scholarly journals OR10-06 Somatrogon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Pediatric Phase 3 Clinical Trial

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Cheri L Deal ◽  
Aleksandra Pastrak ◽  
Lawrence A Silverman ◽  
Srinivas Rao Valluri ◽  
Michael Paul Wajnrajch ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Phase 2 ◽  
Open Label ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Once Daily ◽  
Open Label Extension

Abstract Background: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone (rhGH; somatropin) in development for once weekly treatment of children with growth hormone deficiency (GHD). Somatrogon contains the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) derived from human chorionic gonadotropin. A 12 month phase 2 trial of once weekly Somatrogon vs daily Genotropin in children with GHD demonstrated that 0.66 mg/kg/wk of Somatrogon had a similar benefit - risk profile as 0.24 mg/kg/wk of Genotropin. The open label extension of this phase 2 study has generated an additional 5 years of longitudinal efficacy and safety data with this dose. This report summarizes top line results from a pivotal phase 3 global trial (ClinicalTrials.gov: NCT02968004) designed to investigate the non-inferiority of once weekly Somatrogon hGH-CTP compared to daily hGH after 12 months in treatment-naive prepubertal children with GHD. Methods: The Phase 3 trial enrolled 224 subjects who were randomized in a 1:1 ratio to receive either once weekly Somatrogon hGH-CTP (0.66 mg/kg) or once daily Genotropin (0.24 mg/kg/wk) for 12 months. Randomization was stratified by geographic region, peak GH level and age. The primary endpoint of the study was height velocity (HV) at month 12; secondary endpoints included HV at month 6, change in height SDS at month 6 and 12, IGF-1 and IGF-I SDS, immunogenicity, and safety. Results: At baseline, the mean (SD) age and height SDS of the somatrogon (N=109, 75.2% male) and Genotropin (N=115, 68.7% male) groups were 7.83 (2.66) and -2.94 (1.29) and 7.61 (2.37) and -2.78 (1.27), respectively. One subject in each group discontinued during the 12 month study, and 95% of the completers continued into an open-label extension study. At month 12, mean HV was 10.12 cm/yr in the Somatrogon group and 9.78 cm/yr in the Genotropin group, with the treatment difference of 0.33 cm/year favoring Somatrogon. The lower bound of the two-sided 95% confidence interval of the treatment difference was -0.39, which was higher than the pre-established non-inferiority margin and demonstrated non-inferiority of once weekly somatrogon vs daily Genotropin therapy. Height velocity at month 6 (10.60 cm/yr vs 10.04 cm/yr), change in height SDS at months 6 (0.54 vs 0.48) and 12 (0.92 vs 0.87) were likewise numerically higher in the Somatrogon-treated cohort. The majority of adverse events were mild to moderate in severity (somatrogon: 78.9%, Genotropin: 79.1%) and, overall, weekly somatrogon was generally well-tolerated and comparable to daily Genotropin. Conclusion: Top-line results from the pivotal phase 3 trial demonstrate that Somatrogon (hGH-CTP) given once weekly by sc injection is non-inferior to Genotropin (hGH) given once daily and that once weekly somatrogon administration was generally well-tolerated in patients with pGHD.

scholarly journals Switch Data From the Open-Label Extension of the Pivotal Phase 3 Study of Once Weekly Somatrogon Compared to Daily Somatropin in Pediatric Patients With Growth Hormone Deficiency (pGHD)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A686-A687
Author(s):  
Michael Wajnrajch ◽  
Bradley Scott Miller ◽  
Joel Steelman ◽  
Lawrence A Silverman ◽  
Moshe Phillip ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Recombinant Human Growth Hormone ◽  
Bone Age ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Main Study ◽  
Open Label ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Open Label Extension

Abstract Objectives: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone, consisting of the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG) being developed as a once weekly treatment for children with pGHD. This report summarizes data from the first year of the optional open-label extension (OLE) of the pivotal phase 3 global trial (ClinicalTrials. gov: NCT02968004), comparing the efficacy and safety of children switched from Genotropin (rhGH; somatropin) to somatrogon (Geno/Soma) and children maintained on somatrogon (Soma/Soma). Methods: During the main study, 224 children were randomized to receive either once weekly somatrogon (0.66 mg/kg, n=109) or once daily Genotropin (0.24 mg/kg/wk, n=115) for 12 months. Of these, 222 completed the 12-month main study, and 212 chose to enter the OLE study. By Sept 30, 2020, 161 children (including 76 Geno/Soma) had complete auxological data at month 12 of the OLE. Results: At the end of the main study, mean height velocity and gain in height SDS for the somatrogon cohort were 10.10 cm/year and 0.92; for the Genotropin cohort these were 9.78 cm/year and 0.87. Baseline values for the OLE (Soma/Soma group and Geno/Soma group, respectively): height SDS was -1.95 and -1.84, BMI was 17.03 and 15.48 kg/m2 while bone age was 6.54 and 6.40 years. At month 12 (of the OLE), the mean height velocity and the change in height SDS was 8.04 cm/year and 0.41 (Soma/Soma group) and 8.21 cm/year and 0.47 (Geno/Soma group); BMI was 18.07 and 17.49 kg/m2 and bone age was 8.48 and 8.41 years. IGF-1 SDS values were 1.15, and 1.28, while the IGFBP-3 SDS were 0.29 and 0.42, respectively. Dose reductions were required in 16.3% and 20.4% of patients due to IGF-1 SDS >2. Pubertal status changed from Tanner 1 (at OLE baseline) for 13.6% of Soma/Soma patients and 14.6% of Geno/Soma patients. Mean glucose, HbA1c, thyroid function (free T4 and TSH) and cholesterol (total, LDL and HDL) values remained similar to baseline in both groups across the 12 months OLE. The majority of adverse events in both cohorts were mild to moderate (Soma/Soma 94.2%, Geno/Soma 93.5%) and there were no clinically concerning safety observations. During the first 12 months of the OLE six patients discontinued in the Geno/Soma group due to AEs vs zero in the Soma/Soma group. Conclusions: Height velocities and change in height SDS in the OLE were similar between the Geno/Soma and Soma/Soma cohorts. The main phase of the global pivotal phase 3 trial demonstrated that somatrogon (hGH-CTP) given once weekly is non-inferior to Genotropin (hGH) while the OLE demonstrated that catch-up growth continued into the second year of treatment, with ‘switch’ from Genotropin to somatrogon non-inferior to somatrogon given for two years. Metabolic (glycemic, lipid and thyroid) parameters were similar between groups and not meaningfully different from the main study.

scholarly journals Weekly Lonapegsomatropin in Treatment-Naïve Children with Growth Hormone Deficiency: The Phase 3 heiGHt Trial

2021 ◽  
Author(s):  
Paul S Thornton ◽  
Aristides K Maniatis ◽  
Elena Aghajanova ◽  
Elena Chertok ◽  
Elpis Vlachopapadopoulou ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Bone Age ◽  
Primary Objective ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Weekly Dose ◽  
Open Label ◽  
Phase 3 ◽  
Treatment Naïve

Abstract Context For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections (hGH) is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD. Objective The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin. Design The heiGHt Trial was a randomized, open-label, active-controlled, 52-week phase 3 trial (NCT02781727). Setting This trial took place at 73 sites across 15 countries. Patients This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD. Interventions Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/wk or an equivalent weekly dose of somatropin, delivered daily. Main Outcome Measure The primary end point was annualized height velocity (AHV) at Week 52. Secondary efficacy end points included change from baseline in height standard deviation scores (SDS). Results Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs. 10.3 (0.3) cm/year for daily somatropin (P=0.009), with lonapegsomatropin demonstrating both non-inferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to Week 52 by 1.10 (0.04) vs. 0.96 (0.05) in the weekly lonapegsomatropin vs. daily somatropin groups (P=0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups. Conclusions The trial met its primary objective of non-inferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

scholarly journals OR10-05 Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aristides K Maniatis ◽  
Ulhas Nadgir ◽  
Paul Saenger ◽  
Gail Mick ◽  
Kent L Reifschneider ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Adverse Event ◽  
Growth Hormone Deficiency ◽  
Study Drug ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Adverse Event Profile ◽  
Phase 3 ◽  
Daily Growth ◽  
Treatment Naïve

Abstract Background: The Phase 3 fliGHt Trial evaluated children with growth hormone deficiency (GHD) of a broad range of baseline demographics and treatment durations who switched from daily growth hormone (hGH; somatropin) therapy to once-weekly TransCon hGH. TransCon hGH is an investigational long-acting prodrug consisting of 3 components: hGH, an inert carrier that protects it, and a linker that temporarily binds the two. When injected into the body, at physiologic pH and temperature, unmodified hGH is gradually released in a predictable manner. Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. The primary objective was to assess safety and tolerability over this 26-week trial. Efficacy measures included annualized height velocity (AHV), height standard deviation score (SDS), and insulin-like growth factor 1 (IGF-1) SDS. Results: Of the 146 enrolled subjects, 98.6% completed the trial. Mean age at baseline was 10.6 years (range: 1, 17). The majority (97.9%) were treatment-experienced with a prior daily hGH mean dose of 0.29 mg/kg/week (range: 0.13, 0.49); 3 subjects were treatment-naïve and <3 years old. Just over half the subjects (56.8%) experienced a treatment-emergent adverse event (TEAE), with only 4.1% of subjects experiencing a TEAE considered related to study drug. No TEAE led to discontinuation of study drug. The type and frequency of TEAEs reported were similar to the published adverse event profile of daily hGH therapies. Mean hemoglobin A1c remained 5.2% at baseline and Week 26. No neutralizing antibodies were detected; low-titer anti-hGH binding antibodies were detected in 2.8% of subjects. Growth outcomes were as expected for this treatment-experienced heterogenous population, with a least-squares mean (LSM) AHV of 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). In the age-defined subgroups, mean observed AHV at Week 26 ranged from 8.2 to 16.2 cm/year and mean observed height SDS change from baseline to Week 26 ranged from +0.23 to +0.96. Of note, the linear relationship between average IGF-1 SDS and TransCon hGH doses demonstrated in previous treatment-naïve trials was preserved in this population of treatment-experienced children who had dose titrations. Conclusions: TransCon hGH treatment outcomes, including AHV and height SDS, were as expected across a diversity of ages, disease characteristics, and treatment experiences, reflective of a real-world setting. Dose titrations of TransCon hGH demonstrated a predictable IGF-1 response. Switching to TransCon hGH resulted in a similar adverse event profile to daily hGH therapy.

scholarly journals Results From an Open-Label Extension of the Phase 2 Dose Finding Study of Once Weekly Somatrogon vs Daily Genotropin in Pediatric Patients With Growth Hormone Deficiency (GHD)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A684-A685
Author(s):  
Zvi Zadik ◽  
Nataliya Zelinska ◽  
Violeta Iotova ◽  
Yulia Skorodok ◽  
Oleg A Malievskiy ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Adverse Event ◽  
Pediatric Patients ◽  
Height Velocity ◽  
Target Range ◽  
Phase 2 ◽  
Main Study ◽  
Open Label ◽  
Open Label Extension

Abstract Background: Somatrogon, a long-acting recombinant human growth hormone, is being developed as a once weekly treatment for pediatric patients (pts) with GHD. A phase 2, 12 month study (NCT01592500) in pts with GHD showed that weekly somatrogon at 0.66 mg/kg/week had similar efficacy and safety to daily Genotropin. Pts who completed 12 months of treatment could be enrolled into an open-label extension (OLE). Aims: Evaluate the safety and efficacy of long-term exposure to somatrogon in pediatric pts with GHD who continued in the OLE for up to an additional 5 years. Methods: Methods for the main phase 2 study were published previously (Zelinska et al, 2017), in which 53 pts were randomized to 1 of 3 weekly somatrogon dose cohorts (0.25, 0.48, and 0.66 mg/kg/week) or the daily Genotropin cohort (0.24 mg/kg/week) for 12 months. After the main study (Periods I/II), 48 pts who consented to participate continued in the OLE, consisting of 3 periods: Period III=12 additional months at original somatrogon dose (Genotropin recipients randomized to 1 of the 3 somatrogon dose regimens); Period IV=subsequent years 2-4 with all pts receiving somatrogon at 0.66 mg/kg/week; Period V=ongoing, with pts transitioned from the vial to a pre-filled pen device at the same somatrogon dose (0.66 mg/kg/week). Data up to 1 year of Period V are reported. Results: Overall subject retention in different periods of this long-term study ranged from 87.5% to 97.7%. 39 pts (81.3%) reported at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild or moderate in intensity and most were classified as unrelated to study treatment. 3 pts (6.3%) reported at least 1 serious adverse event (SAE); most SAEs were considered unrelated to study treatment, except for 1 instance of scoliosis. At the end of Period III, the mean annual height velocity (HV) was similar for the 0.25 and 0.48 mg/kg/week dose cohorts (7.73±1.89 and 7.54±1.28 cm/year, respectively) but was higher in the 0.66 mg/kg/week dose cohort (8.81±1.12 cm/year), consistent with the results of the main study. The HV at Periods IV and V showed sustained growth response. Height SDS showed consistent improvement and near normalization of height for age and gender after up to 6 years on somatrogon, irrespective of initial cohort assignment; height SDS at baseline of the main study was -3.98±1.22 and was well within the normal range at -0.69±0.87 at the end of Year 1 in Period V. IGF-1 SDS values remained above baseline and were maintained within the therapeutic target range with weekly somatrogon treatment at all time points in all OLE periods. Anti-drug antibodies (ADAs) were reported in 18 pts, of which 10 pts had ADAs in the main study. The presence of ADAs did not impact efficacy or safety. Conclusions: Somatrogon administered once weekly for up to 5 years after the main study was generally well tolerated and participants showed sustained improvement in annual HV, height SDS, and delta height SDS.

scholarly journals Insulin-like growth factor-1 level is a poor diagnostic indicator of growth hormone deficiency

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hideyuki Iwayama ◽  
Sachiko Kitagawa ◽  
Jyun Sada ◽  
Ryosuke Miyamoto ◽  
Tomohito Hayakawa ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Diagnostic Accuracy ◽  
Growth Hormone Deficiency ◽  
Screening Test ◽  
Characteristic Curve ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Insulin Like Growth Factor ◽  
Predictive Values

AbstractWe evaluated the diagnostic accuracy of insulin-like growth factor-1 (IGF-1) for screening growth hormone deficiency (GHD) to determine the usefulness of IGF-1 as a screening test. Among 298 consecutive children who had short stature or decreased height velocity, we measured IGF-1 levels and performed growth hormone (GH) secretion test using clonidine, arginine, and, in cases with different results of the two tests, L-dopa. Patients with congenital abnormalities were excluded. GHD was defined as peak GH ≤ 6.0 ng/mL in the two tests. We identified 60 and 238 patients with and without GHD, respectively. The mean IGF-1 standard deviation (SD) was not significantly different between the GHD and non-GHD groups (p = 0.23). Receiver operating characteristic curve analysis demonstrated the best diagnostic accuracy at an IGF-1 cutoff of − 1.493 SD, with 0.685 sensitivity, 0.417 specificity, 0.25 positive and 0.823 negative predictive values, and 0.517 area under the curve. Correlation analysis revealed that none of the items of patients’ characteristics increased the diagnostic power of IGF-1. IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Therefore, IGF-1 should not be used alone for GHD screening. A predictive biomarker for GHD should be developed in the future.

Diagnostic accuracy of IGF-1 for screening growth hormone deficiency: a prospective, single-center, diagnostic accuracy study

2021 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Sachiko Kitagawa ◽  
Jyun Sada ◽  
Ryosuke Miyamoto ◽  
Tomohito Hayakawa ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Diagnostic Accuracy ◽  
Growth Hormone Deficiency ◽  
Predictive Value ◽  
Screening Test ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Rank Correlation ◽  
Hormone Deficiency ◽  
Height Velocity

Abstract Purpose We evaluated the diagnostic accuracy of insulin-like growth factor-1 (IGF-1) for screening growth hormone deficiency (GHD) to determine the usefulness of IGF-1 as a screening test. Methods On 298 consecutive children who had short stature or decreased height velocity, we measured IGF-1 levels and performed growth hormone (GH) secretion test using clonidine, arginine, and, in cases with different results of the two tests, L-dopa. Patients with congenital abnormalities were excluded. GHD was defined as peak GH ≤ 6.0 ng/mL in the two tests. Results We identified 60 and 238 patients with and without GHD, respectively. The mean IGF-1 (SD) was not significantly different between the GHD and non-GHD groups (p = 0.23). Receiver operating characteristic curve analysis demonstrated the best diagnostic accuracy at an IGF-1 cutoff of −1.493 SD, with sensitivity of 0.685, specificity of 0.417, positive predictive value of 0.25, negative predictive value of 0.823, and area under the curve of 0.517. Spearman’s rank correlation coefficient showed that IGF-1 (SD) was weakly correlated with age, bone age, height velocity before examination, weight (SD), and BMI (SD) and very weakly correlated with height (SD), target height (SD), and maximum GH peak. Conclusion IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Correlation analysis revealed that none of the items increased the diagnostic power of IGF-1. Therefore, IGF-1 should not be used alone in the screening of GHD. A predictive biomarker for GHD should be developed in the future.

Sign in / Sign up

Export Citation Format

Share Document