title: A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.
abstract: Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84 but was not consistently in agreement with PASI. Improvement in histology was associated with modulation of IL-17 and TNF-α signaling pathways and keratinocyte differentiation target genes. 27 subjects (69%) across all treatment groups, including placebo, experienced at least one treatment emergent adverse event. The majority of AEs were either mild or moderate. Most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%), and psoriatic arthropathy (8%). Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51–89%). Given the interesting signals of clinical activity, impact on gene expression and the generally favorable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01154101.
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.|Center for Clinical and Translational Science, The Rockefeller University, New York, New York, United States of America.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Inna
authors.initials: I
authors.lastname: Cueto
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Artemis
authors.initials: A
authors.lastname: Khacherian
authors.affiliation: Oregon Medical Research Center, PC, Portland, Oregon, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Matheson
authors.affiliation: Paddington Testing Co, Inc., Philadelphia, Pennsylvania, United States of America.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Parish
authors.affiliation: Central Dermatology, St. Louis, Missouri, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Leonardi
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Denise
authors.initials: D
authors.lastname: Shortino
authors.affiliation: Sirtris, a GlaxoSmithKline Company, Cambridge, Massachusetts, United States of America.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haddad
authors.affiliation: Sirtris, a GlaxoSmithKline Company, Cambridge, Massachusetts, United States of America.
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.affiliation: Sirtris, a GlaxoSmithKline Company, Cambridge, Massachusetts, United States of America.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D020536:Enzyme Activators / Q000627:therapeutic use*; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020536:Enzyme Activators; D006574:Heterocyclic Compounds, 2-Ring; C584666:SRT2104; C447939:SIRT1 protein, human; D056564:Sirtuin 1