Citations

Abstract Background and Aims To report results from VISIBLE 2, a randomised, double-blind, placebo-controlled, phase 3 trial evaluating a new subcutaneous [SC] vedolizumab formulation as maintenance treatment in adults with moderately to severely active Crohn’s disease [CD]. Methods Following open-label vedolizumab 300 mg intravenous induction therapy at Weeks 0 and 2, Week 6 clinical responders (≥70-point decrease in CD Activity Index [CDAI] score from baseline) were randomised 2:1 to receive double-blind maintenance vedolizumab 108 mg SC or placebo every 2 weeks until Week 50. Assessments at Week 52 included clinical remission [primary endpoint; CDAI ≤150], enhanced clinical response [≥100-point decrease in CDAI from baseline], corticosteroid-free clinical remission among patients using a corticosteroid at baseline, clinical remission in anti-tumour necrosis factor [anti-TNF]-naïve patients, and safety. Results Following vedolizumab intravenous induction, 275 patients were randomised to vedolizumab SC and 135 to placebo maintenance. At Week 52, 48.0% of patients receiving vedolizumab SC versus 34.3% receiving placebo were in clinical remission [p = 0.008]. Enhanced clinical response at Week 52 was achieved by 52.0% versus 44.8% of patients receiving vedolizumab SC versus placebo, respectively [p = 0.167]. At Week 52, 45.3% and 18.2% of patients receiving vedolizumab SC and placebo, respectively, were in corticosteroid-free clinical remission, and 48.6% of anti-TNF-naïve patients receiving vedolizumab SC and 42.9% receiving placebo were in clinical remission. Injection site reaction was the only new safety finding observed for vedolizumab SC [2.9%]. Conclusions Vedolizumab SC is an effective and safe maintenance therapy in patients with CD who responded to two infusions of vedolizumab intravenous induction therapy.

SummaryBackgroundGastroparesis 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.AimsTo 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.MethodsThis 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.ResultsOverall, 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).ConclusionsTrazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.