Remimazolam can be administered safely under the supervision of endoscopists for outpatient colonoscopy, and it allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. (Clinical trial registration number: NCT02290873.).

Background: Procedural sedation of ASA III/IV patients has increased risk. Remimazolam (an ultra-shortacting benzodiazepine) has proven safe and efficient for outpatient colonoscopy sedation. Methods: A double-blind, randomized, multi-center, parallel group trial was performed, comparing remimazolam to placebo with an additional open-label arm for midazolam in procedural sedation of 79 ASA III/IV patients undergoing colonoscopy. This was the third of 3 Phase III trials for remimazolam in the procedural sedation program. The primary end point was the safety of remimazolam. Results: Of 79 patients randomized at 3 US sites, 77 underwent sedation and colonoscopy (31 received remimazolam, 16 placebo and 30 midazolam). Incidence and frequency of treatment emergent adverse events (TEAEs) were comparable in all three treatment arms, and independent of ASA status. One TEAE leading to discontinuation and one serious TEAE were reported; both in the open label midazolam arm. The efficacy endpoint was achieved for remimazolam, placebo, and midazolam in 87.1%, 0%, and 13.3% of patients ( p < 0.0 0 0 01 for remimazolam versus placebo and versus midazolam, respectively). Conclusions: Remimazolam is safe and efficient in procedural sedation of high risk ASA patients undergoing colonoscopy, showing a safety profile comparable to that in low risk ASA.

Background and Aims Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473—an oral gut-selective pan-JAK inhibitor—from in vitro characterization through a Phase 1b study in patients with UC. Methods TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. Results TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. Conclusion Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686]