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A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis
James G Krueger1, Mayte Suárez-Fariñas1,2, Inna Cueto1
1Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.
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.
Insights
Activation of Sirtuin 1 (SIRT1) with SRT2104 showed histological improvement in psoriasis patients. This suggests SIRT1 activators may be a promising therapeutic approach for inflammatory skin diseases.
Area of Science:
- Dermatology and immunology
- Molecular biology
- Pharmacology
Background:
- Psoriasis is a chronic inflammatory skin condition.
- Sirtuin 1 (SIRT1) activation is an unexplored therapeutic avenue for inflammatory diseases.
Purpose of the Study:
- To evaluate the safety and efficacy of SRT2104, a selective SIRT1 activator, in patients with moderate-to-severe psoriasis.
- To assess the impact of SRT2104 on histological improvement and molecular pathways involved in psoriasis.
Main Methods:
- A randomized, dose-escalating study of 40 patients with moderate-to-severe psoriasis treated with SRT2104 or placebo.
- Skin biopsies were analyzed at baseline and day 84 to assess histological changes.
- Gene expression analysis focused on IL-17 and TNF-α signaling pathways and keratinocyte differentiation.
Main Results:
- 35% of patients receiving SRT2104 achieved significant histological improvement (p<0.0001), associated with modulation of key inflammatory pathways.
- Histological improvement did not consistently correlate with Psoriasis Area and Severity Index (PASI) scores.
- The majority of treatment-emergent adverse events were mild to moderate, with headache and dizziness being most common.
Conclusions:
- SRT2104 demonstrated signals of clinical activity and a generally favorable safety profile in psoriasis patients.
- Further investigation of SIRT1 activators is warranted for the treatment of psoriasis and other inflammatory conditions.
