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Current Opinion in Pediatrics Aug 2017The Pediatric Endocrine Society recently published new guidelines for the use of human growth hormone (hGH) and human insulin-like growth factor-I (hIGF-I) treatment for... (Review)
Review
PURPOSE OF REVIEW
The Pediatric Endocrine Society recently published new guidelines for the use of human growth hormone (hGH) and human insulin-like growth factor-I (hIGF-I) treatment for growth hormone deficiency, idiopathic short stature, and primary IGF-I deficiency in children and adolescents. This review places the new guidelines in historical contexts of the life cycle of hGH and the evolution of US health care, and highlights their future implications.
RECENT FINDINGS
The new hGH guidelines, the first to be created by the Grading of Recommendations Assessment, Development and Evaluation approach, are more conservative than their predecessors. They follow an extended period of hGH therapeutic expansion at a time when US health care is pivoting toward value-based practice. There are strong supporting evidence and general agreement regarding the restoration of hormonal normalcy in children with severe deficiency of growth hormone or hIGF-I. More complex are issues related to hGH treatment to increase growth rates and heights of otherwise healthy short children with either idiopathic short stature or 'partial' isolated idiopathic growth hormone deficiency.
SUMMARY
The guidelines-developing process revealed fundamental questions about hGH treatment that still need evidence-based answers. Unless and until such research is performed, a more restrained hGH-prescribing approach is appropriate.
Topics: Adolescent; Child; Dwarfism, Pituitary; Growth Disorders; Hearing Loss, Sensorineural; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Practice Guidelines as Topic; United States
PubMed: 28525404
DOI: 10.1097/MOP.0000000000000505 -
Clinical Pediatric Endocrinology : Case... 2022In Japan, a pituitary-extracted human GH (phGH), Crescormon®, was approved for the treatment of pituitary dwarfism in 1975. The Study Group of Pituitary Dysfunction was... (Review)
Review
In Japan, a pituitary-extracted human GH (phGH), Crescormon®, was approved for the treatment of pituitary dwarfism in 1975. The Study Group of Pituitary Dysfunction was organized by the Ministry of Health and Welfare (MHW) in 1973 and prepared the "Diagnostic Handbook: Pituitary Dwarfism" guidelines in 1974. Eligibility assessments for phGH treatment were conducted by the research group on pituitary dwarfism (later the Foundation for Growth Science [FGS] GH Treatment Eligibility Assessment Committee); however, there were 200-300 patients on the waiting list. GH treatment has been financially supported by the Grant-in-Aid Program for Chronic Diseases in Childhood, MHW, since 1974. In 1984, phGH was discontinued in the United States due to reports of the onset of Creutzfeldt-Jakob disease in patients treated with phGH. Japan approved the use of methionyl hGH in 1986 and recombinant hGH in 1988. As a result, the phGH disappeared from the market. The role of the Eligibility Assessment Committee of the FGS shifted to the provision of second opinions about diagnoses and treatment appropriateness. Since then, the indications for GH treatment of pediatric growth disorders have expanded to include other pediatric growth disorders such as Turner syndrome, achondroplasia/hypochondroplasia, etc.
PubMed: 35002062
DOI: 10.1297/cpe.2021-0044 -
The Journal of Clinical Endocrinology... Jul 2023The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited.
CONTEXT
The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited.
OBJECTIVE
This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes.
DESIGN
A prospective, observational, posttrial study (NCT03290235).
SETTING, PARTICIPANTS AND INTERVENTION
Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months.
MAIN OUTCOMES MEASURES
Height SD score (Ht SDS) at 12, 24, and 36 months.
RESULTS
A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred.
CONCLUSIONS
PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.
Topics: Humans; Child; Prospective Studies; Human Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Insulin-Like Growth Factor I; Polyethylene Glycols; Recombinant Proteins
PubMed: 36669772
DOI: 10.1210/clinem/dgad039 -
The Journal of Clinical Endocrinology... Jun 2022The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth...
PURPOSE
The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency.
METHODS
Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability.
RESULTS
Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle.
CONCLUSIONS
Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age.
Topics: Body Height; Child; Dwarfism, Pituitary; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans
PubMed: 35428884
DOI: 10.1210/clinem/dgac217 -
The Journal of Clinical Endocrinology... Oct 2021For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (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/week 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 SD 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 noninferiority 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 noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.
Topics: Child; Dwarfism, Pituitary; Female; Follow-Up Studies; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Prognosis
PubMed: 34272849
DOI: 10.1210/clinem/dgab529 -
The Journal of Clinical Endocrinology... Apr 2020Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD).
OBJECTIVE
To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD.
DESIGN
Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851).
SETTING
Clinics in 17 countries.
PATIENTS
Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial.
INTERVENTIONS
Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH.
MAIN OUTCOME MEASURES
Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate.
RESULTS
At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: -1.53% [-2.68; -0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH.
CONCLUSIONS
In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1).
Topics: Biomarkers; Body Composition; Dose-Response Relationship, Drug; Double-Blind Method; Dwarfism, Pituitary; Female; Follow-Up Studies; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Prognosis; Recombinant Proteins
PubMed: 32022863
DOI: 10.1210/clinem/dgaa049 -
The Journal of Clinical Endocrinology... Sep 2023Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians....
CONTEXT
Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians. Somapacitan is a GH derivative in development for once-weekly treatment of GHD.
OBJECTIVE
This work aimed to assess the efficacy and safety of somapacitan, and associated disease/treatment burden, after 4 years of treatment and 1 year after switching to somapacitan from daily GH.
METHODS
This long-term safety extension of a multicenter, controlled phase 2 trial (NCT02616562) took place at 29 sites in 11 countries. Patients were prepubertal, GH-naive children with GHD. Fifty patients completed 4 years of treatment. Patients in the pooled group received somapacitan (0.04, 0.08, 0.16 mg/kg/week) for 1 year, followed by the highest dose (0.16 mg/kg/week) for 3 years. Patients in the switched group received daily GH 0.034 mg/kg/day for 3 years, then somapacitan 0.16 mg/kg/week for 1 year. Main outcome measures were height velocity (HV), change from baseline in HV SD score (SDS), change from baseline in height SDS, disease burden, and treatment burden for patients and parents/guardians.
RESULTS
Changes from baseline in HV and HV SDS were similar and as expected in both groups. Observer-reported outcomes showed that patients and parents/guardians seem to have experienced a reduced treatment burden when switching from daily GH to somapacitan. Most parents/guardians (81.8%) strongly/very strongly preferred somapacitan over daily GH.
CONCLUSIONS
Somapacitan showed similar efficacy and safety in patients who continued somapacitan treatment and those who switched from daily GH to somapacitan. Once-weekly injections may lead to a reduced treatment burden relative to once-daily injections. A plain-language summary of this work is available.
Topics: Child; Humans; Body Height; Drug Administration Schedule; Dwarfism, Pituitary; Human Growth Hormone; Insulin-Like Growth Factor I; Treatment Outcome
PubMed: 36995872
DOI: 10.1210/clinem/dgad183 -
The Journal of Clinical Endocrinology... Apr 2020Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for... (Comparative Study)
Comparative Study Randomized Controlled Trial
CONTEXT
Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD).
OBJECTIVE
The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH.
DESIGN
REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562).
SETTING
This study took place at 29 sites in 11 countries.
PATIENTS
Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial.
INTERVENTIONS
Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously.
MAIN OUTCOME MEASURES
The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS.
RESULTS
At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week-daily GH): 1.7 [95% CI -0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, vs -0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH.
CONCLUSIONS
In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).
Topics: Biomarkers; Child; Child, Preschool; Double-Blind Method; Drug Administration Schedule; Dwarfism, Pituitary; Female; Follow-Up Studies; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Prognosis
PubMed: 31917835
DOI: 10.1210/clinem/dgz310 -
The Journal of Clinical Endocrinology... Apr 2022Current GH therapy requires daily injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for treatment of GH deficiency (GHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Current GH therapy requires daily injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for treatment of GH deficiency (GHD).
OBJECTIVE
Evaluate the efficacy, safety, and tolerability of once-weekly somapacitan after 3 years of treatment.
DESIGN
A multicenter, randomized, controlled, phase 2 study comparing somapacitan and once-daily GH for 156 weeks (NCT02616562).
SETTING
Twenty-nine sites in 11 countries.
PATIENTS
Fifty-nine children with GHD randomized (1:1:1:1) and exposed to treatment. Fifty-three children completed the 3-year period.
INTERVENTIONS
Patients received somapacitan (0.04 [n = 14], 0.08 [n = 15], or 0.16 [n = 14] mg/kg/wk) or daily GH (n = 14) (0.034 mg/kg/d, equivalent to 0.238 mg/kg/wk) subcutaneously during the first year, after which all patients on somapacitan received 0.16 mg/kg/wk.
MAIN OUTCOME MEASURES
Height velocity (HV) at year 3; changes from baseline in height SD score (HSDS), HVSDS, and IGF-I SDS.
RESULTS
The estimated treatment difference (95% CI) in HV for somapacitan 0.16/0.16 mg/kg/wk vs daily GH at year 3 was 0.8 cm/y (-0.4 to 2.1). Change in HVSDS from baseline to year 3 was comparable between somapacitan 0.16/0.16 mg/kg/wk, the pooled somapacitan groups, and daily GH. A gradual increase in HSDS from baseline was observed for all groups. At year 3, mean HSDS was similar for the pooled somapacitan groups and daily GH. Change from baseline to year 3 in mean IGF-I SDS was similar across treatments.
CONCLUSIONS
Once-weekly somapacitan in children with GHD showed sustained efficacy over 3 years in all assessed height-based outcomes with similar safety and tolerability to daily GH. A plain language summary (1) is available for this study.
CLINICAL TRIAL INFORMATION
This study has been registered at ClinicalTrials.gov, number NCT02616562 (REAL 3).
Topics: Body Height; Child; Dwarfism, Pituitary; Growth Hormone; Histidine; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Mannitol; Phenol; Pituitary Hormones, Anterior
PubMed: 34964458
DOI: 10.1210/clinem/dgab928 -
Journal of Pediatric Endocrinology &... Mar 2023Somatrogon 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... (Randomized Controlled Trial)
Randomized Controlled Trial
An open-label extension of a phase 2 dose-finding study of once-weekly somatrogon vs. once-daily Genotropin in children with short stature due to growth hormone deficiency: results following 5 years of treatment.
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.
Topics: Child; Humans; Human Growth Hormone; Insulin-Like Growth Factor I; Dwarfism, Pituitary; Growth Disorders; Growth Hormone; Body Height
PubMed: 36732285
DOI: 10.1515/jpem-2022-0359