Randomised clinical trial: safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK‐906), a dopamine D₂/D₃ receptor antagonist, in patients with gastroparesis

Abstract

Summary 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.

Evaluating the Safety, Tolerability, and Disposition of Trazpiroben, a D2/D3 Receptor Antagonist: Phase I Single‐ and Multiple‐Ascending Dose Studies in Healthy Japanese Participants

“…Following single and multiple doses of trazpiroben in the current analysis, no QTc prolongation–associated or neurologic TEAEs were observed, and no clinically significant differences in clinical laboratory tests, vital signs, or ECG monitoring were observed in participants receiving trazpiroben vs placebo. This is further supported by results from the US phase IIa study in which twice‐daily dosing of trazpiroben over 9 consecutive days was not associated with any clinically significant safety or tolerability issues 24 . These findings suggest trazpiroben is a promising option for the chronic treatment of gastroparesis, and may offer an additional choice of therapy for patients and physicians in a currently limited field.…”

“…In the first‐in‐human, single‐ and multiple‐ascending dose phase I study conducted in 56 healthy participants in the United States (AT‐01C study; NCT03268941), 23 single and multiple doses of trazpiroben were well tolerated in healthy, predominantly White or Black men and women, and no clinically meaningful adverse effects, such as cardiovascular effects, were observed across the whole dose range (5‐300 mg). Furthermore, a recent phase IIa study (NCT03268941) involving 51 patients with idiopathic or diabetic gastroparesis recruited from multiple US clinical research centers evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of trazpiroben and did not identify any safety signals 24 . Following prior analysis in US participants, further information is required on the safety, PK, and PD profile of trazpiroben in wider ethnic populations.…”

The pharmacokinetics of oral trazpiroben (TAK‐906) after organic anion transporting polypeptide 1B1/1B3 inhibition: A phase I, randomized study

“…Additional studies have also been completed or are underway to further elucidate the safety profile of trazpiroben. A recent phase II study (NCT03268941) involving 51 patients with idiopathic or diabetic gastroparesis evaluated the safety, PKs, and pharmacodynamics of trazpiroben and did not identify any Nervous system disorders 3 ( 25 T A B L E 3 Overview of TEAEs reported by participants safety signals, 49 whereas an ongoing phase IIb clinical trial (NCT03544229) is investigating the efficacy and safety of in adult patients with symptomatic idiopathic or diabetic gastroparesis. Notably, these studies imposed restrictions on the use of certain medications (e.g., those that affect gastric motility or gastric pH and antiemetics) throughout the study period and therefore the potential for OATP-mediated DDIs may have been limited.…”

Non-Clinical Safety Pharmacology Evaluations of Trazpiroben (TAK-906), a Novel Dopamine D2/D3 Selective Receptor Antagonist for the Management of Gastroparesis

“…In humans, maximal D 2 receptor engagement was observed to occur at a 10 mg dose of trazpiroben during the first-in-human Phase I trial, with no CNS effects noted at any dose of trazpiroben administered up to the maximum of 300 mg. 38,57 Overall, trazpiroben has displayed a favorable safety profile in both the first-in-human Phase I trial 38 and Phase IIa clinical trial. 58 When considering the pulmonary and toxicokinetic assessments of trazpiroben, further evidence of a favorable safety profile for the compound was observed. Administration at doses ≤ 1000 mg/kg/day was not associated with any biologically relevant changes in tidal volume, respiration rate, or minute volume.…”

“…61 Our results indicate that trazpiroben offers a viable alternative with a favorable cardiac safety profile and minimal potential for prolongation of the QT interval, supporting clinical evidence from the associated Phase I 38 and Phase IIa trials. 58…”