A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis

PLoS One. 2015 Nov 10;10(11):e0142081. doi: 10.1371/journal.pone.0142081. eCollection 2015.

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.

Trial registration: Clinicaltrials.gov NCT01154101.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Double-Blind Method
  • Enzyme Activators / therapeutic use*
  • Female
  • Heterocyclic Compounds, 2-Ring / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Psoriasis / drug therapy*
  • Psoriasis / metabolism
  • Sirtuin 1 / metabolism*
  • Treatment Outcome
  • Young Adult

Substances

  • Enzyme Activators
  • Heterocyclic Compounds, 2-Ring
  • SRT2104
  • SIRT1 protein, human
  • Sirtuin 1

Associated data

  • ClinicalTrials.gov/NCT01154101

Grants and funding

The study was funded by Sirtris, a GSK company (NCT01154101). JH, DS, AG, GPV, EWJ are employees of GSK. GSK provided support in the form of salaries for authors (JH, DS, AG, GPV, EWJ) and design, collection of data, study analysis and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. LCP is employed by Paddington Testing Co, Inc.. CL is employed by Central Dermatology. RM is employed by Oregon Medical Research Center. Paddington Testing Co, Inc., Central Dermatology and Oregon Medical Research Center provided support in the form of salaries for authors LCP, CL and RM respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.