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

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 - 2016/3

Y1 - 2016/3

N2 - CONTEXT: NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration.OBJECTIVES: 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.DESIGN AND SETTING: This was a 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 participated in the study.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 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.RESULTS: 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.CONCLUSION: 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.

AB - CONTEXT: NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration.OBJECTIVES: 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.DESIGN AND SETTING: This was a 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 participated in the study.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 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.RESULTS: 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.CONCLUSION: 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.

KW - Adult

KW - Aged

KW - Dose-Response Relationship, Drug

KW - Female

KW - Human Growth Hormone

KW - Humans

KW - Insulin-Like Growth Factor Binding Protein 3

KW - Insulin-Like Growth Factor I

KW - Lipopeptides

KW - Male

KW - Middle Aged

KW - Prospective Studies

KW - Comparative Study

KW - Journal Article

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1210/jc.2015-1991

DO - 10.1210/jc.2015-1991

M3 - Journal article

C2 - 26727076

SN - 0021-972X

VL - 101

SP - 988

EP - 998

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 3

ER -