TAK-906 / Takeda - LARVOL DELTA

A Tale of Tailocins: Exploring the Role of a Hypervariable Coding Region in Tailocin Antimicrobial Activity and Immunity (ASM Microbe 2024) - "To test these hypotheses, IVS deletion mutants were created in two X. nematophila strains (ATCC19061 and F1)...These findings suggest that hypervariable regions within tailocin-encoding loci contribute to both protection from and activity of tailocins. We will discuss our ongoing research to unravel the molecular mechanisms underlying these observations."

Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK-906) for idiopathic or diabetic gastroparesis. (PubMed, Neurogastroenterol Motil) - P2b | "There was no clinically meaningful difference in efficacy between trazpiroben and placebo in treating gastroparesis, based on the primary endpoint analysis. Trazpiroben was well tolerated with no new safety concerns identified, strengthening evidence supporting its favorable safety profile. NCT number: NCT03544229."

Clinical • Journal • P2b data • Gastroenterology • Gastrointestinal Disorder

The Pharmacokinetics of Oral Trazpiroben (TAK-906) After Organic Anion Transporting Polypeptide 1B1/1B3 Inhibition: A Phase 1, Randomized Study. (PubMed, Clin Transl Sci) - P1 | "Trazpiroben is a dopamine D /D receptor antagonist under development for the treatment of gastroparesis. In this study, trazpiroben was confirmed as a substrate of OATP1B1/1B3, and therefore co-administration of trazpiroben with moderate to strong inhibitors of OATP1B1/1B3 is not recommended. This is also the first assessment of the utility of CPI and CPIII as endogenous biomarkers of OATP1B1/1B3 inhibition after a single intravenous dose of rifampin."

Journal • P1 data • PK/PD data • Gastrointestinal Disorder

Bioavailability and Food Effect Study of Two Formulations of TAK-906 (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Takeda | N=24 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal

Evaluation of the pharmacokinetics of trazpiroben (TAK-906) in the presence and absence of the proton pump inhibitor esomeprazole. (PubMed, Clin Transl Sci) - P1 | "Trazpiroben was well-tolerated in healthy adults following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported. The lack of evidence of any clinically meaningful drug-drug interaction supports the co-administration of esomeprazole with trazpiroben."

Journal • PK/PD data • Gastrointestinal Disorder

Non-Clinical Safety Pharmacology Evaluations of Trazpiroben (TAK-906), a Novel Dopamine D/D Selective Receptor Antagonist for the Management of Gastroparesis. (PubMed, J Exp Pharmacol) - "No trazpiroben-related qualitative electrocardiogram abnormalities were observed. Our results suggest that trazpiroben has limited central nervous system effects and a favorable cardiac safety profile."

Journal • Cardiovascular • Gastrointestinal Disorder

Evaluating the Safety, Tolerability, and Disposition of Trazpiroben, a D /D Receptor Antagonist: Phase I Single- and Multiple-Ascending Dose Studies in Healthy Japanese Participants. (PubMed, Clin Pharmacol Drug Dev) - P2b | "Trazpiroben (TAK-906) is a peripherally selective dopamine D /D receptor antagonist being developed to treat chronic gastroparesis...Results reflected those from healthy US participants, indicating a lack of differences between these ethnic populations in trazpiroben disposition and safety profile. Trazpiroben may represent a promising therapy for chronic gastroparesis across different populations, with further evaluation ongoing in a phase IIb study (NCT03544229)."

Clinical • Journal • P1 data • Gastrointestinal Disorder

Bioavailability and Food Effect Study of Two Formulations of TAK-906 (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Takeda; Trial completion date: Aug 2021 ➔ Mar 2022; Trial primary completion date: Aug 2021 ➔ Feb 2022

Clinical • Trial completion date • Trial primary completion date

Evaluation of the Pharmacokinetics of Trazpiroben (TAK-906), a Peripherally Selective D/D Dopamine Receptor Antagonist, in the Presence and Absence of Itraconazole, a Potent CYP 3A4 Inhibitor. (PubMed, Clin Pharmacol) - P1 | "Treatment options for gastroparesis, such as metoclopramide and domperidone, are limited because of safety concerns, which may be exacerbated in the presence of inhibitors of drug metabolism. There were no clinically relevant abnormalities in any safety parameters. These results indicate that TAK‑906 is relatively insensitive to inhibition of cytochrome P450 3A4, and cardiovascular safety concerns associated with domperidone are unlikely to be elicited by trazpiroben under similar conditions."

Clinical • PK/PD data • Cardiovascular • Gastrointestinal Disorder

A Study to Evaluate the Efficacy and Safety of TAK-906 in Adult Participants With Symptomatic Idiopathic or Diabetic Gastroparesis (clinicaltrials.gov) - P2b; N=242; Completed; Sponsor: Millennium Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gastrointestinal Disorder

Preclinical Evaluation of the Effects of Trazpiroben (TAK-906), a Novel, Potent Dopamine D/D Receptor Antagonist for the Management of Gastroparesis. (PubMed, J Pharmacol Exp Ther) - "Current therapies for gastroparesis, metoclopramide and domperidone, carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Pre-clinical studies have demonstrated low brain penetration and weak affinity for the hERG channel, indicating that trazpiroben is not expected to be associated with central nervous system or cardiovascular safety issues. With these pharmacological properties, trazpiroben may represent a viable new treatment option for gastroparesis due to a potentially improved safety profile relative to existing therapies."

Journal • Preclinical • Atrial Fibrillation • Cardiovascular • Gastroenterology • Gastrointestinal Disorder

Randomised clinical trial: safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK-906), a dopamine D /D receptor antagonist, in patients with gastroparesis. (PubMed, Aliment Pharmacol Ther) - P2 | "Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941."

Clinical • Journal • PK/PD data • Cardiovascular • Gastroenterology • Gastrointestinal Disorder

Bioavailability and Food Effect Study of Two Formulations of TAK-906 (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Takeda; Trial completion date: May 2021 ➔ Aug 2021; Trial primary completion date: May 2021 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date

Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D/D receptor antagonist for gastroparesis, towards cytochrome P450s and transporters. (PubMed, Xenobiotica) - "Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. It is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/1B3, but is not an inhibitor of transporters listed in the DDI guidelines at a clinically relevant dose. This is consistent with findings from CYP3A and P-gp-based clinical assessment showing no substantial change (≤2-fold) in trazpiroben exposure when co-administered with itraconazole.Collectively, trazpiroben has low potential of enzyme-mediated DDIs and is unlikely to act as a perpetrator of transporter-mediated DDIs but there may be a potential to act as a victim of OATP1B1/1B3 DDI that will be evaluated clinically."

Journal • Gastrointestinal Disorder • CYP2C8 • CYP3A4

Bioavailability and Food Effect Study of Two Formulations of TAK-906 (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Takeda; Not yet recruiting ➔ Recruiting

Enrollment open

Bioavailability and Food Effect Study of Two Formulations of TAK-906 (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Takeda

New P1 trial

A Study to Evaluate the Efficacy and Safety of TAK-906 in Adult Participants With Symptomatic Idiopathic or Diabetic Gastroparesis (clinicaltrials.gov) - P2b; N=205; Active, not recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Disorder

Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK-906), a Novel Selective D /D Receptor Antagonist: A Phase 1 Randomized, Placebo-Controlled Single- and Multiple-Dose Escalation Study in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "Therapeutically relevant single and multiple doses of trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of trazpiroben for the treatment of gastroparesis."

Clinical • Journal • P1 data • PK/PD data • Cardiovascular • CNS Disorders • Gastrointestinal Disorder

A Study to Assess Absolute Bioavailability (ABA) of TAK-906 and to Characterize Mass Balance, Pharmacokinetics (PK), Metabolism, and Excretion of [14C]-TAK-906 in Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Completed

Clinical • Trial completion

A Study to Evaluate the Efficacy and Safety of TAK-906 in Adult Participants With Symptomatic Idiopathic or Diabetic Gastroparesis (clinicaltrials.gov) - P2b; N=205; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Active, not recruiting ➔ Recruiting; Trial completion date: Sep 2020 ➔ Jul 2021; Trial primary completion date: Aug 2020 ➔ Jun 2021

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Gastrointestinal Disorder

A Study to Assess Absolute Bioavailability (ABA) of TAK-906 and to Characterize Mass Balance, Pharmacokinetics (PK), Metabolism, and Excretion of [14C]-TAK-906 in Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study to Assess Absolute Bioavailability (ABA) of TAK-906 and to Characterize Mass Balance, Pharmacokinetics (PK), Metabolism, and Excretion of [14C]-TAK-906 in Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Not yet recruiting; Sponsor: Millennium Pharmaceuticals, Inc.

Clinical • New P1 trial

A Study to Evaluate the Efficacy and Safety of TAK-906 in Adult Participants With Symptomatic Idiopathic or Diabetic Gastroparesis (clinicaltrials.gov) - P2b; N=280; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Diabetes • Metabolic Disorders

TAK-906, A NOVEL DOPAMINE D2/D3 RECEPTOR ANTAGONIST FOR THE TREATMENT OF GASTROPARESIS (DDW 2020) - "Background Metoclopramide and domperidone are the only agents available, albeit with substantial restrictions, for the symptomatic treatment of gastroparesis...TAK-906 up to 30 mg/kg orally did not affect motor coordination, while the centrally-acting D2 antagonist chlorpromazine significantly reduced running time (Figure 1). The lack of effect on rotarod performance is indicative of poor central nervous system penetration. Conclusion TAK-906 has a preclinical profile that provides the potential clinical benefits of the presently available agents without their serious adverse events."

Atrial Fibrillation • Cardiovascular

SAFETY PHARMACOLOGY EVALUATIONS OF TAK-906, A NOVEL DOPAMINE D2/D3 SELECTIVE RECEPTOR ANTAGONIST FOR THE MANAGEMENT OF GASTROPARESIS (DDW 2020) - "Background Current gastroparesis therapies are limited, mainly owing to the risk of extrapyramidal symptoms with centrally penetrating metoclopramide, and cardiac safety concerns with the primarily peripherally acting domperidone. Absence of TAK-906 related effects on FOB results and the minimal effects on locomotion suggest limited CNS penetration and reduced risk of extrapyramidal symptoms, even at doses 300-fold greater than those required for efficacy. The lack of a TAK-906-related effect on QRS duration, QT interval corrected for heart rate and ECG abnormalities shows a favorable cardiac safety profile."

Clinical