nnc0195-0092 and Dwarfism--Pituitary

Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration in August 2021 for the treatment of pediatric growth hormone deficiency (GHD). Lonapegsomatropin is a prodrug consisting of unmodified GH transiently conjugated to methoxypolyethylene glycol which enables time-release of GH with a half-life of ~25 hours allowing for once-weekly administration. Clinical trials of lonapegsomatropin have demonstrated positive efficacy results in children (phase 2 and 3) and adults (phase 2) with GHD. The phase 3 trial in children with GHD established non-inferiority and statistical superiority of height velocity with lonapegsomatropin (11.2 cm/yr) compared to daily GH (10.3 cm/yr), with no concerning side effects with lonapegsomatropin. Similar growth responses have been reported in other LAGH products in phase 2 (somapacitan) and phase 3 (somatrogon) trials. Lonapegsomatropin is distributed in temperature-stable, prefilled cartridges at 9 different doses that can be prescribed based upon specific weight brackets designed to deliver approximately 0.24 mg/kg/wk. An electronic delivery device is required to combine the powdered medication with the diluent and deliver the medication subcutaneously through a small gauge needle to the recipient. The pharmacodynamic data from the clinical trials of lonapegsomatropin has been used to develop models to estimate an average IGF-1 value drawn at any time during the weekly injection interval. This average IGF-1 value may be used to for safety monitoring and/or to guide dose adjustment. New LAGH products, including lonapegsomatropin, may potentially improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations.

Topics: Adult; Child; Dwarfism, Pituitary; Histidine; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Mannitol; Phenol; Quality of Life; United States

In standard 52-week phase III clinical trials, once weekly lonapegsomatropin, somatrogon and somapacitan have been found to yield non-inferior height velocities and similar safety profiles to daily GH (DGH) in children with pediatric growth hormone deficiency (PGHD). Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration (FDA) in August 2021 for the treatment of PGHD and has also been approved in other regions of the world. Somatrogon was approved for the treatment of PGHD beginning in some regions beginning in late 2021. Somapacitan was approved by the FDA for the treatment of Adult GHD in August 2020. The phase III clinical trial of somapacitan for the treatment of PGHD has been completed and demonstrated non-inferiority of somapacitan to DGH. New LAGH products may improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations and to understand how the non-physiological pharmacokinetic and pharmacodynamic profiles following administration of each LAGH product relate to short- and long-term safety and efficacy of LAGH therapy.

Topics: Adult; Child; Dwarfism, Pituitary; Growth Hormone; Histidine; Human Growth Hormone; Humans; Mannitol; Phenol; Quality of Life; United States

Growth hormone deficiency (GHD) is characterized by inadequate HG production from the anterior pituitary gland. Adult patients with GHD have increased fat mass, an abnormal lipid profile, decreased lean body mass and bone mineral density, decreased muscle strength and exercise endurance, and a diminished quality of life. Adult GHD (AGHD) has been treated with GH replacement therapy by daily subcutaneous injections. However, the administration of daily injections can be burdensome for some patients and affect treatment adherence. Somapacitan is a new long-acting human GH (hGH) analogue that is administered once a week by subcutaneous injection. It was first approved by the U.S. Food and Drug Administration (FDA) as GH replacement therapy for adults with GHD, becoming the first hGH therapy for AGHD administered by once-weekly injection, compared with other approved hGH therapies for AGHD administered by daily injection. This article reviews the pharmacokinetic, clinical and safety data that led to the approval of somapacitan as the first long-acting GH therapy for adults with GHD.

Topics: Adult; Dwarfism, Pituitary; Human Growth Hormone; Humans; Quality of Life

Adult growth hormone deficiency (AGHD) is a rare endocrine disorder characterized by an abnormal body composition, metabolic abnormalities associated with increased cardiovascular diseases, bone loss, and impaired quality of life. Daily subcutaneous injections with recombinant growth hormone (GH) can alleviate the abnormalities associated with AGHD. Several long-acting GH (LAGH) preparations are currently in development that aim to reduce treatment burden for patients receiving daily GH injections. Somapacitan (Sogroya

Topics: Adult; Dwarfism, Pituitary; Growth Hormone; Human Growth Hormone; Humans; Injections, Subcutaneous; Quality of Life; United States

Topics: Child; Dwarfism, Pituitary; Human Growth Hormone; Humans

Topics: Child; Dwarfism, Pituitary; Human Growth Hormone; Humans

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.. 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.. 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.. 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.. 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: Body Height; Child; Drug Administration Schedule; Dwarfism, Pituitary; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Treatment Outcome

Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD).. Evaluate the efficacy and tolerability of somapacitan in children with GHD after 2 years of treatment and after the switch from daily GH.. A randomized, multinational, open-labelled, controlled parallel group phase 3 trial, comprising a 52-week main phase and 3-year safety extension (NCT03811535).. Eighty-five sites across 20 countries.. A total of 200 treatment-naïve prepubertal patients were randomized and exposed; 194 completed the 2-year period.. Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (0.034 mg/kg/d) during the first year, after which all patients received somapacitan 0.16 mg/kg/wk.. Height velocity (HV; cm/year) at week 104. Additional assessments included HV SD score (SDS), height SDS, IGF-I SDS, and observer-reported outcomes.. HV was sustained in both groups between 52 and 104 weeks. At week 104, mean (SD) for HV between weeks 52 and 104 was 8.4 (1.5) cm/year after continuous somapacitan treatment and 8.7 (1.8) cm/year after 1 year of somapacitan treatment following switch from daily GH. Secondary height-related endpoints also supported sustained growth. Mean IGF-I SDS during year 2 was similar between groups and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or tolerability issues identified. GH patient preference questionnaire results show that most patients and their caregivers (90%) who switched treatment at year 2 preferred once-weekly somapacitan over daily GH treatment.. Somapacitan in children with GHD showed sustained efficacy and tolerability for 2 years, and after switching from daily GH. Patients/caregivers switching from daily GH expressed a preference for somapacitan.. NCT03811535.

Topics: Body Height; Child; Dwarfism, Pituitary; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I

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).. Evaluate the efficacy, safety, and tolerability of once-weekly somapacitan after 3 years of treatment.. A multicenter, randomized, controlled, phase 2 study comparing somapacitan and once-daily GH for 156 weeks (NCT02616562).. Twenty-nine sites in 11 countries.. Fifty-nine children with GHD randomized (1:1:1:1) and exposed to treatment. Fifty-three children completed the 3-year period.. 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.. Height velocity (HV) at year 3; changes from baseline in height SD score (HSDS), HVSDS, and IGF-I SDS.. 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.. 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.. 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

Growth 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.. Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.. Pharmacokinetic/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.. The 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.. This 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.

Topics: Adult; Dwarfism, Pituitary; Estrogens; Female; Histidine; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Mannitol; Phenol; Pituitary Hormones, Anterior

Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD).. To demonstrate efficacy and safety of somapacitan vs daily GH.. REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535).. Eighty-six sites across 20 countries.. 200 treatment-naïve patients were randomized and exposed.. Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously.. The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures.. Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar between treatment groups. At week 52, mean IGF-I SDS values were similar between treatment groups and within normal range (-2 to +2). Safety of somapacitan was consistent with the well-known daily GH profile. Low proportions of injection-site reactions were reported for somapacitan (5.3%) and daily GH (5.9%). Both treatments similarly reduced disease burden from baseline to week 52, whereas a greater treatment burden reduction was observed for somapacitan.. Similar efficacy for somapacitan compared to daily GH was demonstrated over 52 weeks of treatment with comparable safety and mean IGF-I SDS levels in treatment-naïve children with GHD.

Topics: Child; Dwarfism, Pituitary; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I

The 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.. In 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).. No 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.. Somapacitan, 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).

Topics: Adult; Dwarfism, Pituitary; Glucose; Glycated Hemoglobin; Growth Hormone; Human Growth Hormone; Humans; Insulin

Somapacitan is a growth hormone derivative approved for once-weekly treatment of growth hormone deficiency in adults and currently in clinical development for once-weekly dosing in children. The purpose of this study was to obtain non-clinical data from rats to support the safety evaluation of the most abundant metabolites of somapacitan in humans. The aims were to identify somapacitan metabolites and their relative proportions in rat plasma, identify the structure of abundant metabolites and measure the systemic metabolite exposure at the no-observed-adverse-effect level in the rat. After a single dose of radiolabelled somapacitan and analysis by high-performance liquid chromatography with radiochemical detection, seven somapacitan-related metabolites were detected in plasma from male rats, of which six were seen in plasma from female rats. The three most abundant metabolites (M1, M2 and M3) were structurally identified from liquid chromatography and mass spectrometry data, and a fourth metabolite (P1) was characterised from its specific retention time (lacking retention to the stationary phase) in plasma analysis with reversed-phase liquid chromatography and radiochemical detection. The metabolites were products from proteolysis of the peptide backbone in somapacitan. A deamidation product of the M1 metabolite (M1B) was also identified. Following multiple, twice-weekly dosing for 4 weeks, somapacitan was the principal plasma component up to 36 h after dosing. After 36 h, metabolites M1+M1B were the most abundant plasma components. Pharmacokinetic models were developed for somapacitan and metabolite P1 and used for steady-state assessment in the rat. Comparison of our data generated from rats with data from the parallel human study demonstrated that the most abundant metabolites were present in rats at higher levels than in humans. This study has provided non-clinical safety data that contribute to an overall safety assessment of somapacitan.

Topics: Animals; Chromatography, High Pressure Liquid; Dwarfism, Pituitary; Female; Growth Hormone; Histidine; Human Growth Hormone; Male; Mannitol; Phenol; Plasma; Rats