Daily rhGH Research Articles

A novel Y-shaped pegylated recombinant human growth hormone for children with growth hormone deficiency: a phase 3 study.

Pegpesen® is a novel Y-shape pegylated recombinant human growth hormone (rhGH) for once-weekly treatment of children with growth hormone deficiency (GHD). To evaluate the efficacy and safety of Pegpesen® in children with GHD vs daily rhGH. A multicenter, randomized, controlled phase 3 clinical trial with a duration of 52 weeks treatment. 23 centers in China. 391 pediatric participants diagnosed with GHD. Participants were randomized 2:1 to the weekly Pegpesen® group (140 μg/kg/week) or the daily rhGH group (245 μg/kg/week) for 52 weeks. The primary endpoint was the growth velocity (GV) at 52 weeks, and the secondary endpoints mainly involved changes from baseline in height standard deviation scores for chronological age and bone age (ΔHt SDS CA and ΔHt SDS BA). At 52 weeks, the least squares mean (LS Means) of GV was 9.910 cm/year in the Pegpesen® group and 10.037 cm/year in the daily rhGH group. The LS Means difference between groups was -0.127 [95% CI (-0.4868, 0.2332)], confirming that weekly Pegpesen® is non-inferior to daily rhGH. The LS Means of ΔHt SDS CA, ΔHt SDS BA, were similar across both groups (all P > 0.05). Safety profiles and adherence were comparable. Pegpesen® was non-inferior to daily rhGH, with similar safety, lower dosage requirements, thus presenting a new therapeutic option for children with GHD.

7194 The Use Of GloBE-Reg As A Global Platform For Performing Safety & Efficacy Studies Of rhGH Therapy - First Year Results

Abstract Disclosure: M. Alimussina: None. J. Bryce: None. M. Chen: None. S. Koley: None. A. Al-Agha: None. N. Amin: None. N. Atapattu: None. J. Chen: None. Y. Deyanova: None. A. Fu: None. C. Gong: None. V. Iotova: None. D. Janus: None. A. Jorge: Consulting Fee; Self; Novo Nordisk. Grant Recipient; Self; BioMarin. R. Markosyan: None. S. Seneviratne: None. M.G. Shaikh: None. S. Shenoy: None. S. Shepherd: None. L. Tack: None. M. Wasniewska: None. S. Chen: Research Investigator; Self; Pfizer, Inc. S.F. Ahmed: Grant Recipient; Self; GenSci, Novo Nordisk, Pfizer, Inc.. Speaker; Self; Ipsen. Introduction: The Global Registry For Novel Therapies In Rare Bone & Endocrine Conditions (GloBE-Reg, https://globe-reg.net/) project was launched in 2022 with the aim of supporting studies that focus on effectiveness and long-term safety of specific therapies. The project’s initial focus has been on recombinant human growth hormone therapy (rhGH). Although safety information on rhGH therapy has now been collected for several years, there are still existing gaps in our knowledge, especially with the introduction of new indications and novel forms of rhGH. Methods: The GloBE-Reg registry has three layers of datasets, with the first dataset consisting of internationally agreed core data elements that can apply to any rare condition, another set of data elements that allows the selection of a specific therapy and diagnosis, a third set of additional data elements that is made up of the therapy and diagnosis-specific minimum dataset (MDS) and an option to have a more extended dataset. The minimum dataset collects information on the diagnosis, therapy, clinician reported outcomes, patient reported outcomes and adverse events. The platform and the registry received ethics/IRB approval in the UK and is now extending internationally. The fields within the MDS are developed following guidance from short-life expert working groups (EWG). Results: Since its launch in November 2022, 51 centres from 29 countries have registered their interest to use the platform and of these, 14 centres from 11 countries in 3 continents have already included 444 (M:F, 282:162) patients with a median age of 11 yr (range <1, 29). Of these, 317 (71%) were on daily rhGH, 126 (28%) were on long-acting rhGH, one was on daily rhGH as an adult and in one, rhGH therapy had been discussed but not started. Nine different brands of rhGH were being used across these centres for 9 groups of indications, whereas long-acting rhGH was being used for only 4 indications. In addition, there were 11 (3%) cases receiving rhGH for other conditions associated with short stature or growth retardation. The largest indication group was GHD (65%) followed by SGA (10%), TS (7%), PWS (7%), ISS (5%) and others. Of the 444 cases, 67 (15%) had also been entered in other disease registries and 18 (27%) of these 67 had been entered by one centre into the GloBE-Reg through its bulk upload facility. A Childhood GHD MDS is now fully operational and MDS for other conditions are under development. Conclusion: Since its launch, GloBE-Reg has shown that a relatively low-cost platform operated through an academic institution can have sufficient stakeholder acceptability and versatility for collecting information that can support the development of long-term safety and effectiveness studies. The preliminary data that have been collected on rhGH show the long-term utility of the platform for collecting global brand and diagnosis-specific data. Presentation: 6/2/2024

Effect of long-acting PEGylated growth hormone for catch-up growth in children with idiopathic short stature: a 2-year real-world retrospective cohort study

Several evidence gaps exist regarding the use of long-acting polyethylene glycol recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS), particularly studies conducted in real-world settings, with long-term follow-up, involving varied dosing regimens, and in comparison with daily rhGH. The study aimed to evaluate the effectiveness, safety, and adherence of once-weekly PEG-rhGH for catch-up growth in children with prepubertal ISS compared to daily rhGH. A real-world retrospective cohort study was conducted in prepubertal children with ISS in China. Children who voluntarily received once-weekly PEG-rhGH or daily rhGH were included and were followed up for 2 years. Ninety-five children were included, 47 received PEG-rhGH 0.2–0.3 mg/kg weekly and 48 received daily rhGH. Outcome measures included effectiveness in catch-up growth, adverse events, and treatment adherence. Height velocity increased significantly in both groups during rhGH therapy. In children who received PEG-rhGH treatment, height velocity was 10.59 ± 1.37 cm/year and 8.75 ± 0.86 cm/year in the first and second year, respectively, which were significantly more than those who received daily rhGH (9.80 ± 1.05 cm/year, P = 0.002, and 8.03 ± 0.89 cm/year, P < 0.001). The height standard deviation score improved at the end of the second year for all children (P < 0.001). However, children who received PEG-rhGH showed more excellent improvement than those with daily rhGH (1.65 ± 0.38 vs. 1.50 ± 0.36, P = 0.001). In children who received PEG-rhGH, lower missed doses were observed than those with daily rhGH (0.75 ± 1.06 vs. 4.4 ± 2.0, P < 0.001). No serious adverse events were observed. Conclusion: PEG-rhGH demonstrated superior effectiveness and adherence compared to daily rhGH in the treatment of children with ISS. The safety profiles were similar between the two treatments.What is Known:• Recombinant human growth hormone (rhGH) has been used to increase adult height in children with idiopathic short stature (ISS), and its safety profile is comparable to other indications for growth hormone treatment.• The use of long-acting rhGH in children with ISS is still an area of uncertainty.What is New:• This 2-year real-world study provides new evidence that PEGylated rhGH (PEG-rhGH) is more effective than daily rhGH in promoting catch-up growth in children with ISS.• PEG-rhGH also demonstrated superior treatment adherence compared to daily rhGH in children with ISS.• The safety profiles of PEG-rhGH and daily rhGH were found to be similar.

Somapacitan-induced reversible lipoatrophy in an adult woman with hypopituitarism

BackgroundLipoatrophy is rare adverse event (AE) in daily recombinant human growth hormone (rhGH). Data on lipoatrophy in newly developed long-acting GH (LAGH) are scarce. We report the first case of lipoatrophy in adult patient treated with LAGH somapacitan.Case presentationA 38-year-old woman with congenital panhypopituitarism was transitioned from daily rhGH 0.4 mg QD to somapacitan dose 4 mg QW due to non-adherence to daily rhGH. Despite adequate education and regular changing of injection sites, the patient reported reduced subcutaneous tissue at all four injection sites, after the 4th application of somapacitan. Somapacitan was discontinued at patient preference and lipoatrophy completely reversed after 3 months.ConclusionsLipoatrophy caused by somapacitan was completely reversible. We speculate that high initial dose and volume of somapacitan caused delayed diffusion and a direct local lipolytic effect in our patient. Although, titration of somapacitan was initiated as previously reported in REAL2 study protocol, recent clinical guidelines advise more gradual increase of somapacitan dose also in women on oral estogens that are switched from daily rhGH. Importantly, our case and the two previously described cases in children in the REAL 3 study showed that lipoatrophy caused by somapacitan was transient and completely reversible, and that discontinuation of the drug is not always mandatory.

Update on the use of long-acting growth hormone in children.

After extensive research and many years of waiting, long-acting growth hormone (LAGH) formulations have finally become a reality in clinical practice and emerge as a potential solution to address the challenges of daily injections of recombinant human GH (rhGH). In this review, we present a brief history of the development of LAGH and provide a critical analysis of the existing literature on the five LAGH available and approved to date for treatment in children. In clinical trials, LAGH therapy has shown noninferiority compared with daily rhGH therapy in promoting linear growth in children with GH deficiency, with similar rates of adverse events. In the real world, many questions still need to be answered, such as whether a specific group of patients will benefit most from the weekly injection, whether compliance will be better compared with daily rhGH, whether long-term efficacy, monitoring and safety profile will be the same for the different LAGH compounds, and whether the cost-effectiveness will justify their use in different settings.

Long-acting PEGylated growth hormone in children with idiopathic short stature: time to reconsider our diagnostic and treatment policy?

Idiopathic short stature (ISS) is a diagnosis of exclusion, and therefore each child with short stature or slow growth referred to a paediatrician deserves a full medical history and physical examination, as well as radiological and laboratory screening tests. In patients with an increased likelihood of a genetic cause, genetic testing is indicated. Idiopathic short stature is an approved indication for recombinant human growth hormone (rhGH) in the USA but not in most other parts of the world. In a recent article published in this journal, Luo et al reported on the 1-year's results of a multicentre randomized controlled trial (n = 360) on the efficacy and safety of two dosages of long-acting PEGylated rhGH (PEG-rhGH, Jintrolong®) (0.1 or 0.2 mg/kg body weight per week, respectively) in children with ISS compared with an untreated control group. The growth response to the higher dosage was similar to reported data on daily rhGH. In this commentary, we discuss whether the recent data on genetic causes of short stature in children who initially were labelled ISS, and data on the long-term safety of daily rhGH, may influence the balance between risks and benefits of rhGH treatment in children with ISS. We further discuss the pharmacokinetic and -dynamic profile of PEG-rhGH and its potential consequences for long-term safety.

PSAT108 Impact of recombinant human growth hormone (rhGH) on skeletal muscle strength, power, endurance and agility in prepubertal boys with significant short stature: preliminary results

Abstract Objectives To investigate the impact of rhGH on measures of skeletal muscle strength, power, endurance, agility, and lean body mass accrual in prepubertal boys with significant short stature compared to age-matched healthy controls growing normally. Methods 40 prepubertal boys were recruited, 25 with significant short stature -either isolated GH deficiency or idiopathic (mean (SE) age: 8.9±0.3yrs; HT SDS: -2.3±0.1) and 15 normally growing healthy controls (age: 8.8±0.4yrs; HT SDS: -0.3±0.2). All had testing at baseline including anthropometry, blood, DEXA scan (body composition), and indirect calorimetry (resting energy expenditure (REE)). Protocolized muscle function tests were performed by expert personnel including measures of skeletal muscle strength (isokinetic dynamometry (flexion/extension) upper and lower extremities), power (vertical jump), endurance (modified push-ups), and agility (timed shuttle-runs). Boys with short stature were started on daily rhGH (Norditropin®, 0.3mg/kg/w) and baseline studies repeated identically in all at 6 and 12 months. Mixed effects model ANOVA (and 2 sample t-test) was used to compare main outcomes over time between groups (significance p ≤0.05). Results Baseline N=40, 6 months N=34, 12 months N=27 participants thus far. All grew well and remained prepubertal throughout the study. At baseline, there were measurable differences in fat free mass (FFM) between groups: short stature: 15.9±0.5kg, controls: 20.4±1.1 (p=0.001); both groups gained FFM at 12 months, short stature group gained 27.3% (p&amp;lt;0.001) vs. controls 10.7% (p&amp;lt;0.001) (p&amp;lt;0.001 between groups). Measures of agility and power were comparable at baseline between groups, agility improved by 12 months 5.5% in the rhGH-treated group (p=0.007) vs. 2.7% in controls (p=0.178) (p=0.157 between groups); measures of power improved 9.1% in the rhGH-treated group (p=0.001) vs. 3.8% in controls (p=0.386) at 12 months (p&amp;lt;0.258 between groups). There were significant differences between groups in muscle strength at baseline, lower particularly in elbow flexion (biceps) in the short stature group: 79.7±3.7 Newtons vs. controls: 97.6±5.5 (p=0.008), and knee flexion (hamstrings): 82.6±3.4 Newtons vs. 95.7±3.2 (p=0.013). At 12 months the rhGH-treated group improved biceps strength (25.7%, p&amp;lt;0.001), vs. controls (12.5%, p=0.008) (p=0.019 between groups); whereas hamstrings strength improved comparably at 12 months in the rhGH-treated group (24.1%, p=0.008) vs. controls (28.0%, p=0.01) (p=0.79 between groups). Measures of endurance (modified push-ups) at baseline were 17.5±1.5 reps in the short stature group vs. 24.9±3.3 in controls (p=0.057), improving in the rhGH-treated (63%, p&amp;lt;0.001) vs. controls (43%, p=0.07) at 12 months (p=0.959 between groups). There were no significant differences in REE (kcal/kg/d) between groups during 12 months. Conclusion There are significant differences in FFM and skeletal muscle strength and endurance in prepubertal boys with severe short stature compared to healthy age-matched controls. FFM accrual and isokinetic measures of muscle strength, endurance, agility and power improve after 12 months of rhGH, changes approaching measures of those of healthy controls. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The pharmacokinetic and pharmacodynamic properties and short-term outcome of a novel once-weekly PEGylated recombinant human growth hormone for children with growth hormone deficiency.

ObjectivesTo investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of Y-shape branched PEGylated recombinant human growth hormone (YPEG-rhGH) and evaluate its short-term efficacy and safety in children with growth hormone deficiency (GHD).MethodsA total of 43 children with GHD from 12 sites in China were enrolled in this randomized, multicenter, active-controlled, double-blind (YPEG-rhGH doses) trial. Patients were randomized 1:1:1:1 to 100, 120, and 140 μg/kg/week of YPEG-rhGH groups and daily rhGH 35 μg/kg/day groups. The treatment lasted 12 weeks. The primary outcome was the area under the curve of the change of insulin-like growth factor-1 (IGF-1). The secondary outcome was the height velocity (HV) increment at week 12.ResultsA dose-dependent response of maximum plasma concentration (Cmax) and area under the concentration-time curves from 0 to 168 hours (AUC0-168h) were observed for YPEG-rhGH. The ratio of Cmax and the ratio of AUC0-168h from the first to the last dosing were 1.09~1.11 and 1.22~1.26 respectively. A YPEG-rhGH dose-dependent increase in area under effect curve (AUEC) of IGF-1 fold change was observed. Model-derived mean IGF-1 SDS was in the normal range for all three YPEG-rhGH doses. At week 12, HV was 7.07, 10.39, 12.27 cm/year, and 11.58 cm/year for YPEG-rhGH 100, 120, and 140 μg/kg/week and daily rhGH respectively. Adherence and safety were consistent with the profile of daily rhGH. No related serious adverse events were reported.ConclusionThe PK/PD suggests that YPEG-rhGH is suitable for the once-weekly treatment of pediatric GHD. YPEG-rhGH 120 ~ 140 μg/kg/week provides the closest HV increment with similar safety and tolerability compared to daily rhGH 35 μg/kg/day in children with GHD.Clinical Trial Registration ClinicalTrials.gov, identifier [NCT04513171].

PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients.

Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.

The Changing Face of Paediatric Human Growth Hormone Therapy

Human growth hormone (hGH) has been used therapeutically to promote growth in children for over 60 years. Pituitary-extracted hGH has demonstrated positive growth promotion since the early 1960s. In 1985, prion-induced contamination of hGH triggered a global epidemic of Creutzfeldt–Jakob disease that was responsible for its discontinuation. Recombinant hGH immediately replaced pituitary hGH and, being available in large amounts, was used and licenced for therapy in GH-deficient children, followed by approval for non-GH deficient disorders such as Turner syndrome, short stature related to birth size small for gestational age, idiopathic short stature, SHOX deficiency, Prader–Willi syndrome and Noonan syndrome. RhGH therapy was refined by the use of growth prediction models; however, unmet needs, such as the variability in response and non-adherence resulted in the development of long-acting rhGH (LArhGH) molecules, which are currently in clinical trials and have shown non-inferiority in comparison with daily rhGH. It is likely that LArhGH will enter clinical practice in 2022 and 2023 and will need to demonstrate safety in terms of immunogenicity, IGF-1 generation, metabolic status and tolerability of potential injection pain and local reactions.

Evaluation of efficacy and safety of long-acting PEGylated recombinant human growth hormone (Jintrolong) for patients with growth hormone deficiency.

This study aimed to compare the efficacy, safety and metabolic effects of once-weekly pegylated human growth hormone (PEG-rhGH) with daily rhGH in patients with growth hormone deficiency (GHD). 48 patients enrolled in this 12-month single-center, open-label, prospective, randomized controlled trial is allocated to PEG-rhGH 0.12mg/kg/w and 0.20mg/kg/w treatment. Besides, the control group allocated 23 patients treated with daily rhGH 0.28mg/kg/w matched with sex, age, and baseline IGF-1 levels. The primary endpoint included height velocity (HV) and IGF-1 increase at the end of treatment. Other parameters associated with growth, metabolism and safety were also monitored. In terms of HV increase, the efficacy of PEG-rhGH dosed at 0.12mg/kg/w and 0.20mg/kg/w was comparable to that of daily rhGH dosed at 0.28mg/kg/w after 3, 6 and 12 treatment (p>0.05). IGF-1 concentration and IGF-1 SDS were both elevated significantly at 3, 6 and 12months (p=0.000) into normal range following PEG-rhGH treatment. BMI SDS elevated after PEG-rhGH treatment for 3, 6 and 12months (p=0.000). HbA1c elevated after 3 and 12months (p=0.009) and METS-IR elevated after 6months (p=0.019) compared with baseline. The differences of other metabolic indexes (such as blood glucose, blood lipid, etc.) have no statistical significance (p>0.05). No severe adverse event was observed among the three groups. The efficacy and safety were promising and comparable between once-weekly PEG-rhGH and daily rhGH injection within 12months. The negative influence on glucose homeostasis needed attention and monitoring.

Yearly Height Gain Is Dependent on the Truly Received Dose of Growth Hormone and the Duration of Periods of Poor Adherence: Practical Lessons From the French Easypod™ Connect Multicenter Observational Study.

ObjectiveTo study the impact of the true mean daily dose and the true mean number of injections per week on the yearly height gain in short children treated with recombinant human growth hormone (rhGH).Design and Methods220 children from the French Easypod™ Connect Observational Study (ECOS) used the Easypod™ electronic device to record rhGH injections. The mean daily rhGH dose (the sum of the doses truly received divided by the number of days) and mean number of injections per week (the number of injections truly performed divided by the number of weeks) were calculated. Linear mixed models were used to study the impact of short (3-month) and long (1-year) variations in rhGH administration on the yearly height change [as a standard deviation score (SDS)], with time on treatment as a covariate. For each patient, several periods of 3 or 12 months were considered and designated as poorly adherence or fully adherence. We studied the impact of each of period on the height change.ResultsAt treatment initiation, the mean ± SD age was 9.8 ± 3.7 years (females: 47%, prepubertal: 86%) and the mean height was -2.28 ± 0.92 SDS. The mean treatment duration was 3.2 ± 1.1 years (685.2 patient years). 122 patients were GH-deficient, 79 were small for gestational age, and 19 had Turner syndrome. When treatment was computed over 12-month periods, receiving a mean daily dose <0.03 mg/kg.d was associated with a 20% lower mean yearly height gain SDS when<3 injections/week were received (vs.>5 injections/week), whereas maintaining a mean daily dose >0.03 mg/kg.d with<3 injections/week was not associated with a lower yearly height gain SDS (vs.>5 injections/week). For 3-month periods, changes in the daily rhGH dose or the number of injections per week over such short period did not influence the yearly height gain SDS.ConclusionThe 12-month treatment model showed that when poor adherence leads to a low true daily GH dose, the yearly height gain is low. The 3-month treatment model showed that poor adherence for short periods (<3 months) had no impact on the height SDS.

Patient preferences for growth hormone treatment in Japanese children.

BackgroundThere are not clear evidence to date evaluating patients' and caregivers' preferences for the recombinant‐human growth hormone (r‐hGH) injection in children in Japan. This study aimed to quantitatively evaluated the factors driving preferences for daily r‐hGH injections among Japanese children with growth hormone deficiency (GHD) or their caregivers and to determine the relative importance of treatment delivery factors.MethodsThis study was performed among Japanese children with GHD or their caregivers who visited a specialized clinic in Japan as part of their routine care. The participants were asked to complete a web‐based discrete choice experiment (DCE) questionnaire.ResultsChoice‐based conjoint analysis was used to evaluate the relative importance of the attributes of the choice predictors and determine utility scores for each attribute. Of the 47 respondents who participated in this study, 41 were caregivers who responded on behalf of the patients, the remaining six were patients who completed the DCE themselves. The injection schedule was found to be the most important factor for both patients and caregivers; a once‐weekly injection schedule was preferred over a daily injection schedule. Storage and preparation was deemed more important to patients than it was to caregivers, with patients preferring storage at room temperature even if it required additional mixing (reconstitution). Both patients and caregivers showed a clear preference for devices that offered a dose‐setting memory.ConclusionsA less frequent injection schedule may enhance adherence to r‐hGH treatment and expected improve quality of life for GHD patients over the long term.

Sub-Optimal Adherence With Daily Growth Hormones Increases With Each Year of Treatment in a US Commercial Claims Database

Introduction and Objective: Pediatric growth hormone deficiency (pGHD) occurs in approximately 1 in 4,000 children. The main manifestation is short stature managed with daily injections of somatropin, a recombinant human growth hormone (r-hGH). Prior research has shown that children with good adherence with r-hGH have significantly greater linear growth compared to those with sub-optimal adherence. While previous studies have found sub-optimal adherence with daily r-hGH injectables among children with pGHD, to date, r-hGH adherence has not been studied among large, usual-care populations using validated measurements of adherence. We describe adherence to somatropin treatment over 4 years in a population-based study. Materials and Methods: A retrospective cohort analysis of commercially insured patients ≥3 and <16 years, diagnosed with pGHD, newly treated with somatropin from 01 January 2002 through 31 December 2019 (study time period) was conducted using Optum De-identified Clinformatics Data Mart database. Index date was defined as the first prescription for somatropin between 01 July 2002 to 30 September 2019. Four patient cohorts were identified (12, 24, 36, and 48 months of post-index continuous enrollment). The demographic and clinical profiles of children with pGHD treated with daily injections of somatropin who have good adherence and those with sub-optimal adherence were characterized. Good adherence was defined as medication possession ratio (MPR) of ≥ 80%, sub-optimal adherence as MPR <80%. Logistic regression models will evaluate the relationship between demographic characteristics (age, gender, race/ethnicity) and adherence (good vs. sub-optimal). Results: Patient characteristics were similar across each cohort; in the 12-month cohort (n=3091), mean age was 11.34 ±2.89 years, 75.9% were male, 70.9% white, 9.4% Hispanic, 3.6% Asian, and 3.1% black. At 48 months, 1193 (38.6%) of the 12-month cohort remained for follow-up. At 12 months, 80.1% had good adherence and mean (95% CI) MPR was 0.89 (0.88-0.89) while mean (95% CI) MPR at 48 months was 0.82 (0.81-0.83). The proportion with good adherence at months 24, 36, and 48 were 70.2%, 65.6%, and 64.0%, respectively. Adherence was not associated with age or gender. Blacks and Hispanics consistently exhibited lower adherence. At 12 months, good adherence was observed among 85.7% of Asians, 80.0% of whites, 77.2% of Hispanics, and 76.0% of blacks; at 48 months, good adherence was observed among 73.9% of Asians, 65.4% of whites, 56.8% of blacks, and 55.2% of Hispanics. Logistic regression model results will be provided. Conclusion: Although the majority of children with pGHD demonstrated good adherence with a daily r-hGH regimen, sub-optimal adherence increases with treatment duration and is higher among black and Hispanic children. Strategies that facilitate good adherence to r-hGH may support improved clinical outcomes.

Factors Driving Patient Preferences for Growth Hormone Treatment in Japanese Children With Growth Hormone Deficiency

Background: There are no any clear evidence to date has evaluating patients and caregiver preferences for r-hGH (recombinant-human growth hormone) injection in children in Japan. This study quantitatively evaluated the factors driving preferences for daily r-hGH injection among Japanese children with Growth Hormone Deficiency (GHD) or their respective caregivers to determine the relative importance of treatment delivery attributes. This study was performed amongst Japanese children with GHD or their caregivers who visited a specialized clinic in Japan as part of their routine care between June and July 2020. Methods: The participants were asked to complete a web-based discrete choice experiment (DCE) questionnaire using a handheld tablet device during a routine clinical visit. DCE is a quantitative method widely used in healthcare to elicit preferences from participants in the absence of revealed preference data. Choice-based conjoint analysis was used to evaluate the relative importance of attributes as choice predictors and determine utilities for each attribute. Of the 47 respondents who participated in this study, 41 were caregivers who responded on behalf of the patients, and the remaining 6 were patients who completed the DCE themselves. All participants were screened by a clinician to ensure they met all eligibility criteria. Results: The injection schedule was found to be the most important attribute for both patients and caregivers (Relative importance: 43.6%); a once-weekly injection schedule was preferred over a daily injection schedule. For maintenance of injection devices, patients had a stronger preference for reusable pens which can be used by replacing cartridges, while caregivers preferred disposable pen devices. The storage and preparation attribute was deemed more important to patients than it was to caregivers, with patients preferring storage in room temperature even if it needed an additional mixing(reconstitution) step. Both patients and caregivers showed a clear preference for devices that offered a dose setting memory. Conclusion: The results of this study showed that patients prefer a once-weekly injection schedule over a daily injection schedule. A less frequent injection schedule should enhance adherence and compliance to r-hGH treatment over the long term and will also improve QoL in children with GHD. The benefits of a less frequent injection schedule can be further explored using real-world studies.

Prolonged, Controllable Protein Production of cDNA-Encoded hGH Maintained at Therapeutic Serum Levels Following One Systemic Administration of a Non-Viral, Non-Integrating, DNA-and Liposome-Based in vivo Gene Therapy Platform in Immunocompetent Mice

Abstract Recombinant human growth hormone (rhGH), the mainstay of hGH replacement therapy, is injected daily for years to enable children to achieve normal stature. Daily rhGH injections are required because its serum-T1/2 is &amp;lt;20 minutes. Human trials testing T1/2-extending rhGH proteins are promising, but even weekly rhGH administration poses potential short and long-term toxicity risks, including exacerbation of diabetes or hypertension and potential for oncogenesis. Frequent hGH injections produce non-physiologic IGF-I profiles, (peak serum IGF-I frequently supra-normal, trough IGF-I concentrations at baseline). Therefore, a safe, effective, single administration hGH approach that maintains hGH and IGF-I serum concentrations within their respective therapeutic ranges for approximately one year could offer significant advantages. Accordingly, DNARx tested HEDGESTM, it’s non-viral, non-integrating, DNA-and liposome-based systemic, in vivo gene therapy approach to produce long-term hGH serum levels within the therapeutic range (1 -10 ng/ml) in immunocompetent mice. Previously, one systemic HEDGES-human granulocyte colony stimulating factor (hG-CSF, serum T1/2&amp;lt;3 hours) cDNA administration produced durable therapeutic hG-CSF serum levels (Science advances, 2019, 5, 2019). Importantly, simply by modifying selected aspects of HEDGES’s DNA vector and liposomal components, the duration of serum hG-CSF protein production was controllable over a broad temporal range. Long-term assessment of serum hGH in immunocompetent mice was assessed by injecting either one HEDGES administration or one administration followed by one re-dose of DNA vectors expressing either A) wildtype hGH cDNA (HEDGES-1) or B) wildtype hGH fused to selected serum protein T1/2-extending DNA sequences (HEDGES-2), with these results: 1) One HEDGES-1 administration produced slowly-increasing, but sub-therapeutic hGH serum levels from day 7 to day 99 after injection. From day 99 on, serum hGH levels remained within the therapeutic range for &amp;gt; 230 days; 2) Concurrently, hGH-induced elevation of endogenous mouse serum IGF-I levels remained between 1 to 3 fold above baseline. 3) One HEDGES-1 re-injection was administered 35 days after initial injection, a time when hGH serum levels remained sub-therapeutic. By day 7, one re-injection further elevated cDNA-encoded hGH serum levels into the therapeutic range, maintaining them for &amp;gt;175 days; 4) One HEDGES-2 administration produced therapeutic hGH serum levels by day 7 that were maintained for &amp;gt;250 days. These studies demonstrate the feasibility of achieving very long-term therapeutic levels of hGH and IGF-I following 1-2 injections. DNARx is now focused on selectively modifying its HEDGES hGH cDNA vectors and liposomal components to produce hGH serum levels within the therapeutic range for the equivalent of one human year following administration

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs.

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.

Development and Psychometric Evaluation of the Life Interference Questionnaire for Growth Hormone Deficiency (LIQ-GHD) to Assess Growth Hormone Injection Burden in Children and Adults.

BackgroundCurrent recombinant human growth hormone (r-hGH) replacement therapy involves long-term daily subcutaneous injections to treat growth hormone deficiency (GHD) in children and adults. Daily r-hGH injections can be burdensome, often resulting in poor treatment compliance. Clinical outcome assessments (COAs) can capture the burden of these injections from the patient (and caregiver) perspective and may demonstrate the benefit of a less-frequent r-hGH injection regimen, which may ultimately improve treatment compliance and long-term outcomes.ObjectiveTo address this knowledge gap, qualitative research was conducted to inform the development of a new Life Interference Questionnaire for Growth Hormone Deficiency (LIQ-GHD), designed to measure the experiences of patients taking r-hGH GHD injections. A second objective was to evaluate the hypothesized factor structure and preliminary performance of the LIQ-GHD in a cross-sectional observational study.MethodsAn empirical literature review and expert advice meetings were conducted to inform development of the draft LIQ-GHD (pediatric and adult versions). In-person concept elicitation and cognitive debriefing interviews were conducted with GHD patients (and patient dyads including caregivers) to explore and confirm concept coverage and evaluate respondents’ ability to understand the questionnaire. The draft LIQ-GHD was then tested in a cross-sectional field study involving pediatric and adult patients receiving daily r-hGH injections for GHD. The factor structure, reliability, and validity were analyzed for the overall sample and for pediatric, adolescent, and adult subgroups.ResultsResults from the literature review and input from six experts were used to develop and refine the LIQ-GHD, with content covering pen ease of use; regimen convenience; life interference due to regimen; benefit/satisfaction/willingness to continue treatment; regimen choice/preference; intent to comply with regimen; injection-related signs/symptoms; and reasons for missed injections. Twenty-one patient interviews confirmed comprehensive concept coverage and patient/caregiver comprehension of the LIQ-GHD. A total of 224 patients (n = 70 children/caregiver dyads, n = 79 adolescents/caregiver dyads, n = 75 adults) participated in the field study. While most items showed floor effects, confirmatory factor analysis fit statistics were good for the overall sample (root mean square error of approximation = 0.07, comparative fit index = 0.98) and for the full pediatric sample after dropping co-dependent questions from the model. Cronbach’s alpha (α) ranged from 0.746 to 0.905 and intra-class correlation coefficients ranged from 0.761 to 0.918 for the overall sample on LIQ-GHD domains. Scores correlated as predicted with an existing criterion measure in the overall sample and LIQ-GHD domain scores distinguished known groups as expected.ConclusionsThe LIQ-GHD is a new COA for the measurement of r-hGH injection treatment burden. This research provides evidence supporting its content validity, hypothesized factor structure, score reliability, and construct validity in pediatric and adult populations.

Use of PEGylated Recombinant Human Growth Hormone in Chinese Children with Growth Hormone Deficiency: A 24-Month Follow-Up Study.

Objective Once-weekly PEGylated recombinant human growth hormone (rhGH) is the sole long-acting GH formulation available currently for pediatric patients with GH deficiency (GHD). The aim of this study was to evaluate the efficacy and safety of PEGylated rhGH therapy compared to daily rhGH therapy in GHD children treated for two years. Methods A total of 98 children (49 children for the PEGylated rhGH group and 49 children for the daily rhGH group) with GHD were enrolled in this single-center, prospective, nonrandomized cohort study. PEGylated rhGH or daily rhGH was administered for 2 years. Height, height SDS, height velocity (HV), IGF-1, bone age (BA), and adverse events were determined throughout the treatment. Results HV significantly increased over the baseline and was similar in both groups. In the PEGylated rhGH cohort, the mean ± SD HV was improved from 3.78 ± 0.78 cm/y at the baseline to 12.44 ± 3.80 cm/y at month 3, to 11.50 ± 3.01 cm/y at month 6, to 11.00 ± 2.32 cm/y at month 12, and finally 10.08 ± 2.12 cm/y at month 24 in the PEGylated rhGH group. In the daily rhGH group, HV was 3.36 ± 1.00 cm/y at baseline, increasing to 12.56 ± 3.71 cm/y at month 3, to 11.82 ± 2.63 cm/y at month 6, to 10.46 ± 1.78 cm/y at month 12, and to 9.28 ± 1.22 cm/y at month 24. No serious adverse event related to PEGylated rhGH or daily rhGH occurred during the 24-month study. Conclusion PEGylated rhGH replacement therapy is effective and safe in pediatric patients with GHD. The adherence to once-weekly PEGylated rhGH therapy is superior to daily rhGH in children with GHD.

Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study

Background/Aims: To determine the optimal dose of LB03002, a sustained-release, once-weekly formulation of recombinant human growth hormone (rhGH), and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature (ISS). Methods: This multicenter, randomized, open-label, phase II study included GH-naïve, prepubertal children with ISS, randomized to receive daily rhGH 0.37 mg/kg/week (control, n = 16), LB03002 0.5 mg/kg/week (n = 14), or LB03002 0.7 mg/kg/week (n = 16). The primary endpoint was height velocity (HV) change at week 26. Results: At week 26, the least square (LS) means for HV change (cm/year) with control, LB03002 0.5 mg/kg/week, and LB03002 0.7 mg/kg/week were 5.08, 3.65, and 4.38, and the LS means for the change in height standard deviation score were 0.65, 0.49, and 0.58, respectively. The lower bound of the 90% confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change (–1.72) satisfied the noninferiority margin (–1.75). Adverse events were generally mild and short-lived. Conclusion: A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments. LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH.