Project description:Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. The goal of this study was to evaluate the clinical activity and tolerability of multiple doses of SRT2104, a selective activator of SIRT1, in patients with moderate to severe psoriasis after day 84 of treatment. Forty patients were randomized 4:1 to three escalating doses of SRT2104 (250, 500, 1000 mg/d SRT2104 or placebo). Across all SRT2104 groups, 34.6% of patients (9 out of 26; 90% CI 18.0%-54.2%, p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84. To evaluate the changes in expression profile with treatment and to identify pathways involved in histological improvement, a subset of 22 Pre and Post treatment biopsies from 11 patients (4 Placebo, 7 Active Treatment) were hybridized to hgu133plus2 chips. Improvement in histology was associated with modulation of IL-17 and TNF-_ signaling pathways and keratinocyte differentiation target genes. Various studies suggest a crucial role of TNF_ and IL-17 in psoriasis pathogenesis and IL-17/TNF_ synergism induces a strong induction of differentially expressed genes in psoriasis, thus advocating a crucial role of IL-17/TNF_ combination in the molecular basis of disease (Chiricozzi et al., 2010). In the current study, broad scale gene expression profiling revealed that SRT2104 significantly reduced known IL-17 and TNF_ responsive genes including SERPINB4, S100A12, SERPINB3, kynu etc. even though the sample size for this analysis was small. One of the most highly modulated genes by SRT2104 included Kynu, a gene that regulates tryptophan metabolism, known to confer antibacterial effector functions (Daubener and MacKenzie, 1999). Interestingly kynu is part of the etanercept residual genomic profile that is not modulated by etanercept therapy even though clinical efficacy is achieved. Possibly, SRT2104 may be modulating the lipid barrier of the epidermis of psoriatic skin via modulation of keratinocyte diferentiation genes, which would be consistent with the observed improvement in skin histology. These results indicate a combinatorial effect of SRT2104 on TNF_, and IL-17 inflammatory signaling pathways and keratinocyte differentiation that could be a contributing factor towards improvement in clinical scores by the SIRT1 activator, SRT2104.

Project description:Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. The goal of this study was to evaluate the clinical activity and tolerability of multiple doses of SRT2104, a selective activator of SIRT1, in patients with moderate to severe psoriasis after day 84 of treatment. Forty patients were randomized 4:1 to three escalating doses of SRT2104 (250, 500, 1000 mg/d SRT2104 or placebo). Across all SRT2104 groups, 34.6% of patients (9 out of 26; 90% CI 18.0%-54.2%, p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84. To evaluate the changes in expression profile with treatment and to identify pathways involved in histological improvement, a subset of 22 Pre and Post treatment biopsies from 11 patients (4 Placebo, 7 Active Treatment) were hybridized to hgu133plus2 chips. Improvement in histology was associated with modulation of IL-17 and TNF-_ signaling pathways and keratinocyte differentiation target genes. Various studies suggest a crucial role of TNF_ and IL-17 in psoriasis pathogenesis and IL-17/TNF_ synergism induces a strong induction of differentially expressed genes in psoriasis, thus advocating a crucial role of IL-17/TNF_ combination in the molecular basis of disease (Chiricozzi et al., 2010). In the current study, broad scale gene expression profiling revealed that SRT2104 significantly reduced known IL-17 and TNF_ responsive genes including SERPINB4, S100A12, SERPINB3, kynu etc. even though the sample size for this analysis was small. One of the most highly modulated genes by SRT2104 included Kynu, a gene that regulates tryptophan metabolism, known to confer antibacterial effector functions (Daubener and MacKenzie, 1999). Interestingly kynu is part of the etanercept residual genomic profile that is not modulated by etanercept therapy even though clinical efficacy is achieved. Possibly, SRT2104 may be modulating the lipid barrier of the epidermis of psoriatic skin via modulation of keratinocyte diferentiation genes, which would be consistent with the observed improvement in skin histology. These results indicate a combinatorial effect of SRT2104 on TNF_, and IL-17 inflammatory signaling pathways and keratinocyte differentiation that could be a contributing factor towards improvement in clinical scores by the SIRT1 activator, SRT2104. Paired Pre (Day 1) and Post (Day 84) Treatment samples were obtained from 4 Placebo Patients and 7 patients treated with SRT2104 at 3 different doses (250, 500, 1000 mg).

Project description:TITLE:Secukinumab efficacy and safety in Indian patients with moderate-to-severe plaque psoriasis: sub-analysis from FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), a randomized, placebo-controlled, phase 3 study. BACKGROUND:Evidence has suggested Interleukin (IL)-17A to be an important effector cytokine in the pathogenesis of psoriasis. Here, we report results for an Indian sub-population from a multinational study FIXTURE, designed to assess the safety, tolerability, and long-term efficacy of fully human anti-IL-17A monoclonal antibody secukinumab in patients with moderate-to-severe plaque psoriasis. MATERIALS AND METHODS:In this double-dummy, placebo controlled, 52-weeks phase 3 study FIXTURE, 149 Indian patients were randomized 1:1:1:1 to receive secukinumab at a dose of 300 mg or 150 mg, etanercept, or placebo. The study objective was to show the superiority of secukinumab over placebo at week 12, vis-à-vis proportion of patients achieving a reduction of 75% or more from the baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (IGA mod 2011) (co-primary end points). RESULTS:At week 12, 61.0% and 55.9% patients in secukinumab 300 mg and 150 mg groups, respectively, achieved PASI 75 response compared to 20.0% in the etanercept and 7.1% in the placebo groups. Similarly, IGA mod 2011 0 or 1 response was achieved by 43.9% and 20.6% in patients in the secukinumab 300 mg and 150 mg group, respectively, vs. 13.3% in the etanercept and 2.4% in the placebo groups at week 12. Likewise, higher proportions of patients in secukinumab 300 mg (41.5%) and 150 mg (20.6%) group were PASI 90 responders at week 12 than those in the etanercept (10.0%) or placebo (0.0%) groups. The incidences of adverse events (AEs), during the induction period were similar in all the treatment groups. Overall secukinumab was well-tolerated at both doses in the Indian sub-population. CONCLUSION:The results from the Indian sub-population suggest that secukinumab is an efficacious and safe drug for use in moderate-to-severe chronic plaque psoriasis.

Dataset Information

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

Publications

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

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