12 weeks of treatment with an oral SIRT1 activator, SRT2104, leads to clinical improvement and skin microarray modification in patients with psoriasis

Activation of the NAD+‐dependent deacetylase, SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases.Forty patients were randomized 4:1 to three escalating doses of SRT2104 (250, 500, 1000 mg PO qd) or placebo.Across all SRT2104 groups, 34.6% of patients (9 out of 26; 90% CI 18.0%‐54.2%, p <0.0001) with pre‐ and post‐treatment biopsies achieved good to excellent histological improvement.We conducted microarray analysis in skin biopsies from a subset of subjects which included subjects with good to excellent histological improvement (responders) and those which did not achieve histological improvement (non responders).We observed that SRT2104 treatment modulated gene expression of psoriatic gene phenotype believed to be central to the psoriasis pathogenesis including IFN, TNFalpha, IL‐17 signaling and keratinocyte differentiation. A total of 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.The most common AEs 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. Between‐patient variability in exposure was high (AUC CV: 51‐89%). In summary, SRT2104 demonstrated signs of clinical activity, suggesting that modulation of psoriasis through SIRT1‐mediated pathways may represent a novel approach to the management of this disease. Further study is warranted.