David B MacLean1, Hisanori Matsui, Ajit Suri, Rachel Neuwirth, Marc Colombel. 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.
Abstract
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 receivedTAK-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 receivedTAK-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.
RCT Entities:
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.
Authors: Matthew Beymer; Ariel L Negrón; Guiqin Yu; Samuel Wu; Christian Mayer; Richard Z Lin; Ulrich Boehm; Maricedes Acosta-Martínez Journal: Am J Physiol Endocrinol Metab Date: 2014-09-30 Impact factor: 4.310
Authors: Michael N Lehman; Lique M Coolen; Robert A Steiner; Genevieve Neal-Perry; Luhong Wang; Suzanne M Moenter; Aleisha M Moore; Robert L Goodman; Shel Hwa-Yeo; Stephanie L Padilla; Alexander S Kauffman; James Garcia; Martin J Kelly; Jenny Clarkson; Sally Radovick; Andy V Babwah; Silvia Leon; Manuel Tena-Sempere; Alex Comninos; Stephanie Seminara; Waljit S Dhillo; Jon Levine; Ei Terasawa; Ariel Negron; Allan E Herbison Journal: J Neuroendocrinol Date: 2018-04-14 Impact factor: 3.870
Authors: C N Jayasena; A Abbara; S Narayanaswamy; A N Comninos; R Ratnasabapathy; P Bassett; J T Mogford; Z Malik; J Calley; M A Ghatei; S R Bloom; W S Dhillo Journal: Hum Reprod Date: 2015-06-18 Impact factor: 6.918
Authors: C Decourt; V Robert; K Anger; M Galibert; J-B Madinier; X Liu; H Dardente; D Lomet; A F Delmas; A Caraty; A E Herbison; G M Anderson; V Aucagne; M Beltramo Journal: Sci Rep Date: 2016-06-01 Impact factor: 4.379
Authors: Ali Abbara; Pei Chia Eng; Maria Phylactou; Sophie A Clarke; Rachel Richardson; Charlene M Sykes; Chayarndorn Phumsatitpong; Edouard Mills; Manish Modi; Chioma Izzi-Engbeaya; Debbie Papadopoulou; Kate Purugganan; Channa N Jayasena; Lisa Webber; Rehan Salim; Bryn Owen; Paul Bech; Alexander N Comninos; Craig A McArdle; Margaritis Voliotis; Krasimira Tsaneva-Atanasova; Suzanne Moenter; Aylin Hanyaloglu; Waljit S Dhillo Journal: J Clin Invest Date: 2020-12-01 Impact factor: 14.808