Optimal Monitoring of Weekly IGF-I Levels During Growth Hormone Therapy With Once-Weekly Somapacitan.
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ABSTRACT: Context
Somapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration.Objective
To develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing.Design
A pharmacokinetic/pharmacodynamic model was used to simulate IGF-I data in adults and children following weekly somapacitan treatment of GHD.Setting and patients
39 200 IGF-I profiles were simulated with reference to data from 26 adults and 23 children with GHD.Intervention(s)
The simulated dose range was 0.02 to 0.12 mg/kg for adults and 0.02 to 0.16 mg/kg for children. Simulated data with >4 average standard deviation score were excluded.Main outcome measure(s)
Linear models for predicting mean and peak IGF-I levels based on IGF-I samples from different days after somapacitan dose.Results
Robust linear relationships were found between IGF-I sampled on any day after somapacitan dose and the weekly mean (R2 > 0.94) and peak (R2 > 0.84). Prediction uncertainties were generally low when predicting mean from samples taken on any day (residual standard deviation [RSD] ≤ 0.36) and peak from samples taken on day 1 to 4 (RSD ≤ 0.34). IGF-I monitoring on day 4 and day 2 after dose provided the most accurate estimate of IGF-I mean (RSD < 0.2) and peak (RSD < 0.1), respectively.Conclusions
Linear models provided a simple and reliable tool to aid optimal monitoring of IGF-I by predicting mean and peak IGF-I levels based on an IGF-I sample following dosing of somapacitan. A short visual summary of our work is available (1).
SUBMITTER: Juul Kildemoes R
PROVIDER: S-EPMC7823237 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveGrowth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose-responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose-insulin-like growth factor I (IGF-I) responses in AGHD patients.DesignAnalyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.MethodsPharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose-IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.ResultsThe analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7-9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3-4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose-exposure-IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.ConclusionsThis study extends the knowledge of the somapacitan dose-IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.
| S-EPMC9175552 | biostudies-literature
Project description:Objective: Somapacitan is a long-acting, reversible albumin-binding growth hormone (GH) derivative in development. This study aimed to evaluate the safety and efficacy of once-weekly somapacitan versus daily GH over 52 weeks in Japanese patients with adult growth hormone deficiency (AGHD).Design: Phase 3, multicentre, randomized, parallel-group, open-label, active-controlled trial (NCT03075644).Patients: Previously GH-treated Japanese patients with AGHD were randomized 3:1 to somapacitan (n = 46) or daily GH (n = 16) for 20 weeks' dose titration and 32 weeks' fixed-dose treatment.Measurements: Primary endpoint was the incidence of adverse events (AEs). Secondary endpoints included change from baseline to week 52 in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT).Results: Mean (SD) prescribed doses after titration were 1.780 (1.058) mg/week for somapacitan and 0.197 (0.083) mg/day for daily GH. Rate of AEs per 100 patient-years was similar between arms (somapacitan, 312.7; daily GH, 309.8). Four AEs in the somapacitan arm were serious; none were considered treatment-related. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) was maintained from baseline in both arms. No significant differences were observed between arms for change from baseline to week 52 in VAT, SAT or TAT (estimated difference, somapacitan - daily GH [95% CI]: -1.74 [-18.13; 14.66], -11.53 [-35.54; 12.48] and - 12.85 [-47.31; 21.62] cm2 , respectively).Conclusions: Treatment in both groups was well tolerated, with no unexpected safety findings. Impact on adipose tissue was similar to somapacitan and daily GH in patients with AGHD. A short visual summary of our work is available at https://bit.ly/3946YNF.
| S-EPMC7689735 | biostudies-literature
Project description:Abstract Growth hormone (GH) replacement therapy currently requires daily injections. Somapacitan is a long-acting GH-derivative being developed for once-weekly (OW) use in children and adults with GH deficiency (GHD). A phase 2, multinational, randomized, open-label, controlled trial (ClinicalTrials.gov: NCT02616562) investigated the efficacy and safety of OW somapacitan compared with daily GH (Norditropin® FlexPro®). GH-treatment-naïve prepubertal children with GH deficiency received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/wk (n=14) subcutaneous (sc) OW somapacitan, or sc GH 0.034 mg/kg/day (0.24 mg/kg/wk; n=14) for 52 wks, followed by a 104-wk safety extension with all patients on somapacitan receiving 0.16 mg/kg/wk while GH dose was unaltered. Safety endpoints included frequency of adverse events (AEs), including injection-site reactions, and occurrence of anti-somapacitan/anti-human growth hormone (hGH) antibodies. The 52-wk efficacy and safety results have been reported. We report here safety results at 104 wks’ total treatment. Number of AEs (% of patients) was as follows: OW somapacitan 0.04/0.16 mg/kg/wk, 51 (75%); 0.08/0.16 mg/kg/wk, 89 (80%); 0.16/0.16 mg/kg/wk, 89 (100%); and for daily GH, 82 (100%). Nasopharyngitis, influenza, allergic rhinitis and gastroenteritis were the most common AEs across all treatment groups. Pyrexia was more common in the OW somapacitan 0.04/0.16 mg/kg/wk (43.8%) and 0.08/0.16 mg/kg/wk (26.7%) groups vs the higher-dose OW somapacitan and daily GH groups (7.1% each). Most AEs were mild to moderate and unlikely related to treatment. Ten serious AEs were reported in five (8.5%) children and unlikely related to treatment, except two AEs of moderate severity during the first 26 wks: generalized edema and vomiting in one child on 0.16 mg/kg/wk OW somapacitan, rated as probably related to treatment although she was also given intravenous antibiotics for suspected infection. Injection-site reactions were reported in the 0.04/0.16 mg/kg/wk (n=2) and 0.16/0.16 mg/kg/wk (n=1) OW somapacitan groups and in the daily GH group (n=1). Four children (0.04/0.16 mg/kg/wk) and one child (0.16/0.16 mg/kg/wk) had transient anti-somapacitan antibodies; one child (0.16/0.16 mg/kg/wk) had low-titer anti-somapacitan antibodies at two consecutive visits; in one child (daily GH group) with persistent low-titer anti-hGH antibodies, treatment was discontinued at wk 52. All antibodies were non-neutralizing. In conclusion, OW somapacitan was well tolerated at all doses, with no new safety or tolerability issues identified after up to 104 wks of treatment. The frequency, severity and type of AEs were similar in the OW somapacitan and daily GH treatment groups except for pyrexia, which was unlikely related to treatment and more frequently reported in the lowest dose somapacitan group.
| S-EPMC7209577 | biostudies-literature
Project description:Abstract Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial. The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters. Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups. In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.
| S-EPMC9625742 | biostudies-literature
Project description:Growth hormone treatment has effectively restored normal growth in children with growth hormone deficiency (GHD); however, it poses challenges in compliance with a daily growth hormone injection regimen, leading to low adherence and persistence rates. Once-weekly Somapacitan is a potential alternative for treating children with GHD. This study aimed to evaluate the efficacy, safety, and adherence of once-weekly subcutaneous Somapacitan compared to daily growth hormone injection in prepubertal children with GHD. A search for the published records was carried out on 17 October 2023 utilizing the searching feature available on PubMed, Embase, and Scopus. Primary study outcomes included (1) efficacy, measured by height velocity (HV), standard deviation score (SDs), height SDs, insulin-like growth factor-SDs (IGF-I SDs), and bone age vs. chronological age ratio (BA vs. CA); (2) safety, assessed through adverse events and injection site reactions; and (3) adherence, determined by the percentage of the sample completing treatments. Secondary outcomes evaluated disease burden scores, divided into three subgroup domains: emotional well-being, physical functional, and social well-being scores. We retrieved 6 studies that were eligible for the systematic review (417 versus 186 for intervention and control, respectively). Only 2 of the total included studies were eligible for pooled analysis (175 versus 82 for intervention and control, respectively). The efficacy profile of Somapacitan was similar to daily growth hormones, indicated by HV (mean difference (MD = 0.04; p = 0.96), HV SDs (MD = -0.71; p = 0.09), height SDs (MD = 0.11; p = 0.69), IGF-I SDs (MD = 0.06; p = 0.70), and CA vs. BA (MD = 0.67; p = 0.70)), demonstrated similar and non-inferior outcomes. Treatment adherence is 3 times higher in the Somapacitan group as compared to control (OR = 3.02; p = 0.03) with adherence rates reaching 95% and 88% for Somapacitan and Norditropin®, respectively. The disease burden measurement is similar in Somapacitan and daily growth hormones (MD = -0.62; p = 0.83), as indicated by the Growth Hormone Deficiency-Child Impact Measure. In almost all outcomes, the level of confidence is strong. The confidence level in the data is generally strong, but for CA vs. BA and the subgroup of severe adverse events with heterogeneity >50%, the confidence level is moderate. Although the efficacy and safety profiles of Somapacitan were found to be similar to those of daily growth hormones, a reduced frequency of once-weekly Somapacitan injections led to increased adherence. PROSPERO registration: CRD42023473209.
| S-EPMC10887308 | biostudies-literature
Project description:Abstract Background: Growth hormone deficiency (GHD) requires long-term daily injections with GH replacement therapy and is associated with considerable treatment burden. Somapacitan is a long-acting GH derivative being developed for once-weekly dosing in adults and children with GHD. A well-established protraction method, successfully used to extend the half-life of insulin and glucagon-like peptide (GLP)-1, has been applied in developing somapacitan: an albumin-binding moiety (1.3 kDa) is attached to a single amino acid substitution in the GH molecule (22 kDa). Objective: To evaluate the efficacy, safety, and tolerability of three once-weekly somapacitan doses, compared with Norditropin®, a daily GH. Methods: This multicenter, open-label, randomized, controlled phase 2 study (ClinicalTrials.gov: NCT02616562) was double-blind with regard to dose levels of somapacitan, and height assessors were blinded to treatment. GH-treatment-naïve prepubertal children with GHD were randomized to somapacitan (N=45) or Norditropin® (N=14). Patients received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/wk (n=14) subcutaneous (sc) somapacitan once weekly, or sc Norditropin® 0.034 mg/kg/day (0.24 mg/kg/wk; n=14). Patients completed 6 months of treatment as follows: somapacitan 0.04 (n=14), 0.08 (n=15) and 0.16 (n=14) mg/kg/wk, and Norditropin® 0.034 mg/kg/day (n=13). Results: At 6 months, mean (SD) annualized height velocity (HV, cm/year) for the three somapacitan doses was 8.0 (2.0), 10.9 (1.9) and 12.9 (3.5), respectively. HV for the 0.08 and 0.16 mg/kg/wk doses did not differ significantly from HV with Norditropin® (11.4 [3.3]). Insulin-like growth factor (IGF)-I increased dose-dependently: change from baseline in IGF-I standard deviation score (SDS) was 1.08, 2.15 and 3.21 for the somapacitan groups, respectively, when measured at peak of the IGF-I profile over the dosing interval, and 2.03 for Norditropin®. Modeling yielded IGF-I SDS average over the dosing interval for the somapacitan 0.16 mg/kg/wk group that was similar to observed values for Norditropin®. Adverse events were mild-to-moderate and most were evaluated as unrelated to treatment by the investigator. One patient had persistent anti-hGH antibodies of low titer and three patients had a single positive measurement of anti-somapacitan antibodies of low titer. All antibody positive samples were negative for in vitro neutralizing antibodies. There were no clinically relevant changes from baseline to Week 26 in any treatment group in mean HbA1c, fasting glucose or insulin. Tolerability was consistent with known properties of GH. Conclusion: In children with GHD, the efficacy, safety and tolerability of once-weekly somapacitan was similar to that of daily Norditropin®. Results from this phase 2 trial provide support for the initiation of a phase 3 trial of somapacitan in children with GHD.
| S-EPMC6552843 | biostudies-literature
Project description:PurposeThe long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD.MethodsIn post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan).ResultsNo new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-β did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters.ConclusionsSomapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).
| S-EPMC9908671 | biostudies-literature
Project description:In this real-world pilot study, we evaluated the metabolic and endocrinological effects in patients with adult growth hormone deficiency (AGHD) who switched from daily growth hormone (GH) replacement therapy to weekly GH replacement therapy using somapacitan. Eleven patients with AGHD, whose medical treatment aside from GH replacement therapy did not change, were enrolled. We investigated the metabolic and endocrinological parameters between at switching and 6 months after switching from daily GH formulation to somapacitan. The results showed that body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and liver functions were significantly improved 6 months after switching compared to those at switching (each P < .05). Besides, the improvement in HOMA-IR was significantly associated with the period of daily GH replacement therapy before switching (P = .048), while age, sex, improvement in BMI or liver functions, presence of any hormonal deficiency, and the existence of any hormonal replacement therapy significantly associated (P > .05). In addition, switching to GH replacement therapy did not affect endocrinological parameters. In conclusion, this study might indicate that weekly GH replacement therapy with somapacitan could have more beneficial points than daily GH replacement therapy. Considering the cohort of this study was small, future studies with larger cohorts should be necessary to confirm the results of this study.
| S-EPMC10519569 | biostudies-literature
Project description:OBJECTIVE:Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin®. Local tolerability and treatment satisfaction were also assessed. DESIGN:26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). METHODS:Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS:Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171). CONCLUSIONS:In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin.
| S-EPMC5920019 | biostudies-literature
Project description: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).
| S-EPMC7076631 | biostudies-literature