felcisetrag (TAK-954) / Theravance Biopharma, Takeda - LARVOL DELTA

A randomized phase 2 study of the 5-HT4 receptor agonist felcisetrag for postoperative gastrointestinal dysfunction after bowel surgery. (PubMed, Am J Surg) - P2 | "Felcisetrag was well tolerated with no new safety concerns. However, no clinically meaningful difference in time to recovery of gastrointestinal function versus placebo was observed. Further investigation of the utility of 5-HT4 agonists in complicated, open abdominal surgeries may be warranted."

Clinical • Journal • P2 data • Surgery • Gastrointestinal Disorder

Safety and Efficacy of Highly Selective 5-Hydroxytryptamine Receptor 4 Agonists for Diabetic and Idiopathic Gastroparesis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Cureus) - "In conclusion, this meta-analysis underscores a statistically significant improvement in GET and GCSI scores among patients receiving highly selective 5-HT4 agonists (Velusetrag, Felcisetrag, Prucalopride) for both diabetic and idiopathic gastroparesis. While the overall adverse effect profile is deemed acceptable, larger studies with extended follow-up periods are needed to investigate rare and/or serious adverse events. Moreover, future high-quality RCTs comparing the efficacy and safety of these novel agents with currently available agents are essential to further validate these findings."

Journal • Retrospective data • Review • Gastrointestinal Disorder • Pain

Safety and Efficacy of Highly Selective 5-HT4 Agonist (Velusetrag, Felcisetrag, Prucalopride) for Diabetic/Idiopathic Gastroparesis - Systematic Review and Meta-Analysis of Randomized Controlled Trials (ACG 2023) - "We identified 6 RCTs (570 patients with diabetic (48% patients) or idiopathic (51% patients) gastroparesis, mean age 46 and 45.9 years in intervention and placebo group respectively) On meta-analysis, highly selective 5-HT4 agonists demonstrated significantly better pooled GCSI as compared to placebo (mean difference: 4.283, [1.380, 7.186], p< 0.05). Pooled GE time was also significantly better with 5-HT4 agonists (mean difference: 2.534, [1.695, 3.373], p< 0.05). Pooled rates of total adverse events were greater with 5-HT4 agonists (mean difference: 6.975, [1.042, 46.684], p< 0.05)."

Retrospective data • Review • Gastrointestinal Disorder • Pain

A Study of TAK-954 to Treat Gastrointestinal Dysfunction in Adults After Surgery (clinicaltrials.gov) - P2 | N=210 | Completed | Sponsor: Takeda | Recruiting ➔ Completed

Trial completion • Gastrointestinal Disorder

A Study of TAK-954 to Treat Gastrointestinal Dysfunction in Adults After Surgery (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: Takeda | Trial primary completion date: Feb 2022 ➔ Jun 2022

Trial primary completion date • Gastrointestinal Disorder

The Effect of Hepatic Impairment on the Pharmacokinetics of Intravenously Administered Felcisetrag (TAK-954). (PubMed, J Clin Pharmacol) - "Infusions were well tolerated with no discontinuations, severe adverse events, or deaths during the study. Overall, the effect of hepatic impairment on exposure to felcisetrag was minimal, suggesting that dose adjustment may be unnecessary in patients with hepatic impairment."

Journal • PK/PD data • Gastrointestinal Disorder • Hepatology

Clinical and Nonclinical Disposition and In Vitro Drug-Drug Interaction Potential of Felcisetrag, a Highly Selective and Potent 5-HT Receptor Agonist. (PubMed, Eur J Drug Metab Pharmacokinet) - "Felcisetrag is primarily cleared in humans through renal excretion. Although the metabolism of felcisetrag is primarily through CYP3A, the potential for clinically relevant DDI as a victim is significantly reduced as metabolism plays a minor role in the overall clearance."

Journal • Preclinical • Gastrointestinal Disorder

Evaluation of the Pharmacokinetics of Felcisetrag (TAK-954), a 5-HT Receptor Agonist, in the Presence and Absence of Itraconazole, a Potent CYP3A4 Inhibitor. (PubMed, Clin Pharmacol Drug Dev) - P1 | "Peak exposure was similar between regimens (geometric mean ratio, 1.06; 90% confidence interval, 0.96-1.18), and both treatments were well tolerated. These data suggest limited CYP3A4-mediated drug-drug interaction inhibition for felcisetrag."

Journal • PK/PD data • Gastrointestinal Disorder

A Study of TAK-954 to Treat Gastrointestinal Dysfunction in Adults After Surgery (clinicaltrials.gov) - P2; N=180; Recruiting; Sponsor: Takeda; N=375 ➔ 180

Clinical • Enrollment change • Gastrointestinal Disorder

Editorial: felcisetrag-forward movement as a novel prokinetic for gastroparesis. (PubMed, Aliment Pharmacol Ther) - No abstract available

Journal • Gastrointestinal Disorder

Randomised study: effects of the 5-HT receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis. (PubMed, Aliment Pharmacol Ther) - P2 | "I.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short-term treatment of gastric and intestinal motility disorders. ClinicalTrials.gov #NCT03281577."

Clinical • Journal • Gastrointestinal Disorder

A Study to Evaluate the Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and Treatment of Postoperative Gastrointestinal Dysfunction in Participants Undergoing Large- and Small-Bowel Resection (clinicaltrials.gov) - P2; N=375; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Trial completion date: May 2021 ➔ May 2022; Trial primary completion date: Feb 2021 ➔ Feb 2022

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

Postoperative Ileus and Postoperative Gastrointestinal Tract Dysfunction: Pathogenic Mechanisms and Novel Treatment Strategies Beyond Colorectal Enhanced Recovery After Surgery Protocols. (PubMed, Front Pharmacol) - "These include 5HTR agonists (Prucalopride and TAK 954), vagus nerve stimulation of the ENS-macrophage nAChR cholinergic pathway, acupuncture, herbal medications, peripheral acting opioid antagonists (Alvimopen, Methlnaltexone, Naldemedine), anti-bloating/flatulence drugs (Simethiocone), a ghreline prokinetic agonist (Ulimovelin), drinking coffee, and nicotine chewing gum. A better understanding of the pathogenic mechanisms for short and long-term outcomes is necessary before we can develop better prophylactic and treatment strategies."

Clinical • Journal • Review • Constipation • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Mood Disorders • Pain

A Study to Evaluate the Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and Treatment of Postoperative Gastrointestinal Dysfunction in Participants Undergoing Large- and Small-Bowel Resection (clinicaltrials.gov) - P2; N=375; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open

A Study to Evaluate the Mass Balance, Pharmacokinetics (PK), Metabolism and Excretion of TAK-954 Containing Microtracer ([14C]-TAK-954) in Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Completed

Trial completion • Biosimilar

A DOSE-RANGING, RANDOMIZED, PARALLEL, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFECT OF TAK-954 ON GASTROINTESTINAL AND COLONIC TRANSIT IN PATIENTS WITH DIABETIC OR IDIOPATHIC GASTROPARESIS (DDW 2020) - "TAK-954, an IV administered highly selective 5-HT4 receptor agonist, significantly accelerated gastric emptying and colonic transit versus placebo in gastroparesis patients with previously confirmed delayed gastric emptying. TAK-954 was well tolerated. These results support further evaluation of TAK-954 for the treatment of gastric and intestinal motility disorders."

Clinical

A Study to Evaluate the Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and Treatment of Postoperative Gastrointestinal Dysfunction in Participants Undergoing Large- and Small-Bowel Resection (clinicaltrials.gov) - P2; N=375; Active, not recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Beyond organic solvents: Synthesis of a 5-HT4 receptor agonist in water (ACS-Sp 2020) - "We redeveloped the six-step TAK-954 manufacturing sequence to be run entirely in water, replacing five separate organic solvents used in the enabling route, while implementing five direct isolations from aqueous media. Key transformations carried out in aqueous media include a benzimidazole cyclization, amidation, reductive amination, and a selective oxidation of an aliphatic alcohol."

Blinded, Double-Dummy, Parallel-Group, Phase 2a Randomized Clinical Trial to Evaluate the Efficacy and Safety of a Highly Selective 5-Hydroxytryptamine Type 4 Receptor Agonist in Critically Ill Patients With Enteral Feeding Intolerance. (PubMed, JPEN J Parenter Enteral Nutr) - P1/2; "A single dose of 0.5 mg intravenous TAK-954 appears to have at least similar efficacy in accelerating gastric emptying to multiple doses of 10 mg metoclopramide and was not associated with increased AEs."

Clinical • Journal • P2a data

A Study to Evaluate the Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and Treatment of Postoperative Gastrointestinal Dysfunction in Participants Undergoing Large- and Small-Bowel Resection (clinicaltrials.gov) - P2; N=375; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Trial completion date: Aug 2020 ➔ May 2021; Trial primary completion date: May 2020 ➔ Feb 2021

Clinical • Trial completion date • Trial primary completion date

A Study to Evaluate the Effect of Renal Impairment and Dialysis Treatment on the Pharmacokinetics (PK) of a Single Intravenous (IV) TAK-954 (clinicaltrials.gov) - P1; N=31; Completed; Sponsor: Takeda; Recruiting ➔ Completed

Clinical • Trial completion

Effect of TAK-954 on Gastrointestinal and Colonic Transit in Diabetic or Idiopathic Gastroparesis Participants (clinicaltrials.gov) - P2; N=36; Completed; Sponsor: Takeda; Active, not recruiting ➔ Completed

Trial completion

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of TAK-954 in Healthy Adult Participants (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Completed

Clinical • Trial completion

Effect of TAK-954 on Gastrointestinal and Colonic Transit in Diabetic or Idiopathic Gastroparesis Participants (clinicaltrials.gov) - P2; N=41; Active, not recruiting; Sponsor: Takeda; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of TAK-954 in Healthy Adult Participants (clinicaltrials.gov) - P1; N=6; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open