Sustained exposure to the investigational Kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two phase 1 studies.
OBJECTIVE
Kisspeptin-54, an endogenous naturally occurring ligand of the G protein-coupled receptor-54, stimulates GnRH-gonadotropin secretion and suppresses metastases in animal models of cancer but is subject to rapid degradation and inactivation. TAK-448 is an investigational oligopeptide analog of the fully active 10-amino acid C terminus of kisspeptin-54. This phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of TAK-448 in healthy subjects and patients with prostate cancer (PC).


METHODS
Healthy subjects aged 50 years or older received TAK-448 sc as a single-bolus or 2-hour infusion (0.01-6 mg/d; part A) and as a 14-day sc administration (0.01-1 mg/d; part B). In a subsequent, open-label, phase 1 study in PC patients aged 40-78 years, TAK-448 was given as a 1-month depot formulation.


RESULTS
Eighty-two healthy subjects received TAK-448; 30 received placebo. Grades 1-2 adverse events were reported in 26% of subjects during TAK-448 treatment. All dosing regimens resulted in dose-proportional exposures. The maximum observed plasma concentration occurred after 0.25-0.5 hours, and median terminal elimination half-life was 1.4-5.3 hours. T increased approximately 1.3- to 2-fold by 48 hours after a single bolus or 2 hour injections, whereas during the 14-day infusion, at doses above 0.1 mg/d, T dropped to below-baseline values by 60 hours and reached a subsequently sustained below-castration level by day 8. In PC patients, T decreased to less than 20 ng/dL in four of five patients dosed with 12 or 24 mg TAK-448 sc-depot injections. The prostate-specific antigen decreased greater than 50% in all patients dosed with 24 mg.


CONCLUSIONS
Continuous TAK-448 infusion was well tolerated by healthy males and resulted in sustained T suppression. Depot injection in patients with PC similarly reduced T and resulted in prostate-specific antigen responses.
Takeda Pharmaceuticals International Co (D.B.M., A.S., R.N.), Cambridge, Massachusetts 02139; Takeda Pharmaceutical Company, Ltd (H.M.), Kanagawa 251-8555, Japan; and Hospital Edouard Herriot (M.C.), 69003 Lyon, France.
David B
DB
MacLean
Hisanori
H
Matsui
Ajit
A
Suri
Rachel
R
Neuwirth
Marc
M
Colombel
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006262:Health; D006801:Humans; D059648:Kisspeptins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D010919:Placebos; D011471:Prostatic Neoplasms / Q000097:blood* / Q000378:metabolism; D013739:Testosterone / Q000097:blood*
D015507:Drugs, Investigational; D059648:Kisspeptins; D010919:Placebos; C577479:metastin (46-54), acetyl-tyrosyl(46)-hydroxypropyl(47)-threonyl(49)-azaglycyl(51)-methylarginyl(53)-tryptophyl(54)-; D013739:Testosterone; D007986:Luteinizing Hormone