Rasmussen Michael Højby, Janukonyté Jurgita, Klose Marianne, Marina Djordje, Tanvig Mette, Nielsen Lene F, Höybye Charlotte, Andersen Marianne, Feldt-Rasmussen Ulla, Christiansen Jens Sandahl
Department of Global Development (M.H.R., L.F.N.), Novo Nordisk, DK-2860 Søborg Denmark; Medical Department of Diabetes and Endocrinology, Aarhus University Hospital (J.J., J.S.C.), DK-8000 C Aarhus, Denmark; Department of Endocrinology, Rigshospitalet, (M.K., D.M., U.F.-R.), University of Copenhagen, DK-2100 Copenhagen, Denmark; Department of Endocrinology, Odense University Hospital (M.T., M.A.), DK-5000 Odense, Denmark; and Department of Endocrinology, Karolinska University Hospital (C.H.), SE-171 76 Stockholm, Sweden.
J Clin Endocrinol Metab. 2016 Mar;101(3):988-98. doi: 10.1210/jc.2015-1991. Epub 2016 Jan 4.
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.
NNC0195 - 0092是一种可逆的、与白蛋白结合的生长激素衍生物，开发用于每周一次给药。
本研究的目的是评估与每日生长激素相比，多次每周一次剂量的NNC0195 - 0092的安全性、局部耐受性、药效学和药代动力学。
这是一项1期随机、开放标签、活性对照、多剂量、剂量递增试验。
34名接受生长激素治疗的生长激素缺乏成年受试者（男性，n = 25）参与了该研究。
受试者被依次分为四个队列，每个队列8名受试者，每个队列内随机分配（3:1）接受每周一次的NNC0195 - 0092（n = 6），共4周（0.02、0.04、0.08和0.12 mg/kg），或每日注射诺和诺德公司的诺德笔（n = 2），共4周，剂量重复生长激素治疗前的剂量。在开始下一剂量水平的NNC0195 - 0092治疗前进行安全性评估。试验开始前14天停用每日生长激素治疗。采集血样用于评估安全性、药代动力学、药效学（胰岛素样生长因子 - 1和胰岛素样生长因子结合蛋白 - 3）谱以及免疫原性研究。
NNC0195 - 0092剂量为0.02、0.04和0.08 mg/kg时的不良事件数量与每日注射诺和诺德公司的诺德笔相似，而NNC0195 - 0092最高剂量水平（0.
