Dataset Information

Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency.

ABSTRACT: NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration.The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH.This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study.Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies.Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve[0-168h]) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group.Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated, and IGF-1 profiles were consistent with a once-weekly treatment profile. No clinically significant safety and tolerability signals causally related to NNC0195-0092 were identified, nor were any immunogenicity concerns revealed.

SUBMITTER: Rasmussen MH

PROVIDER: S-EPMC4803179 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency.

Rasmussen Michael Højby MH Janukonyté Jurgita J Klose Marianne M Marina Djordje D Tanvig Mette M Nielsen Lene F LF Höybye Charlotte C Andersen Marianne M Feldt-Rasmussen Ulla U Christiansen Jens Sandahl JS

The Journal of clinical endocrinology and metabolism 20160104 3

<h4>Context</h4>NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration.<h4>Objectives</h4>The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH.<h4>Design and setting</h4>This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.<h4>Patients</h4>Thirty-four GH-treated adult subjects ...[more]

PMID: 26727076

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Project description: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). The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. 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). This study took place at 29 sites in 11 countries. Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. 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. 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. 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. 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).

Project description:BackgroundDespite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels.Methodology/principal findingsTwenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal.ConclusionsIn patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults.Trial registrationClinicalTrials.gov NTC00601419.

Project description:Abstract Somapacitan is a long-acting, reversible albumin-binding human growth hormone (GH) derivative based on a proven protraction technology. The objective of this trial was to evaluate the safety, efficacy and treatment satisfaction of once-weekly somapacitan compared with daily GH (Norditropin®) over 52 weeks in Japanese patients with adult GH deficiency (AGHD). This was a phase 3, multicenter, randomized, open-label, parallel-group, active-controlled trial (NCT03075644). Patients previously treated with human GH were randomized 1:3 to either daily GH or somapacitan, respectively, to undergo 20 weeks of dose titration and 32 weeks of fixed-dose treatment. The primary endpoint was the incidence of adverse events (AEs) from baseline to week 53. Secondary endpoints included change from baseline in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT, respectively) assessed with computerized tomography scans; change from baseline in treatment satisfaction evaluated using Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores; and occurrence of anti-somapacitan antibodies. In total, 62 patients were randomized (16 to the daily GH and 46 to the somapacitan treatment arm), of which 60 completed the trial. Baseline characteristics for daily GH vs somapacitan groups, respectively, were: 43.8% vs 47.8% female, 87.5% vs 80.4% adult-onset GH deficiency, mean (SD) age 49.3 (11.5) vs 54.1 (12.1) years, weight 67.9 (12.0) vs 69.4 (22.7) kg, body mass index 24.8 (3.7) vs 26.4 (6.7) kg/m2, and GH dose at screening 0.29 (0.14) vs 0.31 (0.17) mg. Rate of AEs per 100 patient-years was similar between treatment arms (309.8 for daily GH, 312.7 for once-weekly somapacitan); most AEs were mild (97.9% and 93.1%, respectively) and none were severe. Four AEs in the somapacitan arm were serious; all were considered unlikely related to treatment. No anti-somapacitan antibodies were detected during treatment. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) at baseline was maintained with both treatments. The majority of the patients had IGF-I SDS values below +2. No significant differences in VAT, SAT and TAT were seen in both treatment groups after 52 weeks (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. TSQM-9 scores were not significantly different between treatments, but showed a tendency in favor of somapacitan (estimated difference [95% CI]): 4.87 [–3.46; 13.20] for effectiveness, 6.79 [–1.04; 14.61] for convenience, and 6.88 [–1.08; 14.85] for overall satisfaction. No new safety concerns were identified. Improvements in body composition were similar in the GH and somapacitan cohorts. The safety and tolerability of somapacitan in Japanese patients with AGHD were consistent with results from the global phase 3 trial (REAL 1).

Project description: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.

Project description:ContextIn the absence of panhypopituitarism and low serum IGF-I levels, the diagnosis of adult GH deficiency (AGHD) requires confirmation with a GH stimulation test. Macimorelin is a novel, orally active ghrelin mimetic that stimulates GH secretion.ObjectiveThe objective of the study was to determine the diagnostic efficacy and safety of macimorelin in AGHD.DesignThis was a multicenter open-label study comparing the diagnostic accuracy of oral macimorelin with that of arginine+GHRH in AGHD patients and healthy, matched controls. After 43 AGHD patients and 10 controls were tested, the GHRH analog Geref Diagnostic [GHRH(1-29)NH2] became unavailable in the United States. The study was completed by testing 10 additional AGHD patients and 38 controls with macimorelin alone.Main outcome measurePeak GH area under the receiver operating characteristic curve after macimorelin was measured.ResultsFifty AGHD subjects and 48 controls were evaluated. Peak GH levels in AGHD patients and controls after macimorelin were 2.36 ± 5.69 and 17.71 ± 19.11 ng/mL, respectively (P < .0001). With macimorelin, the receiver operating characteristic analysis yielded an optimal GH cut point of 2.7 ng/mL, with 82% sensitivity, 92% specificity, and 13% misclassification rate. For subjects receiving both tests, macimorelin showed discrimination comparable with arginine+GHRH (area under the receiver operating characteristic curve 0.99 vs 0.94, respectively, P = .29). Obesity (body mass index > 30 kg/m(2)) was present in 58% of subjects, and peak GH levels were inversely associated with body mass index in controls (r = -0.37, P = .01). Using the separate cut points of 6.8 ng/mL for nonobese and 2.7 for obese subjects reduced the misclassification rate to 11%. Only 1 drug-related serious adverse event, an asymptomatic QT interval prolongation on the electrocardiogram, was reported.ConclusionOral macimorelin is safe, convenient, and effective in diagnosing AGHD with accuracy comparable with the arginine+GHRH test.

Dataset Information

Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency.

Publications

Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency.

Similar Datasets

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