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 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.

Trial registration: ClinicalTrials.gov NCT01706783.

Figures

Figure 1.

PK mean profiles (log scale) after the first administration and after fourth administration of NNC0195-0092.

Figure 2.

Mean levels (±SEM) of IGF-1 nanograms per milliliter (A) and IGF-1 SDS (B) vs time pretrial, baseline (washout), after the first administration (d 0), and the fourth administration (d 21) of NNC0195-0092 or Norditropin NordiFlex to adults with GHD.

Figure 3.

Mean levels (±SEM) of IGFBP-3 nanograms per milliliter (A) and IGFBP-3 SDS (B) vs time after the first administration (d 0) and the fourth administration (d 21) of NNC0195-0092 or Norditropin NordiFlex to adults with GHD.