT01718041). Aims: To evaluate somavaratan in pre-pubertal children with GHD after 2.5 years of treatment in an ongoing, long-term safety study. Methods: Pediatric doses established in a single dose PK/PD study (n=48) were tested for 6 months at weekly, twice-monthly, and monthly schedules (total 5.0 mg/kg/month; n=64). Sixty patients entered the long-term safety study. All transitioned to the 3.5 mg/kg twice-monthly regimen by beginning of the second year, based on growth and IGF-I responses during the first 6-12 months of treatment. Results: 24 girls and 33 boys with mean baseline age of 7.8 years were evaluable. Mean IGF-I SDS was 1.49 at screening vs. 0.59 at peak (3-5 days post injection) and 0.47 at trough (end of dosing cycle) during Year 2. IGF-I SDS excursions >2.0 occurred in 8 patients receiving the 3.5 mg/kg twice-monthly dose, of which 2 were >3.0. Increasing dose to 3.5 mg/kg twice-monthly resulted in similar HV between Years 1 and 2 (8.08 and 7.83 cm/year, respectively) and continued improvement in height-SDS (-2.6 [baseline] vs. -2.1 and -1.6, respectively). Mean increases in bone age and height age exceeded years on study. Differences between chronological age and bone age decreased over time. Treatment-related adverse events (AE) were generally mild and transient, with rates decreasing over time and no safety signals reported. Conclusions: Somavaratan improved IGF-I and HV with declining AEs over 2.5 years in pre-pubertal children with GHD. The 3.5 mg/kg twice-monthly dose, currently under evaluation in an ongoing phase 3 trial (VELOCITY; NCT02339090), is supported by comparable US NCGS estimates of second year HV from daily rhGH. Clinical implications: Somavaratan may reduce the need for daily dosing of rhGH, thus enabling a lighter treatment burden without compromising safety or efficacy in children with GHD.

Background: Efficacy of growth hormone replacement therapy is compromised when patients fail to adhere to prescribed daily injections of recombinant human growth hormone (rhGH); noncompliance has been reported in up to 77% of patients with GHD. Somavaratan is a novel rhGH fusion protein with an extended half-life that allows less frequent dosing, compared to daily rhGH. Clinically meaningful improvements in height velocity and insulin-like growth factor (IGF)-I were previously demonstrated with weekly, twice-monthly, and monthly dosing of somavaratan in pre-pubertal children with GHD (VISTA Trial; NCT01718041). Aims: Treatment adherence to at-home dosing of somavaratan was evaluated in this long-term safety study. Methods: In the initial Phase 2 study, 64 patients were randomized to weekly, twice-monthly, and monthly dosing groups for a total of 5.0 mg/kg per month for 6 months. Sixty patients were enrolled in the long-term safety study (NCT02068521). All patients transitioned to the 3.5 mg/kg twice-monthly dose by the beginning of the second year, based on growth and IGF-I responses observed in the first 6-12 months of treatment. Over the 24-month observation period of the long-term safety study, injections were administered at home by caregivers, who recorded treatment adherence in electronic patient-reported outcome diaries (eDiary; Bracket, Inc.). Results: The mean baseline age of patients in the long-term safety study was 7.8±2.4 years. Over 5000 SC injections were administered with at-home dosing. Dosing adherence with the 3.5 mg twice-monthly dose was 99.6%, with 2266 of 2276 intended doses administered. Intended dose schedule of 15±2 days was maintained with a mean dosing interval of 15.2±2.03 days for all doses administered. Conclusions: Adherence to somavaratan was reported at nearly 100% over 24 months of treatment. These findings suggest that long-term adherence may be improved in children with GHD who receive somavaratan and that a twice-monthly treatment schedule is achieved in these patients. Treatment adherence is being monitored with the eDiary in an ongoing Phase 3 trial of somavaratan at the 3.5 mg/kg twice-monthly dose (NCT02339090). Clinical implications: Somavaratan may reduce the burden of daily GH replacement therapy by use of longer treatment intervals, including the twice-monthly schedule used in this long-term safety study.

• Beginning the second treatment year, all subjects received 3.5 mg/kg somavaratan twice monthly, based on growth and IGF-I responses observed in Year 110 Figure 1. Somavaratan Structure-Function 3-Year Safety and Efficacy Update of the VERTICAL and VISTA Trials of Somavaratan (VRS-317), a Long-Acting rhGH, in Children with Growth Hormone Deficiency (GHD) Bradley S. Miller1, Wayne V. Moore2, Patricia Y. Fechner3, Quentin L. Van Meter4, John S. Fuqua5, David Ng6, Eric Humphriss7, R. William Charlton7, George M. Bright7 1University of Minnesota Masonic Children's Hospital, Minneapolis, MN; 2Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, MO; 3Seattle Children's Hospital and University of Washington, Seattle, WA 4Van Meter Pediatric Endocrinology, PC, Atlanta, GA; 5Indiana University School of Medicine, Indianapolis, IN; 6ResearchPoint Global, Inc., Austin, TX; 7Versartis, Inc, Menlo Park, CA

CONTEXT:Somavaratan (VRS-317) is a long-acting form of recombinant human GH under development for children and adults with GH deficiency (GHD).OBJECTIVES:To determine the optimal somavaratan dose regimen to normalize IGF-1 in pediatric GHD and to evaluate safety and efficacy of somavaratan over 6 months.DESIGN:Open-label, multicenter, single ascending dose study followed by 6-month randomized comparison of 3 dosing regimens.SETTING:Twenty-five United States pediatric endocrinology centers.PATIENTS:Naive-to-treatment, prepubertal children with GHD (n = 68).INTERVENTION(S):Patients received single sc doses of somavaratan (0.8, 1.2, 1.8, 2.7, 4.0, or 6.0 mg/kg) during the 30-day dose-finding phase, then were randomized to somavaratan 1.15 mg/kg weekly, 2.5 mg/kg twice monthly, or 5.0 mg/kg monthly for 6 months.MAIN OUTCOME MEASURES:Safety, pharmacokinetics, pharmacodynamics, 6-month height velocity (HV).RESULTS:Somavaratan pharmacokinetics was linearly proportional to dose; dose-dependent increases in the magnitude and duration of IGF-1 responses enabled weekly, twice-monthly or monthly dosing. A single dose of somavaratan sustained IGF-1 responses for up to 1 month. No somavaratan or IGF-1 accumulation occurred with repeat dosing. Mean annualized HVs for somavaratan administered monthly, twice monthly, or weekly (7.86 ± 2.5, 8.61 ± 2.7, and 7.58 ± 2.5 cm/y, respectively) were similar between groups. Adverse events were mostly mild and transient.CONCLUSIONS:Somavaratan demonstrated clinically meaningful improvements in HV and IGF-1 in prepubertal children with GHD, with no significant differences between monthly, twice-monthly, or weekly dosing.