Ron G. Rosenfeld’s research while affiliated with Oregon Health & Science University and other places

Unlabelled: Body proportions are the objective parameters of harmonious growth and reflect the interplay of genetic, environmental, metabolic, and hormonal actions. Mutations in the growth hormone receptor gene (GHR) result in severe growth failure. The study of individuals affected with these mutations can inform us about the role of growth peptides in harmonious, proportional growth. Methods: In this epidemiological, non-interventional study, we compared the anthropometric measurements and body proportions of an Ecuadorian cohort of adult subjects with GH insensitivity (GHI) due to a homozygous mutation at codon 180/exon 6 of the GHR, to their carrier and non-carrier relatives, and to non-carrier unrelated controls. We also investigated the relations between serum IGF-I concentrations and auxological determinations. Results: In this cohort of 201 adults, gender-specific distributions of height (Ht), lower segment, upper segment, arm span, head circumference (HC), hand and foot length were lower in the GHI subjects than in the other groups. The GHI individuals had the lowest lower segment/Ht, the highest upper segment/Ht, the lowest arm span/Ht and the highest head circumference/Ht ratio. Hand and foot length/Ht ratios were not uniformly affected. Serum IGF-I concentration displayed a positive logarithmic correlation with all body measurements but were negatively correlated with the head circumference/Ht ratio. Conclusions: These findings indicate that subjects homozygous for the GHR mutation have disharmonious body proportions due to abnormal GH/IGF-I action on the growth of the long bones. Contrary to common assumptions, disruption of the GH-IGF axis results in disproportionality and disharmonious growth.

Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia.

Disclosure: Z. Zadik: None. N. Zelinska: Consulting Fee; Self; Novo Nordisk, Berlin-Chemie, Medtronic, Sanofi-Aventis. Research Investigator; Self; MacroGenics, Novo Nordisk, Pfizer, Inc., Merck, OPKO Health, Ferring Pharmaceuticals, Teva Pharmaceutical Industries Ltd., Parexel, Genexine. Speaker; Self; Medtronic, Berlin-Chemie, ACINO, Novo Nordisk, Pfizer, Inc., Sanofi-Aventis, Johnson &Johnson, Wörwag Pharma. V. Iotova: Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Novo Nordisk, Pfizer, Inc., Swixx, Sandoz, Berlin-Chemie. Y. Skorodok: None. O.A. Malievskiy: None. N. Mauras: Consulting Fee; Self; Agios. Grant Recipient; Self; Novo Nordisk, Abbvie. Research Investigator; Self; OPKO Health, Abbvie, Beta Bionics. S.R. Valluri: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. A. Pastrak: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. R. Wang: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone, is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (pGHD). This abstract describes results from up to 8 y of study (main study + open label extension [OLE]) evaluating the efficacy and safety of somatrogon in pGHD. Methods: This randomized, open-label, dose-finding Phase 2 study comprised 5 treatment periods. Subjects were randomized 1:1:1:1 to once-weekly somatrogon (titrated up to 0.25, 0.48, or 0.66 mg/kg/wk) or once-daily Genotropin (0.24 mg/kg/wk) for 12 mo of the main study (periods I and II), after which they were eligible to enroll in the OLE (periods III-V). In period III, somatrogon recipients continued at their previous dose; Genotropin recipients were re-randomized to 1 of the 3 somatrogon doses. In period IV (OLE Year (Y)2–4), all subjects switched to somatrogon 0.66mg/kg/wk; in period V (OLE Y5 onward), all subjects switched from single-use somatrogon vials to prefilled pen devices (somatrogon 0.66 mg/kg/wk). Results: Of 53 subjects who completed the main study, 48 entered the OLE. At OLE entry, 66.7% were male, all but 1 were pubertal Tanner stage 1, and mean (SD) age was 7.7 (2.1) y. At OLE Y6 end, there were 30 subjects with a mean±SD height velocity (HV) of 6.47±2.07 cm/y and a mean±SD height SD score (HT SDS) of 0.43±0.94. At OLE Y7 end, 26 subjects had a mean±SD HV of 5.31±1.68 cm/y and a mean HT SDS of 0.44±0.96. Four subjects achieved final height (defined as HV <1 cm/y). Their HVs in the last 6-mo interval and last assessed heights were: subject 1: 0.54 cm/y, 174.5 cm; subject 2: 0.7 cm/y, 173.2 cm; subject 3: 0.56 cm/y, 179.5 cm; and subject 4: 0.19 cm/y, 168.7 cm. Somatrogon efficacy was not affected by positive test results for antidrug antibodies (ADA). HV and cumulative ΔHT SDS (cΔHT SDS) were similar between subjects who tested ADA+ vs ADA-: at OLE Y6 end, 15 who tested ADA+ had HV 6.47±1.69 cm/y and cΔHT SDS 3.09±1.04; and 15 who tested ADA- had HV 6.48±2.46 cm/y and cΔHT SDS 3.62±1.40. At OLE Y7 end, 14 subjects who tested ADA+ had HV 5.22±1.52 cm/y and cΔHT SDS 3.06±0.98; 12 who tested ADA- had HV 5.42±1.91 cm/y and cΔHT SDS 3.75±1.39. In OLE Y7, TEAEs were reported in 35.5% subjects, which was lower than the main study (69.0%) and OLE Y1–6 (range: 41.9–57.5%). No serious TEAEs or TEAEs leading to study drug withdrawal occurred in OLE Y7. Study drug–related TEAEs occurred in 2 subjects: keeled chest acquired and scoliosis in 1 and arthralgia in 1. No deaths were reported throughout the OLE. Conclusion: Following up to 8 y of somatrogon treatment, including 7 y of the OLE, subjects demonstrated continued growth, 4 achieved final height, and somatrogon maintained a favorable safety profile. Testing ADA+ did not appear to affect subject growth. Clinicaltrials.gov: NCT01592500. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Saturday, June 17, 2023

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

Introduction: Although the majority of Growth Hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects. Case presentation: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/ml; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5), and ALS (565 mU/ml; 1500-3500) were also low. GH stimulation test was normal, and GHBP markedly elevated (6300pmol/L; 240-3000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels. Conclusion: We describe the first synonymous heterozygous GHR splicing variant in exon 9 encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.

Objectives Somatrogon is a long-acting recombinant human growth hormone (GH) employed as a once-weekly treatment for children with GH deficiency (GHD). A 12-month, phase 2 study of once-weekly somatrogon vs. once-daily GH (Genotropin ® ) was initiated, after which participants could enroll into an open-label extension (OLE) evaluating the safety and efficacy of long-term somatrogon treatment. Methods There were five study periods, Periods I and II were 6 months each while Periods III, IV, and V were 12 months each. In the main study (Periods I and II), 53 prepubertal children with GHD were randomized to once-weekly somatrogon (0.25, 0.48, or 0.66 mg/kg/week) or once-daily Genotropin (0.034 mg/kg/day); 48 continued into the OLE, consisting of Period III (original somatrogon dose; Genotropin recipients randomized to one of three somatrogon doses), Period IV (somatrogon 0.66 mg/kg/week), and Period V (prefilled somatrogon pen [0.66 mg/kg/week]). Results At the end of Period III, the mean ± SD annual height velocity (HV) for 0.25, 0.48, and 0.66 mg/kg/week somatrogon groups was 7.73 ± 1.89, 7.54 ± 1.28, and 8.81 ± 1.12 cm/year, respectively; HV was sustained during Periods IV/V. Height SD scores (SDS) showed progressive improvement throughout the OLE, regardless of initial cohort assignment, approaching the normal range (−0.69 ± SD 0.87) at the end of Period V Year 1. Mild or moderate treatment-emergent adverse events were reported in 81.3% of participants, most unrelated to study drug. Conclusions Up to 5 years of once-weekly somatrogon was well tolerated and resulted in sustained improvement in height SDS and delta height SDS in prepubertal short children with GHD. Clinicaltrials.gov:NCT01592500.

The growth hormone (GH)–insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

Background Somatrogon is a long-acting recombinant human growth hormone (hGH) currently in development as a once-weekly injectable treatment for children with growth hormone deficiency (GHD). In a phase 2 (NCT01592500) and a phase 3 (NCT02968004) study, patients received either once-weekly somatrogon or once-daily Genotropin. Aims Compare the phase 2 and 3 study results with growth data from published literature and a database of children treated with once-daily Genotropin. Methods In the 12-month main portion of the phase 2 study (004), patients were randomized to 1 of 3 once-weekly somatrogon doses (0.25, 0.48, and 0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 004, patients continued into the open-label extension (OLE), consisting of an additional 12 months at the original somatrogon dose (Genotropin recipients were randomized to 1 of the 3 somatrogon dose regimens), after which all patients received somatrogon at 0.66 mg/kg/week. In the 12-month main portion of the phase 3 study (006), patients were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 006, all patients received somatrogon (0.66 mg/kg/week) in an OLE. Four year growth data from 004 and 006 were pooled and analyzed, then compared with growth data from matched subsets of hGH-treated patients as reported by Ranke and Lindberg1 (Genotropin dose: 0.22-0.31 mg/kg/week) and Bakker et al,2 (hGH dose: most patients received 0.3 mg/kg/week) and with data from a matched cohort from the Pfizer International Growth Study Database (KIGS), in which patients received once-daily Genotropin (0.20-0.28 mg/kg/week). Results The combined mean height velocity (HV) at the end of the 12-month main portions of study 004 and 006 was 10.37 cm/year for somatrogon-treated patients. The Year 1 mean HV reported by Ranke and Lindberg for children with a chronological average-centered age of 7.5 years was 9.4 cm/year and 8.3 cm/year for children with severe and moderate GHD, respectively. The Year 1 mean HV reported by Bakker et al for children with idiopathic GHD aged 7.5 years at the beginning of hGH therapy was ∼10 cm/year (for males and females). The mean annual HVs during the OLE period were 9.37, 8.97, and 9.03 cm/year at OLE Year 1, 2 and 3 in somatrogon-treated patients, which were numerically greater than HVs of 7.09, 6.35, and 6.08 cm/year at the corresponding annual visit in the matched KIGS cohort (Genotropin dose: 0.20–0.28 mg/kg/week). Conclusions Comparisons with published literature and the KIGS database indicate that children treated with once-weekly somatrogon (0.66 mg/kg/week) showed good growth, compared with children treated with once-daily hGH, strengthening the expectation that somatrogon-treated children are likely to achieve a satisfactory final adult height. References 1.Ranke and Lindberg. JCEM. 2010;95(3): 1229-1237. 2.Bakker, Frane, et al. JCEM. 2008;93(2): 352-357. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:37 p.m. - 12:42 p.m.

Background Achondroplasia is associated with disproportionate short stature and significant and potentially severe medical complications. Vosoritide is the first medicine to treat the underlying cause of achondroplasia and data from phase 3 and phase 2 extension studies showed effects on growth and body proportions. However, there are currently no long-term data available on the direct impact on endpoints such as medical complications and health-related quality of life (HRQoL). This study explored the perceived impact of achondroplasia on medical complications, HRQoL, healthcare resource use and mortality, and potential modifying effects of vosoritide, based on published evidence and expert opinion. Structured expert opinion was obtained by an international modified Delphi study among 14 experts in managing achondroplasia performed on a virtual platform and consisting of an explorative phase followed by an anonymous individual rating round. Results Overall, the panelists expect that in individuals starting long-term treatment between 2 years of age and puberty, growth velocity increases observed in the clinical trials will be maintained until final height is reached (92% agreement) and will likely result in clinically meaningful improvements in upper-to-lower body segment ratio (85%). Earlier treatment initiation will likely result in a greater final height (100%) and more likely improve proportionality (92%) than later treatment. Although current data are limited, ≥ 75% of panelists find it conceivable that the earlier long-term treatment is started, the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. A positive effect of vosoritide on the incidence of surgeries through lifetime was considered more likely with earlier long-term treatment (90%). Conclusions This explorative study, based on international expert opinion, provides further insight into the medical and functional impacts of achondroplasia and how these might be modified through long-term use of vosoritide. The results can be used to guide the direction and design of future research to validate the assumptions and to discuss potential treatment outcomes with disease modifying therapies with families and clinicians.