A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis. Academic Article uri icon

Overview

abstract

  • UNLABELLED: 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. TRIAL REGISTRATION: Clinicaltrials.gov NCT01154101.

authors

  • Krueger, James Glenn
  • Suárez-Fariñas, Mayte
  • Cueto, Inna
  • Khacherian, Artemis
  • Matheson, Robert
  • Parish, Lawrence C
  • Leonardi, Craig
  • Shortino, Denise
  • Gupta, Akanksha
  • Haddad, Jonathan
  • Vlasuk, George P
  • Jacobson, Eric W

publication date

  • November 10, 2015

Research

keywords

  • Enzyme Activators
  • Heterocyclic Compounds, 2-Ring
  • Psoriasis
  • Sirtuin 1

Identity

PubMed Central ID

  • PMC4640558

Scopus Document Identifier

  • 84953288368

Digital Object Identifier (DOI)

  • 10.1038/jid.2010.340

PubMed ID

  • 26556603

Additional Document Info

volume

  • 10

issue

  • 11