First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males.
BACKGROUND
This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) 'FSH-CTP' (Org 36286), a long-acting recombinant FSH like substance, consisting of the alpha-subunit of human FSH and a hybrid beta-subunit. The latter is composed of the beta-subunit of human FSH and the C-terminus part (CTP) of the beta-subunit of human chorionic gonadotrophin (HCG).


METHODS
In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 microg FSH-CTP with an interval of approximately 4 weeks between each injection.


RESULTS
No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (+/- SD) C(max) was 0.426 (+/- 0.116) ng/ml, mean t(1/2) and AUC(0-infinity) were 94.7 (+/- 26.2) h and 81.5 (+/- 18.8) ng.h/ml respectively. Compared with recFSH (Puregon), the half life of FSH-CTP was increased 2-3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed.


CONCLUSIONS
The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.
Bouloux
P M
PM
Centre for Neuroendocrinology, University College London, London, UK.
Handelsman
D J
DJ
Jockenhövel
F
F
Nieschlag
E
E
Rabinovici
J
J
Frasa
W L
WL
de Bie
J J
JJ
Voortman
G
G
Itskovitz-Eldor
J
J
D000328:Adult; D000818:Animals; D000906:Antibodies / Q000097:blood; D000941:Antigens / Q000276:immunology; D016466:CHO Cells / Q000276:immunology; D018997:Chorionic Gonadotropin, beta Subunit, Human; D006224:Cricetinae; D004958:Estradiol / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043373:Follicle Stimulating Hormone, Human; D037201:Follicle Stimulating Hormone, beta Subunit; D015292:Glycoprotein Hormones, alpha Subunit; D006207:Half-Life; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy*; D007265:Inhibins / Q000097:blood; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D013739:Testosterone / Q000097:blood
D000906:Antibodies; D000941:Antigens; D018997:Chorionic Gonadotropin, beta Subunit, Human; D043373:Follicle Stimulating Hormone, Human; D037201:Follicle Stimulating Hormone, beta Subunit; D015292:Glycoprotein Hormones, alpha Subunit; D011993:Recombinant Fusion Proteins; C437186:follicle stimulating hormone, human, with HCG C-terminal peptide; D013739:Testosterone; D004958:Estradiol; D007265:Inhibins; D005640:Follicle Stimulating Hormone