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Reversible albumin-binding GH possesses a potential once-weekly treatment profile in adult growth hormone deficiency

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Rasmussen, Michael Højby ; Janukonyté, Jurgita ; Klose, Marianne ; Marina, Djordje ; Tanvig, Mette ; Nielsen, Lene F ; Höybye, Charlotte ; Andersen, Marianne ; Feldt-Rasmussen, Ulla ; Christiansen, Jens Sandahl. / Reversible albumin-binding GH possesses a potential once-weekly treatment profile in adult growth hormone deficiency. I: The Journal of clinical endocrinology and metabolism. 2016 ; Bind 101, Nr. 3. s. 988-98.

Bibtex

@article{c8715b8bdf1049f5b84dee0530ac27bc,
title = "Reversible albumin-binding GH possesses a potential once-weekly treatment profile in adult growth hormone deficiency",
abstract = "CONTEXT: NNC0195-0092 is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration.OBJECTIVES: Evaluate safety, local tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of multiple once-weekly doses of NNC0195-0092, compared with daily GH.DESIGN AND SETTING: Phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.PATIENTS: Thirty-four GH-treated adult subjects (male, n=25) with GH deficiency (GHD).INTERVENTIONS AND MAIN OUTCOME MEASURES: 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({\textregistered}) (n=2) for 4 weeks with a dose replicating the pre-trial 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 trial start. Blood samples were drawn for assessment of safety, PK, PD (IGF-I and IGFBP-3) profiles, and immunogenicity studies.RESULTS: Numbers of adverse events (AEs) were similar at the 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 dose levels versus daily injections of Norditropin NordiFlex({\textregistered}), whereas the number of AEs was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (AUC(0-168h)) and Cmax) increased in a dose-dependent manner, and a dose-dependent increase in IGF-I levels was observed. IGF-I profiles were elevated for at least one week, and for the 0.02 mg/kg and 0.04 mg/kg NNC0195-0092 doses, the observed IGF-I levels were similar to the levels for the active control group.CONCLUSION: Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GHD were well tolerated and IGF-I 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.",
author = "Rasmussen, {Michael H{\o}jby} and Jurgita Janukonyt{\'e} and Marianne Klose and Djordje Marina and Mette Tanvig and Nielsen, {Lene F} and Charlotte H{\"o}ybye and Marianne Andersen and Ulla Feldt-Rasmussen and Christiansen, {Jens Sandahl}",
year = "2016",
month = jan,
day = "4",
doi = "10.1210/jc.2015-1991",
language = "English",
volume = "101",
pages = "988--98",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The/Endocrine Society",
number = "3",

}

RIS

TY - JOUR

T1 - Reversible albumin-binding GH possesses a potential once-weekly treatment profile in adult growth hormone deficiency

AU - Rasmussen, Michael Højby

AU - Janukonyté, Jurgita

AU - Klose, Marianne

AU - Marina, Djordje

AU - Tanvig, Mette

AU - Nielsen, Lene F

AU - Höybye, Charlotte

AU - Andersen, Marianne

AU - Feldt-Rasmussen, Ulla

AU - Christiansen, Jens Sandahl

PY - 2016/1/4

Y1 - 2016/1/4

N2 - CONTEXT: NNC0195-0092 is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration.OBJECTIVES: Evaluate safety, local tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of multiple once-weekly doses of NNC0195-0092, compared with daily GH.DESIGN AND SETTING: Phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.PATIENTS: Thirty-four GH-treated adult subjects (male, n=25) with GH deficiency (GHD).INTERVENTIONS AND MAIN OUTCOME MEASURES: 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 pre-trial 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 trial start. Blood samples were drawn for assessment of safety, PK, PD (IGF-I and IGFBP-3) profiles, and immunogenicity studies.RESULTS: Numbers of adverse events (AEs) were similar at the 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 dose levels versus daily injections of Norditropin NordiFlex(®), whereas the number of AEs was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (AUC(0-168h)) and Cmax) increased in a dose-dependent manner, and a dose-dependent increase in IGF-I levels was observed. IGF-I profiles were elevated for at least one week, and for the 0.02 mg/kg and 0.04 mg/kg NNC0195-0092 doses, the observed IGF-I levels were similar to the levels for the active control group.CONCLUSION: Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GHD were well tolerated and IGF-I 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.

AB - CONTEXT: NNC0195-0092 is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration.OBJECTIVES: Evaluate safety, local tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of multiple once-weekly doses of NNC0195-0092, compared with daily GH.DESIGN AND SETTING: Phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.PATIENTS: Thirty-four GH-treated adult subjects (male, n=25) with GH deficiency (GHD).INTERVENTIONS AND MAIN OUTCOME MEASURES: 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 pre-trial 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 trial start. Blood samples were drawn for assessment of safety, PK, PD (IGF-I and IGFBP-3) profiles, and immunogenicity studies.RESULTS: Numbers of adverse events (AEs) were similar at the 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 dose levels versus daily injections of Norditropin NordiFlex(®), whereas the number of AEs was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (AUC(0-168h)) and Cmax) increased in a dose-dependent manner, and a dose-dependent increase in IGF-I levels was observed. IGF-I profiles were elevated for at least one week, and for the 0.02 mg/kg and 0.04 mg/kg NNC0195-0092 doses, the observed IGF-I levels were similar to the levels for the active control group.CONCLUSION: Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GHD were well tolerated and IGF-I 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.

U2 - 10.1210/jc.2015-1991

DO - 10.1210/jc.2015-1991

M3 - Journal article

C2 - 26727076

VL - 101

SP - 988

EP - 998

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 3

ER -

ID: 46005207