TY - JOUR
T1 - Randomised clinical trial
T2 - safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK-906), a dopamine D2/D3 receptor antagonist, in patients with gastroparesis
AU - Kuo, Braden
AU - Scimia, Cecilia
AU - Dukes, George
AU - Zhang, Wenwen
AU - Gupta, Saurabh
AU - Chen, Chunlin
AU - Chuang, Emil
AU - Camilleri, Michael
N1 - Funding Information:
: BK and MC serve as advisors to Takeda Pharmaceuticals and conduct research supported by Takeda Pharmaceuticals. They received no personal financial remuneration. CS was a Takeda employee at the time the study was performed and was involved in the trial oversight, interpretation of the data and writing the clinical study report; she is currently a Medical Director at Rhythm Pharmaceuticals Inc, Boston, MA, USA. GD was a contracted employee of Takeda Pharmaceuticals InternationalCo. at the time the study was performed. WZ is an employee of Takeda Pharmaceuticals, the study sponsor that provided funding for this study. SG was a Takeda employee at the time the study was performed and was the biomarker lead for the programme. CC was a Takeda employee at the time the study was performed; he is currently at Bayer Pharmaceuticals, Boston, MA, USA. EC was a Takeda employee at the time the study was performed; he is currently Vice President at Precision Medicine, San Diego, CA, USA. The study sponsor was involved in the design of the study, interpretation of the data, and preparation, review and approval of the manuscript. Declaration of personal interests
Funding Information:
Steve Banner, PhD, of Oxford PharmaGenesis, Oxford, UK, provided medical writing assistance, which was supported by Takeda Pharmaceutical Company, Ltd.
Publisher Copyright:
© 2021 John Wiley & Sons Ltd
PY - 2021/8
Y1 - 2021/8
N2 - Background: Gastroparesis is a chronic gastric motility disorder. Dopamine D2/D3 receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK-906), a dopamine D2/D3 receptor antagonist, is under development for chronic treatment of moderate-to-severe gastroparesis. Nonclinical data suggest trazpiroben will have D2/D3 receptor antagonism comparable with metoclopramide or domperidone. Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice-daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis. Methods: This phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, respectively. Results: Overall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t1/2z 4-5 hours), and D2/D3 receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume-to-fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs −26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182). Conclusions: Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.
AB - Background: Gastroparesis is a chronic gastric motility disorder. Dopamine D2/D3 receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK-906), a dopamine D2/D3 receptor antagonist, is under development for chronic treatment of moderate-to-severe gastroparesis. Nonclinical data suggest trazpiroben will have D2/D3 receptor antagonism comparable with metoclopramide or domperidone. Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice-daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis. Methods: This phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, respectively. Results: Overall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t1/2z 4-5 hours), and D2/D3 receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume-to-fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs −26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182). Conclusions: Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.
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U2 - 10.1111/apt.16451
DO - 10.1111/apt.16451
M3 - Article
C2 - 34148244
AN - SCOPUS:85108576624
SN - 0269-2813
VL - 54
SP - 267
EP - 280
JO - Alimentary Pharmacology and Therapeutics
JF - Alimentary Pharmacology and Therapeutics
IS - 3
ER -