A Randomized, Placebo-Controlled, Single-Blind, Dose-Escalation, First-Time-in-Human Study to Assess the Safety and Pharmacokinetics of Single and Repeat Doses of SRT3025 in Normal Healthy Volunteers

The main purpose of the study is to see how safe SRT3025 (study drug) is when given at different doses. The study will also investigate how the study drug is taken up, metabolised (chemically broken down), distributed through the body and excreted. A further aim is to look at how taking the study drug after eating might change this process.

Start Date03 Jun 2011

Sponsor / Collaborator

Sirtris Pharmaceuticals, Inc.

100 Clinical Results associated with SRT-3025

100 Translational Medicine associated with SRT-3025

100 Patents (Medical) associated with SRT-3025

Literatures (Medical) associated with SRT-3025

01 Mar 2021·NephrologyQ4 · MEDICINE

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline

Q4 · MEDICINE

Article

Author: Thai, Kerri ; Desjardins, Jean‐Francois ; Kabir, Golam ; Veitch, Matthew R. ; Zhang, Yanling ; Gilbert, Richard E. ; Connelly, Kim A.

AbstractAimThe use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting.MethodsWe used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin‐converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX.ResultsWhile enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria.ConclusionThese findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

01 Jan 2019·Acta HaematologicaQ4 · MEDICINE

Sirt1 in the Regulation of Interferon Gamma in Severe Aplastic Anemia

Q4 · MEDICINE

Article

Author: Wang, Ting ; Wang, Huaquan ; Lin, Xiaoyun ; Liu, Chunyan ; Shao, Zonghong

Recent studies have indicated that Sirt1 plays critical roles in the suppression of inflammation, T cell activation, and differentiation of hematopoietic progenitor cells. Severe aplastic anemia (SAA) is an immune-mediated disease that is characterized by elevated cytotoxic lymphocytes and type 1 cytokines. As a negative effector cytokine, interferon gamma (IFNγ) takes part in aplastic anemia through its inhibitory effect on hematopoiesis. In this study, we investigated the role of Sirt1 in the regulation of IFNγ in patients with SAA. A significant decrease in relative SIRT1 (p< 0.05) and increase in IFNG (p< 0.05) expression levels was observed in the sorted CD8+T cells of SAA patients compared to the controls. There was a significant negative correlation (r = –0.53, p < 0.05) between SIRT1 and IFNG expression in SAA patients. SRT3025, a Sirt1 activator, was shown to significantly reduce IFNγ (p < 0.01) and elevate Sirt1 (p < 0.05) expression in the CD8+T cells of SAA patients, and also showed a therapeutic role in an aplastic anemia mouse model. In conclusion, the defective Sirt1 may be correlated to the abnormal IFNγ expression in SAA patients, and activation of Sirt1 signaling may help improve the inflammatory status of SAA.

01 Jan 2017·The American Journal of PathologyQ2 · MEDICINE

Sirtuin 1 Activation Reduces Transforming Growth Factor-β1–Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease

Q2 · MEDICINE

Article

Author: Gilbert, Richard E ; Wu, Xinglin ; Thai, Kerri ; Zhang, Yanling ; Kapus, Andras ; Kepecs, David ; Connelly, Kim A

Most forms of chronic, progressive kidney disease are characterized by fibrosis whereby the prototypical prosclerotic growth factor, transforming growth factor β (TGF-β), is thought to play a pivotal role. With the recent understanding that TGF-β's canonical signaling pathway may be modified by acetylation as well as phosphorylation, we explored the role of the NAD⁺-dependent lysine deacetylase, sirtuin 1 (SIRT1) in fibrogenesis in the cell culture, animal model, and human settings. In vitro, the increase in collagen production that results from TGF-β1 stimulation was ameliorated by the allosteric modifier of Sirt1 deacetylase, SRT3025, in association with a reduction in Smad3 reporter activity. In the remnant kidney model (subtotally or 5/6 nephrectomized rats) that develops progressive kidney disease in association with TGF-β overexpression, administration of SRT3025 attenuated glomerular filtration rate decline and proteinuria without affecting blood pressure. Glomerulosclerosis and tubulointerstitial fibrosis were similarly reduced with Sirt1 activation as were cardiac structure and function in this rodent model of primary kidney and secondary cardiac disease. Relating these findings to the human setting, we noted a reduction in SIRT1 mRNA in kidney biopsies obtained from individuals with focal glomerulosclerosis. Together these studies highlight the potential of SIRT1 activation as a therapeutic strategy in progressive, fibrotic kidney disease.

100 Deals associated with SRT-3025

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 1	GB	Sirtris Pharmaceuticals, Inc.	03 Jun 2011

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