Correlation Between Baseline IGF-I, Dose, and Response to Once-Monthly Somavaratan, a Long-Acting Recombinant Human Growth Hormone (rhGH), in the Open-Label, Dose-Finding, International, Phase 2 VITAL Study in Adults with Growth Hormone Deficiency (AGHD) (NCT02526420)

Presentation Number: SUN 440
Date of Presentation: April 2nd, 2017

Martin Bidlingmaier*1, Daniela Rogoff2, Trish Rice3, Maria Koltowska-Häggström2, Bert Bakker2, Eric Humphriss2, Christian J Strasburger4 and Beverly M.K. Biller5
1Klinikum der Universität München, München, Germany, 2Versartis, Inc., Menlo Park, CA, 3Premier Research, Naperville, IL, 4Charité-Universitätsmedizin, Berlin, Germany, 5Massachusetts General Hospital, Boston, MA

Abstract

IGF-I levels have limited utility in diagnosing AGHD due to overlap with non-GHD (1). This overlap is apparent even with severe GHD identified by provocative GH tests and increases with advanced age. Some of the disparity in IGF-I levels is due to timing of GHD onset (2). Somavaratan, a novel long-acting rhGH fusion protein with 30- to 60-fold longer t1/2 than daily rhGH, is under development for treatment of pediatric and adult GHD and showed promising results in early clinical trials (3,4). In an ad hoc analysis on preliminary data from the recently completed Ph 2 dose-finding VITAL study in AGHD, we evaluated relationships between baseline (BL) IGF-I levels and somavaratan dose and IGF-I response. The relationship between BL IGF-I and years since diagnosis was also assessed. Subjects received 5 monthly doses of somavaratan, with up to 4 dose adjustments permitted to achieve mean IGF-I SDS between BL and Day 8 of 0-1.5. Starting dose was 0.6, 0.8, or 1.0 mg/kg for subjects ≥ 35 years of age, < 35 years, or women on oral estrogen, respectively. Results are presented as mean ± SD. Of 36 subjects enrolled (18 M, 18 F; age, 46.1 ± 13.1 years, range: 24-70), 33 completed the 5 doses. BL IGF-I SDS had a significant effect on dose (mg) of somavaratan administered in the study (P < 0.0001). A negative correlation was observed between BL IGF-I-SDS and somavaratan dose needed to reach target IGF-I SDS range, with higher doses needed in subjects with lower BL IGF-I (r = -0.70). The mean somavaratan dose (across all doses received in the study) was 83 ± 66 mg in subjects with BL IGF-I SDS ≤ -1 (n = 19; age: 42.2 ± 12.4) and 42 ± 14 mg in subjects with BL IGF-I SDS > -1 (n = 17; age: 50.5 ± 12.8) (P < 0.0001). Mean IGF-I SDS at Day 8 was 1.21 ± 1.96 vs. 3.00 ± 1.45 in subjects with BL IGF-I SDS ≤ -1 and > -1, respectively (P < 0.0001). While ΔIGF-I between pre-dose and Day 8 across all doses was greater in subjects with BL ≤ -1 SDS (3.73 ± 1.92 and 2.86 ± 1.74 for BL IGF-I SDS ≤ -1 and > -1, respectively (P = 0.0022), adjustment of Day 8 IGF-I response by dose received (ΔIGF-I SDS for 100 mg of somavaratan = 100*ΔIGF /actual dose [mg]) showed a greater response in subjects with BL IGF-I > -1SDS (adjusted ΔIGF-I: 6.1 ± 3.8 and 7.0 ± 4.3 in BL IGF-I SDS ≤ -1 and > -1, respectively; P < 0.0001). BL IGF-I SDS strongly correlated with years since diagnosis (r = ‑0.71), with longer duration of disease associated with lower IGF-I levels, despite similar magnitude of GH response to stimulation test. For subjects with BL IGF-I SDS ≤ -1, mean time since diagnosis was 17 years, compared with 4 years for subjects with BL IGF-I SDS > -1 (P = 0.0002). In conclusion, among adults with GHD, there is a clear distinction of IGF-I response to somavaratan and dose requirement based on BL IGF-I level. Subjects with BL IGF-I SDS > -1 require a lower dose to reach target IGF-I SDS not only because of higher starting BL IGF-I, but also due to greater response to treatment, suggesting higher sensitivity to rhGH.

 

Disclosure: MB: Investigator, Pfizer, Inc., Investigator, OPKO, Investigator, Genexine, Investigator, IDS, Speaker, Pfizer, Inc., Speaker, Sandoz, Speaker, Diasorin, Ad Hoc Consultant, Versartis, Inc., Ad Hoc Consultant, OPKO, Ad Hoc Consultant, Sandoz, Ad Hoc Consultant, Genexine. DR: Employee, Versartis, Inc., Employee, Versartis, Inc.. TR: Employee of CRO, Versartis, Inc.. MK: Consultant, Versartis, Inc.. BB: Employee, Versartis, Inc., Employee, Versartis, Inc.. EH: Employee, Versartis, Inc., Employee, Versartis, Inc.. CJS: Medical Advisory Board Member, Versartis, Inc., Investigator, Versartis, Inc.. BMKB: Principal Investigator, Novo Nordisk, Ad Hoc Consultant, Novo Nordisk, Ad Hoc Consultant, Pfizer, Inc., Principal Investigator, Opko, Principal Investigator, Versartis, Inc., Ad Hoc Consultant, Versartis, Inc..