Activation of sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for the treatment of inflammatory diseases. In this study, 40 patients with moderate to severe psoriasis (4:1) were randomised to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo.
In all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and at day 84, but were not consistently in agreement with PASI. The improvement in histology was associated with modulation of IL-17 and TNF-α signalling pathways and target genes of keratinocyte differentiation. 27 subjects (69%) in all treatment groups, including placebo, experienced at least one treatment-emergent adverse event.
Most adverse events were mild or moderate. The most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%) and psoriatic arthropathy (8%). Mean drug exposure increased in a dose-dependent manner for increasing doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51-89%). Given the interesting signs of clinical activity, the impact on gene expression and the generally favourable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted.
Editorial Staff La Fonte della Giovinezza