Tuesday, December 28, 2010

Pegylated Long-Acting Human Growth Hormone Possesses a Promising Once-Weekly Treatment Profile, and Multiple Dosing Is Well Tolerated in Adult Patient

Esben Søndergaard, Marianne Klose, Mette Hansen, Birgit Sehested Hansen, Marianne Andersen, Ulla Feldt-Rasmussen, Torben Laursen, Michael Højby Rasmussen*, and Jens Sandahl Christiansen

Aarhus University Hospital (E.S., T.L., J.S.C.), DK-8000, Aarhus C, Denmark; Rigshospitalet (M.K., U.F.-R.), Copenhagen University, DK-2100, Copenhagen, Denmark; Odense University Hospital (M.H., M.A.), DK-5000, Odense, Denmark; and Global Development (B.S.H., M.H.R.), Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

* To whom correspondence should be addressed. E-mail: mhr@novonordisk.com.

Background: Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration.

Objectives: Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD).

Subjects and Methods: Thirty-three adult patients with GHD, age 20–65 yr, body mass index 18.5–35.0 kg/m2, and glycated hemoglobin of 8.0% or below. Fourteen days before randomization, subjects discontinued daily rhGH. NNC126-0083 (0.01, 0.02, 0.04, and 0.08 mg/kg) was given sc once weekly for 3 wk (NNC126-0083 for six subjects and placebo for two subjects). Blood samples were collected up to 168 h after the first and up to 240 h after the third dosing. Physical examination, antibodies, and local tolerability were assessed.

Results: NNC126-0083 was well tolerated with no difference in local tolerability compared with placebo and with no signs of lipoatrophy. A more than dose-proportional exposure was observed at the highest NNC126-0083 dose (0.16 mg protein/kg). Steady-state pharmacokinetics seemed achieved after the second dosing. A clear dose-dependent pharmacodynamic response in circulating IGF-I levels was observed [from a predose mean (SD) IGF-I SD score of -3.2 (1.7) to peak plasma concentration of -0.5 (1.3), 1.6 (1.3), 2.1 (0.5), and 4.4 (0.9) in the four dose groups, respectively].

Conclusion: After multiple dosing of NNC126-0083, a sustained pharmacodynamic response was observed. NNC126-0083 has the potential to serve as an efficacious, safe, and well-tolerated once-weekly treatment of adult patients with GHD.

From http://jcem.endojournals.org/cgi/content/abstract/jc.2010-1931v1