THU170 Clinical And Immunological Response To Somatrogon In Two Siblings With A Homozygous Whole Gene Deletion Of The Growth Hormone 1 Gene

Disclosure: R. Gupta: None. R. Khadgawat: None. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. M.T. Dattani: Advisory Board Member; Self; Ferring Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sandoz. Consulting Fee; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Speaker; Self; Pfizer, Inc., Novo Nordisk, Sandoz, Ipsen. L. Dyer: Employee; Self; GeneDx. B. Friedman: Employee; Self; GeneDx. J. Korth-Bradley: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.L. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J. Hsiao: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone (LAGH), is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (GHD). A global Phase 3 study in pediatric subjects with GHD compared the efficacy and safety of once-weekly somatrogon (0.66 mg/kg/wk) vs once-daily Genotropin® (0.24 mg/kg/wk) in a 12-mo main study, followed by an open-label extension (OLE) where all subjects received somatrogon (0.66 mg/kg/wk). Results: Subjects #1 (male; 6 y) and #2 (female; 9 y) are siblings from India randomized in the main study to somatrogon and Genotropin, respectively. Both had severe growth and weight attenuation at baseline, with peak GH levels (GH stimulation test) of 0.1 ng/ml; their IGF-1 standard deviation scores (SDS) were -3.96 and -3.94, respectively. At main study Mo 12, subject #1 had an annual height velocity (HV) of 11.77 cm/year (height SDS improved from -7.48 to -6.4) and IGF-I SDS increased to -1.84. After a 116-day drug holiday (started at the end of main study Mo 12), he continued into the OLE; at OLE Mo 9, his HV decreased to 3.08 cm/y, there was no additional improvement in height SDS (-6.76) and his IGF-1 SDS was -2.31. A test for anti-drug antibodies (ADAs) to somatrogon was positive at main study Mo 6; tests for ADAs, and neutralizing antibodies (NAbs) were positive at Mo 12. At OLE ∼Mo 1 and 3, tests were ADA+ and NAb-; at OLE Mo 6 and 9, tests were ADA-. At main study Mo 12, subject #2 had an annual HV of 11.87 cm/year (height SDS improved from -9.93 to -7.36); IGF-I SDS increased to -2.97. After a 123-day drug holiday, she switched to somatrogon during the OLE (per protocol) and had an HV of 10.01 cm/y and IGF-1 SDS of -1.83 at OLE Mo 9. Low titer ADAs to human GH were detected during the drug holidays. In the OLE, anti-GH ADAs were still detected, but at very low titers and tests were NAb−. Whole exome sequencing revealed a homozygous whole gene deletion of the GH1 gene in both siblings. Both completed the main study and OLE without any serious adverse events or dose reductions. Conclusions: Both siblings have classic congenital isolated GHD due to a homozygous GH1 deletion. Development of anti-GH ADAs and growth attenuation during GH therapy are likely due to lack of exposure to GH during fetal life followed by exposure to exogenous GH. The variability in antibody production and heterogeneity in clinical responsiveness to GH replacement has been well described, even in siblings,(1) and if encountered in clinical practice, should prompt clinicians to consider the possibility of a GH1 deletion. To our knowledge, this is the first description of GH1 deletions in LAGH-treated subjects and the study findings are wholly consistent with those for daily GH products. Clinicaltrials.gov: NCT02968004 Reference: Ghosh et al. J Clin Res Pediatr Endocrinol 2021;13:456-60. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Thursday, June 15, 2023