Randomised Clinical Trial

Safety, Pharmacokinetics and Pharmacodynamics of Trazpiroben (TAK-906), a Dopamine D2/D3 Receptor Antagonist, in Patients With Gastroparesis

Braden Kuo; Cecilia Scimia; George Dukes; Wenwen Zhang; Saurabh Gupta; Chunlin Chen; Emil Chuang; Michael Camilleri

Disclosures

Aliment Pharmacol Ther. 2021;54(3):267-280. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Gastroparesis is a chronic motility disorder of the stomach characterised by delayed gastric emptying in the absence of mechanical obstruction, such as pyloric stenosis.[1,2] Common symptoms reported by patients with gastroparesis include nausea, vomiting, belching and bloating, early satiety, abdominal pain and postprandial fullness. Symptoms are usually chronic and frequently fluctuate in severity.[1,3] The underlying mechanisms that predominantly lead to gastroparesis include neuromuscular dysfunction, involving derangement of extrinsic neural control (particularly vagal function), and dysfunction of the intrinsic nerves and interstitial cells involved in the local control of gastrointestinal muscle function.[1] Gastroparesis may be idiopathic, or associated with diabetes mellitus or neurological disorders, or occur following a viral or bacterial infection, as well as following medical intervention (iatrogenic or postsurgical).[1]

Despite the overall low prevalence of gastroparesis, it has a disease burden similar to that of other important gastrointestinal diseases such as inflammatory bowel disease. The absence of approved drugs for the chronic treatment of gastroparesis together with its disease burden add to a large unmet medical need, particularly for patients with type 1 diabetes melitus.[2,4–8]

Treatment options for patients with gastroparesis are limited. Dietary modifications, such as reduction in high-fat solid meals and replacement with small, frequent, liquid-based meals, or diets consisting of small particles that are digested easily interspersed with snacks to maintain caloric intake, are the first-line treatment options in all patients with gastroparesis regardless of severity.[1,9] If dietary modification proves unsuccessful, prokinetic and antiemetic medications such as metoclopramide (5-HT4 agonist, 5-HT3 and dopamine D2 antagonist) and domperidone (a dopamine D2/D3 receptor antagonist) can be prescribed.[1,10–15] Dopamine D2 and D3 receptors are validated targets in the treatment of gastroparesis, and antagonism of these receptors with metoclopramide and domperidone is effective in reducing symptoms in patients with gastroparesis, albeit with variable levels of effectiveness. However, both drugs are associated with safety concerns and unwanted adverse events (AEs), underlining the need for an efficacious treatment for gastroparesis with a favourable safety profile.[2,16–33]

Trazpiroben (previously referred to as TAK-906 or ATC-1906M) is a D2/D3 receptor antagonist currently under development for the chronic treatment of patients with moderate-to-severe diabetic gastroparesis or idiopathic gastroparesis. Trazpiroben-induced D2/D3 receptor antagonism has been demonstrated in in vitro studies evaluating receptor binding affinity and activity, as well as in in vivo studies of prolactin secretion in rats and apomorphine-induced emesis in dogs.[34]

Based on preclinical pharmacology data, trazpiroben is anticipated to have comparable D2/D3 receptor antagonism to metoclopramide or domperidone but without their central nervous system or cardiovascular safety concerns. The zwitterionic structure of trazpiroben limits brain penetration, thereby decreasing central nervous system effects, whereas the low affinity of trazpiroben for the human ether-á-go-go-related gene potassium channel (IC50 of 15.6 μmol/L for trazpiroben vs 57 nmol/L for domperidone) reduces the potential for cardiac QTc prolongation/arrhythmia.[34–38]

Therefore, trazpiroben may represent an effective treatment for gastroparesis with a potentially favourable safety profile compared with currently available treatments in the same pharmacological class.

Our aim was to conduct a phase 2a pilot study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of trazpiroben in participants with gastroparesis.

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