A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers

Vincenzo Libri, Andrew P Brown, Giulio Gambarota, Jonathan Haddad, Gregory S Shields, Helen Dawes, David J Pinato, Ethan Hoffman, Peter J Elliot, George P Vlasuk, Eric Jacobson, Martin R Wilkins, Paul M Matthews, Vincenzo Libri, Andrew P Brown, Giulio Gambarota, Jonathan Haddad, Gregory S Shields, Helen Dawes, David J Pinato, Ethan Hoffman, Peter J Elliot, George P Vlasuk, Eric Jacobson, Martin R Wilkins, Paul M Matthews

Abstract

Background: SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD(+)-dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers.

Methods: Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity.

Results: SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation.

Conclusions: SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients.

Trial registration: ClinicalTrials.gov NCT00964340.

Conflict of interest statement

Competing Interests: At the time this publication was written, JH, EH, PEGPV and EJ were employed by Sirtris Pharmaceuticals, a GlaxoSmithKline company developing SR2104 and related molecules. APB, GG, and PMM were employed by GlaxoSmithKline Research and Development (GSK R&D), Ltd. VL was employed by GSK R&D until April 2009. APB is currently employed by Imanova, Centre of Imaging Sciences, London, UK. The other authors declared no conflicts of interest. The above competing interests do not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT 2010 Flow Diagram.
Figure 1. CONSORT 2010 Flow Diagram.
The schema graphically outlines the design and conduct of the clinical study.
Figure 2. Mean plasma concentration versus time…
Figure 2. Mean plasma concentration versus time plots for SRT2104 on day 1 and 28, following multiple dose administration of 0.5 g/day (top panel) and 2.0 g/day (lower panel) to elderly male and female volunteers.
Figure 3. Lipid profile at baseline and…
Figure 3. Lipid profile at baseline and after 28 days treatment with placebo and SRT2104 (0.5 g/day and 2.0 g/day).
[Black dots indicate points that are two interquartile ranges outside the means; * P

Figure 4. Oral glucose tolerance tests (OGTTs)…

Figure 4. Oral glucose tolerance tests (OGTTs) at baseline and after 28 days treatment placebo…

Figure 4. Oral glucose tolerance tests (OGTTs) at baseline and after 28 days treatment placebo (upper) SRT2104 0.5 g/day (middle) or SRT2104 2.0 g/day (lower panel).

Figure 5. Insulin (left) and C-Peptide (right)…

Figure 5. Insulin (left) and C-Peptide (right) concentration–time curves at baseline (screening) and after 28…

Figure 5. Insulin (left) and C-Peptide (right) concentration–time curves at baseline (screening) and after 28 days treatment with placebo (upper) SRT2104 0.5 g/day (middle) or SRT2104 2.0 g/day (lower panel).

Figure 6. Representative example of magnetic resonance…

Figure 6. Representative example of magnetic resonance images and 31 P Magnetic resonance spectroscopy results.

Top…

Figure 6. Representative example of magnetic resonance images and 31P Magnetic resonance spectroscopy results.
Top left panel: intra-abdominal (red) and subcutaneous (yellow) adipose tissue maps overlaid on coronal and sagittal body MRI images from a single subject. Bottom left panel: dynamic series of 31P MRS spectra acquired serially during exercise and recovery from a single subject as described in Methods. Right panel: box plot of PCr recovery time change from baseline (day −1) to day 27 for the placebo, SRT2104 0.5 g/day and 2.0 g/day groups.
Figure 4. Oral glucose tolerance tests (OGTTs)…
Figure 4. Oral glucose tolerance tests (OGTTs) at baseline and after 28 days treatment placebo (upper) SRT2104 0.5 g/day (middle) or SRT2104 2.0 g/day (lower panel).
Figure 5. Insulin (left) and C-Peptide (right)…
Figure 5. Insulin (left) and C-Peptide (right) concentration–time curves at baseline (screening) and after 28 days treatment with placebo (upper) SRT2104 0.5 g/day (middle) or SRT2104 2.0 g/day (lower panel).
Figure 6. Representative example of magnetic resonance…
Figure 6. Representative example of magnetic resonance images and 31P Magnetic resonance spectroscopy results.
Top left panel: intra-abdominal (red) and subcutaneous (yellow) adipose tissue maps overlaid on coronal and sagittal body MRI images from a single subject. Bottom left panel: dynamic series of 31P MRS spectra acquired serially during exercise and recovery from a single subject as described in Methods. Right panel: box plot of PCr recovery time change from baseline (day −1) to day 27 for the placebo, SRT2104 0.5 g/day and 2.0 g/day groups.

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