Theravance Biopharma Announces Positive Top-Line Results from Phase 2b Study of Velusetrag (TD-5108) in Patients with Gastroparesis
The study was conducted in 232 patients with either diabetic or idiopathic gastroparesis who received either velusetrag (5, 15 or 30 mg) or placebo, administered orally as a once daily dose. After four weeks of dosing, when the primary assessments were made, patients in the 5 mg velusetrag treatment arm demonstrated statistically significant improvements in symptom scores compared to placebo in two separate patient reported outcome (PRO) tools: the Gastroparesis Cardinal Symptom Index (GCSI) (nominal p = 0.0327) and the Gastroparesis Rating Scale (GRS) (nominal p = 0.0159). Improvements in GRS total score were maintained at 12 weeks of treatment (nominal p = 0.0427). Compared to placebo, patients in the 5 mg treatment arm also demonstrated statistically significant improvements in gastric emptying time (nominal p < 0.001) and in individual disease-specific symptom scores including post-prandial fullness/early satiety, bloating and upper abdominal pain (all nominal p < 0.05). Importantly, the symptom improvements seen with 5 mg of velusetrag were observed in both diabetic and idiopathic gastroparesis patients.
The primary endpoint analysis included a pre-specified analysis of each dose against placebo to report nominal p-values. The analysis also included multiplicity adjustments of p-values to account for three dose comparisons to placebo. Patients in the 15 and 30 mg velusetrag study arms did not demonstrate nominally statistically significant improvements in gastroparesis symptoms versus placebo, possibly due to an increased frequency in gastrointestinal side effects at these doses that may have been caused by rapid emptying of the stomach. The lack of dose response resulted in a lack of statistical significance across the three doses when adjusted for multiplicity. As a result, the statistical comparisons for the 5 mg dose are not adjusted for multiple comparisons, and all are quoted as nominal. Of note, the 15 mg and 30 mg doses remained highly statistically significant compared to placebo in gastric emptying time (nominal p < 0.001), as measured by scintigraphy.
"We are very encouraged by the results of this study as they demonstrate not only consistent evidence of improved gastric emptying but also meaningful improvement in gastroparesis symptoms following treatment with 5 mg of velusetrag. The findings from this study demonstrate that a 5 mg dose was sufficient to ameliorate the symptoms of gastroparesis. We believe that these findings provide clear evidence of the potential benefit of velusetrag in patients with gastroparesis, a debilitating disease in significant need of therapeutic innovation," said
Velusetrag was shown to be generally well-tolerated, with rates of AEs and SAEs comparable between the 5 mg dose and placebo. The most commonly reported AEs across all groups (active treatment and placebo) were diarrhea, nausea and headache. Consistent with velusetrag's mechanism of action, patients receiving treatment demonstrated higher rates of diarrhea and nausea/vomiting than those receiving placebo, and these rates were numerically highest in the 15 and 30 mg arms of the study. Diabetic subjects treated with velusetrag generally maintained adequate glucose control throughout the study, and there were no episodes of hyperglycemia reported. There was no difference in the number of cardiac adverse events, with four events reported in placebo subjects and four events reported in all velusetrag treated subjects. There were no deaths reported in the study.
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About the Phase 2b Study
The study was a multicenter, double-blind, placebo-controlled, parallel group Phase 2b characterizing the impact on symptoms and gastric emptying of multiple doses of velusetrag administered once daily over 12 weeks of therapy. The study enrolled 232 subjects with diabetic or idiopathic gastroparesis with documented gastric delay, by either gastric emptying scintigraphy (GES) or gastric emptying breath test (GEBT), and documented symptoms prior to and throughout the baseline period. Two daily patient reported outcomes (PRO) tools were used to characterize symptom change: the Gastroparesis Cardinal Symptom Index (GCSI), which assessed the severity of three cardinal symptom domains; and the Gastroparesis Rating Scale (GRS), which assessed severity, frequency and timing of seven symptom domains, including the three symptom domains in the GCSI. GRS is a proprietary PRO tool being developed by the Company with academic collaboration. The primary endpoint in the study was mean GCSI score at the end of week 4 of the treatment period.
Gastroparesis is a disorder characterized by delayed gastric emptying and symptoms of gastric retention in the absence of mechanical obstruction. In
Velusetrag is an oral, once-daily investigational medicine discovered internally and developed for gastrointestinal motility disorders. The compound has been granted Fast Track designation by the U.
Velusetrag is a highly selective agonist with high intrinsic activity at the human 5-HT4 receptor. 5-hydroxytryptamine receptor 4 (5-HT4) agonists are established as gastrointestinal (GI) prokinetic agents for the treatment of GI tract dysfunction, such as chronic constipation. Velusetrag (or TD-5108) is a 5-HT4 receptor agonist that demonstrates high in vitro intrinsic activity and selectivity for the 5-HT4 receptor and has no significant affinity for all other receptor types, ion channels, or enzymes tested.
A previous Phase 2 trial of velusetrag showed that all three doses of velusetrag (5, 15 and 30 mg) reduced gastric emptying time (GE t1/2) compared to placebo in patients with either diabetic or idiopathic gastroparesis. The completed Phase 2 trial was the first study to evaluate gastric emptying, a diagnostic criterion for gastroparesis, in a patient population including both diabetic and idiopathic gastroparesis patients, as opposed to diabetic gastroparesis patients only. In addition, velusetrag has completed a 400-patient Phase 2 proof-of-concept study in chronic idiopathic constipation, demonstrating statistically significant prokinetic activity at all three doses tested in that study.
Velusetrag is being developed by
Our pipeline of internally discovered product candidates includes potential best-in-class medicines to address the unmet needs of patients being treated for serious conditions primarily in the acute care setting. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S.,
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