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.
Author(s): MacLean DB(1), Matsui H, Suri A, Neuwirth R, Colombel M.
Affiliation(s): Author information:
(1)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.
Publication date & source: 2014, J Clin Endocrinol Metab. , 99(8):E1445-53
BACKGROUND/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).
DESIGN: 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.
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