title: Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis.
abstract: BACKGROUND
  Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC).
  
  
  METHODS
  Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin.
  
  
  RESULTS
  Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score ≤2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures.
  
  
  CONCLUSIONS
  SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted.
authors.affiliation: *Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; †Quantitiative Sciences, GlaxoSmithKline, Bangalore, India; ‡Quantitative Sciences, Clinical Statistics, GlaxoSmithKline, Research Triangle Park, North Carolina; §Computational Biology, GlaxoSmithKline, Research Triangle Park, North Carolina; ‖Sirtris, a GlaxoSmithKline Company, Cambridge, Massachusetts; and ¶Academic Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Sands
authors.forename: Shashidhar
authors.initials: S
authors.lastname: Joshi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haddad
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Freudenberg
authors.forename: Deepa Elizabeth
authors.initials: DE
authors.lastname: Oommen
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffmann
authors.forename: Stewart W
authors.initials: SW
authors.lastname: McCallum
authors.forename: Eric
authors.initials: E
authors.lastname: Jacobson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004311:Double-Blind Method; D020536:Enzyme Activators / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012449:Safety; D056564:Sirtuin 1 / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D020536:Enzyme Activators; D006574:Heterocyclic Compounds, 2-Ring; C584666:SRT2104; C447939:SIRT1 protein, human; D056564:Sirtuin 1