velusetrag (TD-5108) / Innoviva - LARVOL DELTA

Velusetrag for the Treatment of Chronic Intestinal Pseudo-Obstruction (CIPO). (clinicaltrials.gov) - P2 | N=17 | Completed | Sponsor: Alfasigma S.p.A. | Active, not recruiting ➔ Completed

Trial completion

SAFETY AND EFFICACY OF VELUSETRAG IN CHRONIC INTESTINAL PSEUDO-OBSTRUCTION: A PHASE II PROOF-OF-CONCEPT STUDY (UEGW 2024) - "A VEL prokinetic effect was confirmed by a decreased number of pseudo-obstructive episodes and a normalization of constipation, two main clinical features of CIPO. VEL was also well-tolerated and safe, with no serious drug-related adverse event reported.VelusetragPlaceboNumber of pseudo-obstructive episodes012012During treatment periodn (%)27 (90.00)2 (6.67)1 (3.33)23 (76.67)7 (23.33)0During wash-out periodn (%)30 (100.00)0029 (96.67)1 (3.33)0Bristol scale class at pre-treatmentConstipation (Total: 4) Normal (Total: 3) Diarrhea (Total: 16)Total (Total: 23)Constipation (Total: 3)Normal (Total: 3)Diarrhea (Total: 17)Total (Total: 23)Bristol scale class at end of treatmentConstipation n (%)00003 (100.00)02 (11.76)5 (21.74)Normal n (%)4 (100.00)1 (33.33)1 (6.25)6 (26.09)02 (66.67)2 (11.76)4 (17.39)Diarrhea n (%)02 (66.67)15 (93.75)17 (73.91)01 (33.33)13 (76.47)14 (60.87)Tab. 1: Number of pseudo-obstructive episodes (30 evaluable pairs) and stool consistency (23 evaluable..."

Clinical • P2 data • Cardiovascular • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Rare Diseases

The 5HT4R agonist velusetrag efficacy on neuropathic chronic intestinal pseudo-obstruction in PrP-SCA7-92Q transgenic mice. (PubMed, Front Pharmacol) - "We demonstrated that the PrP-SCA7-92Q Tg line, a model originally developed to mimic spinocerebellar ataxia, is suitable to study CIPO pathology and can be useful in establishing new therapeutic strategies, such as in the case of velusetrag. Our results suggest that velusetrag is a promising compound to treat patients affected by CIPO or intestinal dysmotility disease."

Journal • Preclinical • Ataxia • CNS Disorders • Gastrointestinal Disorder • Movement Disorders • Rare Diseases

SAFETY AND EFFICACY OF VELUSETRAG IN CHRONIC INTESTINAL PSEUDO-OBSTRUCTION: PHASE II PROOF-OF-CONCEPT STUDY (DDW 2024) - "No cardiovascular adverse reactions or serious treatment emergent adverse events were observed in both treatment groups. ConclusionVEL was well-tolerated and resulted in the decrease of number of pseudo-obstructive episodes and of constipation severity two main clinical features of CIPO."

Clinical • P2 data • Cardiovascular • CNS Disorders • Constipation • Gastrointestinal Disorder • Rare Diseases

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

Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson's disease. (PubMed, NPJ Parkinsons Dis) - "Ultimately, Velusetrag restored a well-balanced intestinal microbial composition comparable to non-Tg mice. Based on these promising data, we are confident that Velusetrag is potentially eligible for clinical studies to treat constipation in PD patients."

Journal • Preclinical • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Inflammation • Inflammatory Bowel Disease • Movement Disorders • Parkinson's Disease • GFAP • IL1B • NEFH • TNFA

Velusetrag for the Treatment of Chronic Intestinal Pseudo-Obstruction (CIPO). (clinicaltrials.gov) - P2 | N=17 | Active, not recruiting | Sponsor: Alfasigma S.p.A.

New P2 trial

A randomized, double-blind, placebo-controlled, phase 2b study of the efficacy and safety of velusetrag in subjects with diabetic or idiopathic gastroparesis. (PubMed, Neurogastroenterol Motil) - P2 | "Velusetrag treatment was generally well-tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short-term improvement in gastroparesis symptoms."

Clinical • Journal • P2b data • Gastrointestinal Disorder

Pharmacotherapeutic advances for chronic idiopathic constipation in adults. (PubMed, Expert Opin Pharmacother) - "Among emerging agents, elobixibat, a drug blocking the reabsorption of bile acids, is a promising one, especially in slow transit constipation. Linaclotide, lubiprostone and plecanatide, by a secretacogue action, improve stool consistency and increase colonic transit. Apart from prucalopride, approved in Europe for refractory chronic idiopathic constipation patients, the selective 5-HT4 agonists velusetrag and naronapride are in advanced development. In addition, relamorelin, a ghrelin agonist, seems promising for accelerating colonic transit...On the other hand, the experience with these new agents is still limited, especially for long-term treatment. Another important point is that these new treatments for chronic idiopathic constipation are not available worldwide and their use could be somewhat limited by their still relatively high cost."

Journal • Constipation • Gastroenterology • Gastrointestinal Disorder

Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study. (PubMed, Aliment Pharmacol Ther) - P2 | "Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938)."

Clinical • Journal • P2 data • Gastrointestinal Disorder

Bisacodyl: A review of pharmacology and clinical evidence to guide use in clinical practice in patients with constipation. (PubMed, Neurogastroenterol Motil) - "A recent network meta-analysis concluded that bisacodyl showed similar efficacy to prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, and sodium picosulfate for the primary endpoint of ≥3 complete spontaneous bowel movements (CSBM)/week and an increase of ≥1 CSBM/week over baseline. The aim of the current review was to provide an overview of the historic background, structure, function, and mechanism of action of bisacodyl. Additionally, we discuss the important features and studies for bisacodyl to understand its peculiar characteristics and guide its use in clinical practice, but also stimulate research on open questions."

Clinical • Journal • Review • Constipation • Gastroenterology • Gastrointestinal Disorder

Synergistic effect between 5-HT4 receptor agonist and phosphodiesterase 4-inhibitor in releasing acetylcholine in pig gastric circular muscle in vitro. (PubMed) - Eur J Pharmacol - "The synergistic effect between 5-HT4 receptor agonists and PDE4-inhibitors demonstrates that the intracellular pathway of the 5-HT4 receptors located on cholinergic neurons towards pig gastric circular muscle is controlled by PDE4. Combining a 5-HT4 receptor agonist with a PDE4-inhibitor might thus enhance its gastroprokinetic effect."

Journal • Biosimilar

Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis. (PubMed, Lancet Gastroenterol Hepatol) - "Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown."

Journal • Retrospective data • Review • Constipation • Pain

The Diabetic and Idiopathic Gastroparesis Efficacy, Safety, and Tolerability (DIGEST) Study (clinicaltrials.gov) - P2; N=233; Completed; Sponsor: Theravance Biopharma R & D, Inc.; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Diabetes • Metabolic Disorders

Serotonin 5-HT Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson's Disease. (PubMed, Int J Mol Sci) - "In the present study, we investigated the effects of the serotonin 5-HT receptor (5-HTR) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD."

Journal

Comparative Efficacy of Drugs for the Treatment of Chronic Constipation: Quantitative Information for Medication Guidelines. (PubMed, J Clin Gastroenterol) - "The data provided in this study may be a valuable supplement to the medication guidelines for the treatment of chronic constipation."

Clinical • Journal

New developments in the treatment of gastroparesis and functional dyspepsia. (PubMed, Curr Opin Pharmacol) - "Novel approaches under evaluation in these conditions are the fundus relaxing agents acotiamide and buspirone and the antidepressant mirtazapine in FD. For gastroparesis, recently studied agents include the prokinetic ghrelin agonist relamorelin, the prokinetic serotonergic agents velusetrag and prucalopride, the anti-emetic aprepitant and per-endoscopic pyloric myotomy procedures."

Journal • Review

EFFICACY OF VELUSETRAG TREATMENT IN PATIENTS WITH IDIOPATHIC GASTROPARESIS: SUBGROUP ANALYSIS OF A PHASE 2B STUDY (UEGW 2019) - "VEL treatment for 12 weeks reduced gastroparesis symptoms, with greatest effect for the 5-mg dose; demonstrated gastroprokinetic activity at all doses; and was well tolerated in patients with idiopathic gastroparesis. Future phase 3 studies will further evaluate VEL efficacy in this population."

Clinical • P2b data

"Dr Kuo @MGHMedicine discusses phase 2 study of velusetrag @theravance for treatment of #gastroparesis (#diabetes and idiopathic): effective and well tolerated #ddw19 #motility" (@waikitlo_md)

P2 data

Velusetrag Improves Gastoparesis Both in Symptoms and Gastric Emptying in Patients with Diabetic Or Idiopathic Gastroparesis in a 12-Week Global Phase 2B Study (DDW 2019) - "VEL treatment demonstrated a powerful prokinetic effect, reduced gastroparesis symptoms, and was generally well tolerated in patients with both diabetic and idiopathic gastroparesis, setting the stage for future phase 3 studies evaluating efficacy of VEL in patients with gastroparesis."

Clinical • P2b data