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Sarah J Tabrizi - One of the best experts on this subject based on the ideXlab platform.
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d10 pharmacodynamic biomarkers for Selisistat the paddington project
Journal of Neurology Neurosurgery and Psychiatry, 2014Co-Authors: Giuseppe Pollio, Luisa Massai, Ruth Farmer, G. Bernhard Landwehrmeyer, Göran Westerberg, Daniela Diamanti, Chris Frost, Letizia Magnoni, Sarah J Tabrizi, Russell ThomasAbstract:Background Siena Biotech is developing a highly selective SIRT1 inhibitor, Selisistat, as a potentially disease-modifying therapy for Huntington’s disease. Selisistat has shown to ameliorate HD phenotypes in HD preclinical models, from cells expressing mutant huntingtin to transgenic Drosophila and R6/2 mice before entering the clinical trials. Selisistat recently completed the Phase II Study, assessing safety and tolerability in HD patients. Aim Evaluate possible Selisistat pharmacodynamic biomarkers to support further clinical progression. Within the EC funded project PADDINGTON, a transcriptional profile and huntingtin protein levels were evaluated in biological samples from HD patients treated with placebo or Selisistat at different doses. Methods HD patients were randomised to receive different doses of Selisistat or placebo. Serial blood sampling was collected at different time points after Selisistat administration. Peripheral blood mononuclear cells (PBMCs) were employed to detect HTT protein levels by a validated ELISA bioassay. Whole blood samples were analysed through RT-qPCR to validate a previous identified transcriptional signature. Results Four transcripts were found specifically modulated by Selisistat in whole blood samples, confirming the transcriptional signature. Moreover, the ELISA in PBMCs has proven to reliably measure of circulating HTT despite the low protein levels and high individual variability. Conclusions The quantisation of circulating HTT levels as well as gene expression evaluation represents a promising avenue towards monitoring disease progression and therapeutic interventions. Additionally, transcriptional signatures could be useful to draw hypotheses for target engagement and mechanism of action through the pathway analysis of the modulated genes. Final results for both investigations will be presented.
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n02 safety and tolerability of Selisistat for the treatment of huntington s disease results from a randomised double blind placebo controlled phase ii trial
Journal of Neurology Neurosurgery and Psychiatry, 2014Co-Authors: Ralf Reilmann, Sigurd D. Süssmuth, Chiara Mariotti, Andrea H. Németh, Carsten Saft, Ferdinando Squitieri, Oliver Quarrell, Josef Priller, Sarah J Tabrizi, David CraufurdAbstract:Background Selisistat is a first-in-class SirT1 inhibitor shown to be safe and well tolerated in healthy volunteers and HD patients in short-term studies. Objective To evaluate safety and tolerability of Selisistat over 12 weeks in patients with Huntington’s disease (HD). Design/methods This was a double-blind, placebo-controlled, international multi-centre study of Selisistat in individuals with Stage I-III HD. Participants (30–70 yrs) with genetically confirmed HD, a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of ≥ 5 and a Total Functional Capacity ≥ 5 were randomised (1:1:1) to Selisistat 50 or 200 mg or placebo once daily for 12 weeks. Safety and tolerability were evaluated by monitoring adverse events, vital signs, ECG and laboratory safety data throughout the study. Blood sampling for pharmacokinetics and soluble mutant huntingtin levels were collected throughout. Results/outcome A total of 144 patients were randomised and 125 patients (87%) completed the study. There were 9 serious adverse events, three in each treatment group, including one death in the placebo group. The most common adverse events were reversible increases in liver function tests without accompanying increases in bilirubin. All of these occurred in the Selisistat groups; while most of these increases were Conclusions Apart from increases in liver function tests in a subset of patients, Selisistat was safe and well tolerated, and a trend for modulation of the levels of soluble mutant huntingtin was observed. Acknowledgement Supported by Siena Biotech SpA.
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safety and tolerability of Selisistat for the treatment of huntington s disease results from a randomized double blind placebo controlled phase ii trial s47 004
Neurology, 2014Co-Authors: Ralf Reilmann, Chiara Mariotti, Sigurd Suessmuth, Andrea H. Németh, Carsten Saft, Ferdinando Squitieri, Oliver Quarrell, Josef Priller, Sarah J Tabrizi, David CraufurdAbstract:OBJECTIVE: To evaluate safety and tolerability of Selisistat over 12 weeks in patients with Huntington’s Disease (HD). BACKGROUND: Selisistat is a first-in-class SirT1 inhibitor shown to be safe and well tolerated in healthy volunteers and HD patients in short-term studies. DESIGN/METHODS: This was a double-blind, placebo-controlled, international multi-centre study of Selisistat in individuals with Stage I-III HD. Participants (30-70 yrs) with genetically confirmed HD, a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of >=5 and a Total Functional Capacity >=5 were randomized (1:1:1) to Selisistat 50 or 200 mg or placebo once daily for 12 weeks. Safety and tolerability were evaluated by monitoring adverse events, vital signs, ECG and laboratory safety data throughout the study. Blood sampling for pharmacokinetics and soluble mutant huntingtin levels were collected throughout. RESULTS: A total of 144 patients were randomized and 125 patients (87%) completed the study. There were 9 serious adverse events, three in each treatment group, including one death in the placebo group. The most common adverse events were reversible increases in liver function tests without accompanying increases in bilirubin. All of these occurred in the Selisistat groups; while most of these increases were <3×ULN, three events were classified as serious. No clinically relevant changes in the UHDRS readouts were observed during the relatively short treatment period. Levels of soluble mutant huntingtin in peripheral blood mononuclear cells showed borderline statistically significant (p=0.058 , p=0.075) increases of similar magnitude at 12 weeks compared to placebo in the 50mg and 200mg groups respectively, that reverted to levels consistent with the placebo group at follow-up. CONCLUSIONS: Apart from increases in liver function tests in a subset of patients, Selisistat was safe and well tolerated, and a trend for modulation of the levels of soluble mutant huntingtin was observed. Study supported by: Siena Biotech SpA. Disclosure: Dr. Reilmann has received personal compensation for activities with Novartis, Siena Biotech, Neursearch Inc., Ipsen, Teva Neuroscience, Lundbeck, and Medivation. Dr. Reilmann has received personal compensation for activities with the Journal of Huntington9s Disease. Dr. Reilmann has received research support from the High-Q-Foundation, the Cure Huntington9s Disease Initiative Foundation, the Deutsche Forschungsgemeinschaft, and the European Huntington9s Disease Network. Dr. Squitieri has nothing to disclose. Dr. Priller has nothing to disclose. Dr. Saft has received personal compensation for activities with Temmler Pharma as a speaker. Dr. Saft has received research support from Neurosearch, Novartis and Siena Biotech. Dr. Mariotti has nothing to disclose. Dr. Suessmuth has nothing to disclose. Dr. Nemeth has nothing to disclose. Dr. Tabrizi has nothing to disclose. Dr. Quarrell has nothing to disclose. Dr. Craufurd has nothing to disclose. Dr. Rickards has nothing to disclose. Dr. Rosser has nothing to disclose. Dr. Borje has nothing to disclose. Dr. Michaela has nothing to disclose. Dr. Angieszka has nothing to disclose. Dr. Fischer has nothing to disclose. Dr. Macdonald has nothing to disclose. Dr. Munoz-Sanjuan has nothing to disclose. Dr. Pacifici has received personal compensation for activities with Science Applications International Corp. as a consultant. Dr. Frost has nothing to disclose. Dr. Farmer has nothing to disclose. Dr. Landwehrmeyer has received personal compensation for activities with Siena Biotech SPA and AOP Orphan. Dr. Landwehrmeyer has received research support from the European Commission, CHDI Foundation, Medivation, NeuroSearch, Novartis, Medesis, and Amarin. Dr. Westerberg has nothing to disclose.
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from biology to the bedside sirtuins as targets for disease modification in huntington s disease Selisistat preclinical data and preliminary phase i results
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: S S Haider, Ruth Farmer, S D Sissumuth, D I Crauford, Göran Westerberg, Andrea Caricasole, Bernhard Landwehrmeyer, Chris Frost, R Andre, Sarah J TabriziAbstract:To date no disease modifying therapy has shown efficacy in Huntington9s Disease (HD). The PADDINGTON (Pharmacodynamic Approaches to Disease Modification in Huntington9s Disease) Project, funded by the European Union9s Seventh Framework Programme, aims to develop biomarkers to quantify disease modification. As part of this project, early phase clinical trials of Selisistat (SEN0014196), an inhibitor of SirT1 (silencing information regulator T1) developed by Siena Biotech, are in progress. Sirtuins, which are deacetylating enzymes, are potential targets in aging, metabolism and neurodegeneration. Selisistat has a novel mode of action that may be pathologically relevant for Huntington9s Disease. Inhibition of SirT1 in transgenic mice and Drosophila HD models lowers mutant Huntingtin protein levels and ameliorates HD phenotypes. In cellular models, modulation of Huntingtin acetylation and clearance is proposed as a potential mechanism. A first time in human study, employing a randomized, double-blind, placebo-controlled design with single dose escalation and multiple dose format, demonstrated safety and tolerability in healthy volunteers with low incidence of adverse events. A Phase 1B study in 55 HD patients, encompassing six EU sites (Germany, Poland and the UK), was carried out over 14-days at two dose levels with a randomized, double-blind, placebo-controlled, parallel group design. A Phase 2 study, involving a 12 week dosing period is underway across Europe including 7 UK sites. Here we present safety, tolerability and pharmacodynamic data from the Phase 1B study.
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f02 Selisistat soluble htt protein levels as a potential pharmacodynamic readout
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Göran Westerberg, Luisa Massai, Giuseppe Tripepi, Enrica Diodato, Giuseppe Pollio, Andrea Caricasole, Simonetta Bernocco, Letizia Magnoni, Sarah J Tabrizi, Bernhard LandwehrmeyerAbstract:Background Siena Biotech SpA is developing Selisistat (SEN0014196) as a potentially disease-modifying therapy for HD. Selsistat is a potent and selective SirT1 inhibitor (IC50 98 nM) that has shown benefit across a range of preclinical models for HD, from cells and neurons infected with mutant huntingtin to transgenic Drosophila and R6/2 mice. The compound has shown to be safe and well tolerated in healthy volunteers and with a favourable pharmacokinetic profile. Aim To develop a sensitive and quantitative (ELISA-based) readout for the detection of total soluble HTT protein in biological matrices, and to investigate the effects of Selisistat on HTT protein levels in Peripheral Blood Mononuclear Cells (PBMC) samples deriving from a Phase 1B study in HD patients. Methods This assay is based on a sandwich ELISA format and uses an electrochemiluminescent read-out to quantify the HTT protein level in PBMC extracts. The PBMCs are lysed by sonication and extracted by centrifugation. The supernatant is applied to a streptavidin-coated MSD plate which has been previously treated by addition of a biotinylated anti-mouse antibody followed by a mouse monoclonal anti HTT (1844–2131 aa) antibody. After incubation, bound HTT is detected using a rabbit anti-HTT (513–590 aa) secondary antibody followed by a Sulfotag conjugated anti-rabbit detection antibody. The signal is quantified by adding MSD read buffer and reading using the Meso Scale Discovery Sector Imager. Results and Conclusions The effects of two dose levels of Selisistat and placebo on total soluble HTT levels in PBMC samples from HD patients in a 14-day Phase1B study will be presented.
Göran Westerberg - One of the best experts on this subject based on the ideXlab platform.
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safety pharmacokinetics pharmacogenomics and qt concentration effect modelling of the sirt1 inhibitor Selisistat in healthy volunteers
British Journal of Clinical Pharmacology, 2015Co-Authors: Göran Westerberg, Joseph A Chiesa, Giuseppe Pollio, Claus A. F. Andersen, Borje Darpo, Daniela Diamanti, Letizia Magnoni, Meijian ZhouAbstract:Aim Selisistat (SEN0014196), a first-in-class SirT1 inhibitor, is being developed as a disease-modifying therapy for Huntington's disease. This first-in-human study investigated the safety, pharmacokinetics and pharmacogenomics of single and multiple doses of Selisistat in healthy male and female subjects.
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d10 pharmacodynamic biomarkers for Selisistat the paddington project
Journal of Neurology Neurosurgery and Psychiatry, 2014Co-Authors: Giuseppe Pollio, Luisa Massai, Ruth Farmer, G. Bernhard Landwehrmeyer, Göran Westerberg, Daniela Diamanti, Chris Frost, Letizia Magnoni, Sarah J Tabrizi, Russell ThomasAbstract:Background Siena Biotech is developing a highly selective SIRT1 inhibitor, Selisistat, as a potentially disease-modifying therapy for Huntington’s disease. Selisistat has shown to ameliorate HD phenotypes in HD preclinical models, from cells expressing mutant huntingtin to transgenic Drosophila and R6/2 mice before entering the clinical trials. Selisistat recently completed the Phase II Study, assessing safety and tolerability in HD patients. Aim Evaluate possible Selisistat pharmacodynamic biomarkers to support further clinical progression. Within the EC funded project PADDINGTON, a transcriptional profile and huntingtin protein levels were evaluated in biological samples from HD patients treated with placebo or Selisistat at different doses. Methods HD patients were randomised to receive different doses of Selisistat or placebo. Serial blood sampling was collected at different time points after Selisistat administration. Peripheral blood mononuclear cells (PBMCs) were employed to detect HTT protein levels by a validated ELISA bioassay. Whole blood samples were analysed through RT-qPCR to validate a previous identified transcriptional signature. Results Four transcripts were found specifically modulated by Selisistat in whole blood samples, confirming the transcriptional signature. Moreover, the ELISA in PBMCs has proven to reliably measure of circulating HTT despite the low protein levels and high individual variability. Conclusions The quantisation of circulating HTT levels as well as gene expression evaluation represents a promising avenue towards monitoring disease progression and therapeutic interventions. Additionally, transcriptional signatures could be useful to draw hypotheses for target engagement and mechanism of action through the pathway analysis of the modulated genes. Final results for both investigations will be presented.
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from biology to the bedside sirtuins as targets for disease modification in huntington s disease Selisistat preclinical data and preliminary phase i results
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: S S Haider, Ruth Farmer, S D Sissumuth, D I Crauford, Göran Westerberg, Andrea Caricasole, Bernhard Landwehrmeyer, Chris Frost, R Andre, Sarah J TabriziAbstract:To date no disease modifying therapy has shown efficacy in Huntington9s Disease (HD). The PADDINGTON (Pharmacodynamic Approaches to Disease Modification in Huntington9s Disease) Project, funded by the European Union9s Seventh Framework Programme, aims to develop biomarkers to quantify disease modification. As part of this project, early phase clinical trials of Selisistat (SEN0014196), an inhibitor of SirT1 (silencing information regulator T1) developed by Siena Biotech, are in progress. Sirtuins, which are deacetylating enzymes, are potential targets in aging, metabolism and neurodegeneration. Selisistat has a novel mode of action that may be pathologically relevant for Huntington9s Disease. Inhibition of SirT1 in transgenic mice and Drosophila HD models lowers mutant Huntingtin protein levels and ameliorates HD phenotypes. In cellular models, modulation of Huntingtin acetylation and clearance is proposed as a potential mechanism. A first time in human study, employing a randomized, double-blind, placebo-controlled design with single dose escalation and multiple dose format, demonstrated safety and tolerability in healthy volunteers with low incidence of adverse events. A Phase 1B study in 55 HD patients, encompassing six EU sites (Germany, Poland and the UK), was carried out over 14-days at two dose levels with a randomized, double-blind, placebo-controlled, parallel group design. A Phase 2 study, involving a 12 week dosing period is underway across Europe including 7 UK sites. Here we present safety, tolerability and pharmacodynamic data from the Phase 1B study.
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f02 Selisistat soluble htt protein levels as a potential pharmacodynamic readout
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Göran Westerberg, Luisa Massai, Giuseppe Tripepi, Enrica Diodato, Giuseppe Pollio, Andrea Caricasole, Simonetta Bernocco, Letizia Magnoni, Sarah J Tabrizi, Bernhard LandwehrmeyerAbstract:Background Siena Biotech SpA is developing Selisistat (SEN0014196) as a potentially disease-modifying therapy for HD. Selsistat is a potent and selective SirT1 inhibitor (IC50 98 nM) that has shown benefit across a range of preclinical models for HD, from cells and neurons infected with mutant huntingtin to transgenic Drosophila and R6/2 mice. The compound has shown to be safe and well tolerated in healthy volunteers and with a favourable pharmacokinetic profile. Aim To develop a sensitive and quantitative (ELISA-based) readout for the detection of total soluble HTT protein in biological matrices, and to investigate the effects of Selisistat on HTT protein levels in Peripheral Blood Mononuclear Cells (PBMC) samples deriving from a Phase 1B study in HD patients. Methods This assay is based on a sandwich ELISA format and uses an electrochemiluminescent read-out to quantify the HTT protein level in PBMC extracts. The PBMCs are lysed by sonication and extracted by centrifugation. The supernatant is applied to a streptavidin-coated MSD plate which has been previously treated by addition of a biotinylated anti-mouse antibody followed by a mouse monoclonal anti HTT (1844–2131 aa) antibody. After incubation, bound HTT is detected using a rabbit anti-HTT (513–590 aa) secondary antibody followed by a Sulfotag conjugated anti-rabbit detection antibody. The signal is quantified by adding MSD read buffer and reading using the Meso Scale Discovery Sector Imager. Results and Conclusions The effects of two dose levels of Selisistat and placebo on total soluble HTT levels in PBMC samples from HD patients in a 14-day Phase1B study will be presented.
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q02 a randomised double blind placebo controlled phase ib pharmacodynamic study with Selisistat sen0014196 in hd patients
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Sigurd D. Süssmuth, Giuseppe Tripepi, C Andersen, M Dibacco, G. Bernhard Landwehrmeyer, Sarah J Tabrizi, Göran WesterbergAbstract:Background Siena Biotech SpA is developing Selisistat (SEN0014196) as a potentially disease-modifying therapy for HD. Selsistat is a potent and selective SirT1 inhibitor (IC50 98 nM) that has shown benefit across a range of preclinical models for HD, from cells and neurons transfected with mutant huntingtin to transgenic Drosophila and R6/2 mice. The compound has shown to be safe and well tolerated in healthy volunteers and has a favourable pharmacokinetic profile. Aim The current study was designed to provide biophase samples for analysis of a series of potential target engagement and disease-modification read-outs, helping to establish a proof-of-principle and aid in dose selection for future safety and efficacy studies. Methods A total of 63 HD patients with a wide range of CAG repeats and disease burden scores were screened across six sites in Germany (Bochum, Ulm), Poland (Krakow, Warsaw) and the UK (London, Manchester). Patients were randomised to receive either 10 or 100 mg of Selisistat or placebo for 2 weeks. Safety data collected included vital signs, ECGs, clinical laboratory parameters and type and frequency of adverse events. Clinical assessments included UHDRS and a cognitive battery. Serial blood sampling for pharmacokinetics and pharmacodynamics was performed on days 1 and 14 and at follow-up after a washout phase of 14 days. Results and Conclusions A total of 55 patients completed the treatment as per protocol; there were four screening failures and four patients withdrew consent. No Serious Adverse Events were reported and no patient withdrew from the study as a result of an adverse event. We will present full data on safety, tolerability, pharmacokinetics and clinical assessments, while pharmacodynamic data will be reported elsewhere.
Sigurd D. Süssmuth - One of the best experts on this subject based on the ideXlab platform.
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an exploratory double blind randomized clinical trial with Selisistat a sirt1 inhibitor in patients with huntington s disease
British Journal of Clinical Pharmacology, 2015Co-Authors: Sigurd D. Süssmuth, Giuseppe Tripepi, Ruth Farmer, Claus A Andersen, Marco Di Bacco, Claudia Lamanna, Salman Haider, Bernhard Landwehrmeyer, Chris Frost, Enrica DiodatoAbstract:AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of Selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of Selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by Selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
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n02 safety and tolerability of Selisistat for the treatment of huntington s disease results from a randomised double blind placebo controlled phase ii trial
Journal of Neurology Neurosurgery and Psychiatry, 2014Co-Authors: Ralf Reilmann, Sigurd D. Süssmuth, Chiara Mariotti, Andrea H. Németh, Carsten Saft, Ferdinando Squitieri, Oliver Quarrell, Josef Priller, Sarah J Tabrizi, David CraufurdAbstract:Background Selisistat is a first-in-class SirT1 inhibitor shown to be safe and well tolerated in healthy volunteers and HD patients in short-term studies. Objective To evaluate safety and tolerability of Selisistat over 12 weeks in patients with Huntington’s disease (HD). Design/methods This was a double-blind, placebo-controlled, international multi-centre study of Selisistat in individuals with Stage I-III HD. Participants (30–70 yrs) with genetically confirmed HD, a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of ≥ 5 and a Total Functional Capacity ≥ 5 were randomised (1:1:1) to Selisistat 50 or 200 mg or placebo once daily for 12 weeks. Safety and tolerability were evaluated by monitoring adverse events, vital signs, ECG and laboratory safety data throughout the study. Blood sampling for pharmacokinetics and soluble mutant huntingtin levels were collected throughout. Results/outcome A total of 144 patients were randomised and 125 patients (87%) completed the study. There were 9 serious adverse events, three in each treatment group, including one death in the placebo group. The most common adverse events were reversible increases in liver function tests without accompanying increases in bilirubin. All of these occurred in the Selisistat groups; while most of these increases were Conclusions Apart from increases in liver function tests in a subset of patients, Selisistat was safe and well tolerated, and a trend for modulation of the levels of soluble mutant huntingtin was observed. Acknowledgement Supported by Siena Biotech SpA.
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q02 a randomised double blind placebo controlled phase ib pharmacodynamic study with Selisistat sen0014196 in hd patients
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Sigurd D. Süssmuth, Giuseppe Tripepi, C Andersen, M Dibacco, G. Bernhard Landwehrmeyer, Sarah J Tabrizi, Göran WesterbergAbstract:Background Siena Biotech SpA is developing Selisistat (SEN0014196) as a potentially disease-modifying therapy for HD. Selsistat is a potent and selective SirT1 inhibitor (IC50 98 nM) that has shown benefit across a range of preclinical models for HD, from cells and neurons transfected with mutant huntingtin to transgenic Drosophila and R6/2 mice. The compound has shown to be safe and well tolerated in healthy volunteers and has a favourable pharmacokinetic profile. Aim The current study was designed to provide biophase samples for analysis of a series of potential target engagement and disease-modification read-outs, helping to establish a proof-of-principle and aid in dose selection for future safety and efficacy studies. Methods A total of 63 HD patients with a wide range of CAG repeats and disease burden scores were screened across six sites in Germany (Bochum, Ulm), Poland (Krakow, Warsaw) and the UK (London, Manchester). Patients were randomised to receive either 10 or 100 mg of Selisistat or placebo for 2 weeks. Safety data collected included vital signs, ECGs, clinical laboratory parameters and type and frequency of adverse events. Clinical assessments included UHDRS and a cognitive battery. Serial blood sampling for pharmacokinetics and pharmacodynamics was performed on days 1 and 14 and at follow-up after a washout phase of 14 days. Results and Conclusions A total of 55 patients completed the treatment as per protocol; there were four screening failures and four patients withdrew consent. No Serious Adverse Events were reported and no patient withdrew from the study as a result of an adverse event. We will present full data on safety, tolerability, pharmacokinetics and clinical assessments, while pharmacodynamic data will be reported elsewhere.
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q01 sirt 1 mediated modulation of circulating cytokines in huntington s disease pharmacodynamics results from phase 1b study of Selisistat a sirt 1 inhibitor
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Salman Haider, Sigurd D. Süssmuth, Ruth Farmer, Göran Westerberg, Ralph Andre, Bernhard Landwehrmeyer, Maria Björkqvist, Chris Frost, Sarah J TabriziAbstract:Background Evidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington9s disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly elevated in a group of subjects predicted to be, on average, 16 years from disease, with a parallel post-mortem cytokine expression profile seen in HD striatum. Furthermore, LPS stimulation of HD monocytes reveals an inherent hyper-reactivity that is similar to that seen in microglia, suggesting a cell-autonomous effect of mutant huntingtin in peripheral myeloid cells as well as in the CNS. Sirtuins, which are deacetylating enzymes, have been implicated as potential targets in ageing, metabolism and neurodegeneration. Selisistat, a member of the sirtuin deacetylase family and an inhibitor of SirT1 (Silencing information regulator T1), has a novel mode of action that may be pathologically relevant for HD. A Phase 1B study encompassing six EU sites (Germany, Poland and the UK) was carried out in 55 early-stage HD patients over 14 days at two dose levels (10 and 100 mg OD), with a randomised, double-blind, placebo-controlled, parallel group design. Aim To determine if the innate immune system is a potential target for Selisistat. Methods Cytokine assays were carried out using the MesoScale Discovery (MSD) multiplex platform, as per the manufacturer9s recommendations, and analysed on a SECTOR 2400 instrument. The cytokines of interest included IL-1b, IL-6, IL-8 and TNF-α. The operator was blinded to the disease state of each sample during processing and statistical analysis was performed independently. Results and Conclusions Here we will present comparative analysis of the plasma cytokine profile of Huntington9s disease patients at four time points, screening, baseline, day 14 and day 28, in each of the three treatment arms of the study.
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sirt 1 mediated modulation of circulating cytokines in huntington s disease pharmacodynamics results from phase 1b study of Selisistat a sirt 1 inhibitor
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Salman Haider, Sigurd D. Süssmuth, Ruth Farmer, Ralph Andre, Bernhard Landwehrmeyer, Maria Björkqvist, Chris Frost, G Westerberg, Sarah J TabriziAbstract:Background Evidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington9s disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly elevated in a group of subjects predicted to be, on average, 16 years from disease, with a parallel post-mortem cytokine expression profile seen in HD striatum. Furthermore, LPS stimulation of HD monocytes reveals an inherent hyper-reactivity that is similar to that seen in microglia, suggesting a cell-autonomous effect of mutant huntingtin in peripheral myeloid cells as well as in the CNS. Sirtuins, which are deacetylating enzymes, have been implicated as potential targets in ageing, metabolism and neurodegeneration. Selisistat, a member of the sirtuin deacetylase family and an inhibitor of SirT1 (Silencing information regulator T1), has a novel mode of action that may be pathologically relevant for HD. A Phase 1B study encompassing six EU sites (Germany, Poland and the UK) was carried out in 55 early-stage HD patients over 14 days at two dose levels (10 and 100 mg OD), with a randomised, double-blind, placebo-controlled, parallel group design. Aim To determine if the innate immune system is a potential target for Selisistat. Methods Cytokine assays were carried out using the MesoScale Discovery (MSD) multiplex platform, as per the manufacturer9s recommendations, and analysed on a SECTOR 2400 instrument. The cytokines of interest included IL-1b, IL-6, IL-8 and TNF-α. The operator was blinded to the disease state of each sample during processing and statistical analysis was performed independently. Results and Conclusions Here we will present comparative analysis of the plasma cytokine profile of Huntington9s disease patients at four time points, screening, baseline, day 14 and day 28, in each of the three treatment arms of the study.
Bernhard Landwehrmeyer - One of the best experts on this subject based on the ideXlab platform.
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an exploratory double blind randomized clinical trial with Selisistat a sirt1 inhibitor in patients with huntington s disease
British Journal of Clinical Pharmacology, 2015Co-Authors: Sigurd D. Süssmuth, Giuseppe Tripepi, Ruth Farmer, Claus A Andersen, Marco Di Bacco, Claudia Lamanna, Salman Haider, Bernhard Landwehrmeyer, Chris Frost, Enrica DiodatoAbstract:AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of Selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of Selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by Selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
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from biology to the bedside sirtuins as targets for disease modification in huntington s disease Selisistat preclinical data and preliminary phase i results
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: S S Haider, Ruth Farmer, S D Sissumuth, D I Crauford, Göran Westerberg, Andrea Caricasole, Bernhard Landwehrmeyer, Chris Frost, R Andre, Sarah J TabriziAbstract:To date no disease modifying therapy has shown efficacy in Huntington9s Disease (HD). The PADDINGTON (Pharmacodynamic Approaches to Disease Modification in Huntington9s Disease) Project, funded by the European Union9s Seventh Framework Programme, aims to develop biomarkers to quantify disease modification. As part of this project, early phase clinical trials of Selisistat (SEN0014196), an inhibitor of SirT1 (silencing information regulator T1) developed by Siena Biotech, are in progress. Sirtuins, which are deacetylating enzymes, are potential targets in aging, metabolism and neurodegeneration. Selisistat has a novel mode of action that may be pathologically relevant for Huntington9s Disease. Inhibition of SirT1 in transgenic mice and Drosophila HD models lowers mutant Huntingtin protein levels and ameliorates HD phenotypes. In cellular models, modulation of Huntingtin acetylation and clearance is proposed as a potential mechanism. A first time in human study, employing a randomized, double-blind, placebo-controlled design with single dose escalation and multiple dose format, demonstrated safety and tolerability in healthy volunteers with low incidence of adverse events. A Phase 1B study in 55 HD patients, encompassing six EU sites (Germany, Poland and the UK), was carried out over 14-days at two dose levels with a randomized, double-blind, placebo-controlled, parallel group design. A Phase 2 study, involving a 12 week dosing period is underway across Europe including 7 UK sites. Here we present safety, tolerability and pharmacodynamic data from the Phase 1B study.
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f02 Selisistat soluble htt protein levels as a potential pharmacodynamic readout
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Göran Westerberg, Luisa Massai, Giuseppe Tripepi, Enrica Diodato, Giuseppe Pollio, Andrea Caricasole, Simonetta Bernocco, Letizia Magnoni, Sarah J Tabrizi, Bernhard LandwehrmeyerAbstract:Background Siena Biotech SpA is developing Selisistat (SEN0014196) as a potentially disease-modifying therapy for HD. Selsistat is a potent and selective SirT1 inhibitor (IC50 98 nM) that has shown benefit across a range of preclinical models for HD, from cells and neurons infected with mutant huntingtin to transgenic Drosophila and R6/2 mice. The compound has shown to be safe and well tolerated in healthy volunteers and with a favourable pharmacokinetic profile. Aim To develop a sensitive and quantitative (ELISA-based) readout for the detection of total soluble HTT protein in biological matrices, and to investigate the effects of Selisistat on HTT protein levels in Peripheral Blood Mononuclear Cells (PBMC) samples deriving from a Phase 1B study in HD patients. Methods This assay is based on a sandwich ELISA format and uses an electrochemiluminescent read-out to quantify the HTT protein level in PBMC extracts. The PBMCs are lysed by sonication and extracted by centrifugation. The supernatant is applied to a streptavidin-coated MSD plate which has been previously treated by addition of a biotinylated anti-mouse antibody followed by a mouse monoclonal anti HTT (1844–2131 aa) antibody. After incubation, bound HTT is detected using a rabbit anti-HTT (513–590 aa) secondary antibody followed by a Sulfotag conjugated anti-rabbit detection antibody. The signal is quantified by adding MSD read buffer and reading using the Meso Scale Discovery Sector Imager. Results and Conclusions The effects of two dose levels of Selisistat and placebo on total soluble HTT levels in PBMC samples from HD patients in a 14-day Phase1B study will be presented.
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q01 sirt 1 mediated modulation of circulating cytokines in huntington s disease pharmacodynamics results from phase 1b study of Selisistat a sirt 1 inhibitor
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Salman Haider, Sigurd D. Süssmuth, Ruth Farmer, Göran Westerberg, Ralph Andre, Bernhard Landwehrmeyer, Maria Björkqvist, Chris Frost, Sarah J TabriziAbstract:Background Evidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington9s disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly elevated in a group of subjects predicted to be, on average, 16 years from disease, with a parallel post-mortem cytokine expression profile seen in HD striatum. Furthermore, LPS stimulation of HD monocytes reveals an inherent hyper-reactivity that is similar to that seen in microglia, suggesting a cell-autonomous effect of mutant huntingtin in peripheral myeloid cells as well as in the CNS. Sirtuins, which are deacetylating enzymes, have been implicated as potential targets in ageing, metabolism and neurodegeneration. Selisistat, a member of the sirtuin deacetylase family and an inhibitor of SirT1 (Silencing information regulator T1), has a novel mode of action that may be pathologically relevant for HD. A Phase 1B study encompassing six EU sites (Germany, Poland and the UK) was carried out in 55 early-stage HD patients over 14 days at two dose levels (10 and 100 mg OD), with a randomised, double-blind, placebo-controlled, parallel group design. Aim To determine if the innate immune system is a potential target for Selisistat. Methods Cytokine assays were carried out using the MesoScale Discovery (MSD) multiplex platform, as per the manufacturer9s recommendations, and analysed on a SECTOR 2400 instrument. The cytokines of interest included IL-1b, IL-6, IL-8 and TNF-α. The operator was blinded to the disease state of each sample during processing and statistical analysis was performed independently. Results and Conclusions Here we will present comparative analysis of the plasma cytokine profile of Huntington9s disease patients at four time points, screening, baseline, day 14 and day 28, in each of the three treatment arms of the study.
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sirt 1 mediated modulation of circulating cytokines in huntington s disease pharmacodynamics results from phase 1b study of Selisistat a sirt 1 inhibitor
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Salman Haider, Sigurd D. Süssmuth, Ruth Farmer, Ralph Andre, Bernhard Landwehrmeyer, Maria Björkqvist, Chris Frost, G Westerberg, Sarah J TabriziAbstract:Background Evidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington9s disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly elevated in a group of subjects predicted to be, on average, 16 years from disease, with a parallel post-mortem cytokine expression profile seen in HD striatum. Furthermore, LPS stimulation of HD monocytes reveals an inherent hyper-reactivity that is similar to that seen in microglia, suggesting a cell-autonomous effect of mutant huntingtin in peripheral myeloid cells as well as in the CNS. Sirtuins, which are deacetylating enzymes, have been implicated as potential targets in ageing, metabolism and neurodegeneration. Selisistat, a member of the sirtuin deacetylase family and an inhibitor of SirT1 (Silencing information regulator T1), has a novel mode of action that may be pathologically relevant for HD. A Phase 1B study encompassing six EU sites (Germany, Poland and the UK) was carried out in 55 early-stage HD patients over 14 days at two dose levels (10 and 100 mg OD), with a randomised, double-blind, placebo-controlled, parallel group design. Aim To determine if the innate immune system is a potential target for Selisistat. Methods Cytokine assays were carried out using the MesoScale Discovery (MSD) multiplex platform, as per the manufacturer9s recommendations, and analysed on a SECTOR 2400 instrument. The cytokines of interest included IL-1b, IL-6, IL-8 and TNF-α. The operator was blinded to the disease state of each sample during processing and statistical analysis was performed independently. Results and Conclusions Here we will present comparative analysis of the plasma cytokine profile of Huntington9s disease patients at four time points, screening, baseline, day 14 and day 28, in each of the three treatment arms of the study.
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early phase disease modification trials with Selisistat optical coherence tomography as a biomarker in huntington s disease
Doctoral thesis UCL (University College London)., 2019Co-Authors: Salman HaiderAbstract:Huntington’s disease (HD) is a monogenic neurodegenerative disorder with no known cure. Selisistat is a novel, highly potent Sirt1 inhibitor with supportive pre-clinical data. Facilitation of autophagy and amelioration of transcriptional dysregulation are proposed as mechanisms of action. A first in disease Phase 1B study showed safety and tolerability. The peripheral immune dysfunction in HD could be modulated by Sirtuins which have both pro and anti-inflammatory activities. However Selisistat did not alter the cytokine profile in this study. Phase 2 data over a longer duration was also well tolerated however potential hepatotoxicity is a concern. Sub-analysis of clinical assessments did not reveal any significant effect. Confirmation of proposed mechanisms of action is lacking and no Phase III studies are planned. Significant clinical heterogeneity exists in HD phenotypes which must reflect differing neuronal susceptibilities. A novel total motor score based sub-division of HD phenotypes failed to demonstrate any changes in a whole brain voxel-based morphometry (VBM) analysis. Clinical assessment alone lacks sensitivity over shorter time-spans in HD, and thus reliable, tolerable and sensitive biomarkers are required. Optical coherence tomography is a potential novel biomarker. The hypothesis that neuroretinal structures may be surrogate marker of intracranial disease was tested in a pilot biomarker study, the first of its kind in HD. Evidence of a statistically significant (p < 0.01) reduction in macular volume in HD subjects versus age and sex-matched controls is seen. No change in RFNL measures was seen. A correlation with increasing disease severity on ordinal regression was also noted. No correlation of macular volume and RNFL thickness with change in whole brain and caudate volumes. Furthermore, OCT was well tolerated by the majority of participants. Retinal abnormalities in HD have been confirmed in three subsequent independent OCT studies.
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Early phase disease modification trials with Selisistat & optical coherence tomography as a biomarker in Huntington's disease
2019Co-Authors: Salman HaiderAbstract:Huntington’s disease (HD) is a monogenic neurodegenerative disorder with no known cure. Selisistat is a novel, highly potent Sirt1 inhibitor with supportive pre-clinical data. Facilitation of autophagy and amelioration of transcriptional dysregulation are proposed as mechanisms of action. A first in disease Phase 1B study showed safety and tolerability. The peripheral immune dysfunction in HD could be modulated by Sirtuins which have both pro and anti-inflammatory activities. However Selisistat did not alter the cytokine profile in this study. Phase 2 data over a longer duration was also well tolerated however potential hepatotoxicity is a concern. Sub-analysis of clinical assessments did not reveal any significant effect. Confirmation of proposed mechanisms of action is lacking and no Phase III studies are planned. Significant clinical heterogeneity exists in HD phenotypes which must reflect differing neuronal susceptibilities. A novel total motor score based sub-division of HD phenotypes failed to demonstrate any changes in a whole brain voxel-based morphometry (VBM) analysis. Clinical assessment alone lacks sensitivity over shorter time-spans in HD, and thus reliable, tolerable and sensitive biomarkers are required. Optical coherence tomography is a potential novel biomarker. The hypothesis that neuroretinal structures may be surrogate marker of intracranial disease was tested in a pilot biomarker study, the first of its kind in HD. Evidence of a statistically significant (p < 0.01) reduction in macular volume in HD subjects versus age and sex-matched controls is seen. No change in RFNL measures was seen. A correlation with increasing disease severity on ordinal regression was also noted. No correlation of macular volume and RNFL thickness with change in whole brain and caudate volumes. Furthermore, OCT was well tolerated by the majority of participants. Retinal abnormalities in HD have been confirmed in three subsequent independent OCT studies.
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an exploratory double blind randomized clinical trial with Selisistat a sirt1 inhibitor in patients with huntington s disease
British Journal of Clinical Pharmacology, 2015Co-Authors: Sigurd D. Süssmuth, Giuseppe Tripepi, Ruth Farmer, Claus A Andersen, Marco Di Bacco, Claudia Lamanna, Salman Haider, Bernhard Landwehrmeyer, Chris Frost, Enrica DiodatoAbstract:AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of Selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of Selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by Selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
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q01 sirt 1 mediated modulation of circulating cytokines in huntington s disease pharmacodynamics results from phase 1b study of Selisistat a sirt 1 inhibitor
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Salman Haider, Sigurd D. Süssmuth, Ruth Farmer, Göran Westerberg, Ralph Andre, Bernhard Landwehrmeyer, Maria Björkqvist, Chris Frost, Sarah J TabriziAbstract:Background Evidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington9s disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly elevated in a group of subjects predicted to be, on average, 16 years from disease, with a parallel post-mortem cytokine expression profile seen in HD striatum. Furthermore, LPS stimulation of HD monocytes reveals an inherent hyper-reactivity that is similar to that seen in microglia, suggesting a cell-autonomous effect of mutant huntingtin in peripheral myeloid cells as well as in the CNS. Sirtuins, which are deacetylating enzymes, have been implicated as potential targets in ageing, metabolism and neurodegeneration. Selisistat, a member of the sirtuin deacetylase family and an inhibitor of SirT1 (Silencing information regulator T1), has a novel mode of action that may be pathologically relevant for HD. A Phase 1B study encompassing six EU sites (Germany, Poland and the UK) was carried out in 55 early-stage HD patients over 14 days at two dose levels (10 and 100 mg OD), with a randomised, double-blind, placebo-controlled, parallel group design. Aim To determine if the innate immune system is a potential target for Selisistat. Methods Cytokine assays were carried out using the MesoScale Discovery (MSD) multiplex platform, as per the manufacturer9s recommendations, and analysed on a SECTOR 2400 instrument. The cytokines of interest included IL-1b, IL-6, IL-8 and TNF-α. The operator was blinded to the disease state of each sample during processing and statistical analysis was performed independently. Results and Conclusions Here we will present comparative analysis of the plasma cytokine profile of Huntington9s disease patients at four time points, screening, baseline, day 14 and day 28, in each of the three treatment arms of the study.
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sirt 1 mediated modulation of circulating cytokines in huntington s disease pharmacodynamics results from phase 1b study of Selisistat a sirt 1 inhibitor
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Salman Haider, Sigurd D. Süssmuth, Ruth Farmer, Ralph Andre, Bernhard Landwehrmeyer, Maria Björkqvist, Chris Frost, G Westerberg, Sarah J TabriziAbstract:Background Evidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington9s disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly elevated in a group of subjects predicted to be, on average, 16 years from disease, with a parallel post-mortem cytokine expression profile seen in HD striatum. Furthermore, LPS stimulation of HD monocytes reveals an inherent hyper-reactivity that is similar to that seen in microglia, suggesting a cell-autonomous effect of mutant huntingtin in peripheral myeloid cells as well as in the CNS. Sirtuins, which are deacetylating enzymes, have been implicated as potential targets in ageing, metabolism and neurodegeneration. Selisistat, a member of the sirtuin deacetylase family and an inhibitor of SirT1 (Silencing information regulator T1), has a novel mode of action that may be pathologically relevant for HD. A Phase 1B study encompassing six EU sites (Germany, Poland and the UK) was carried out in 55 early-stage HD patients over 14 days at two dose levels (10 and 100 mg OD), with a randomised, double-blind, placebo-controlled, parallel group design. Aim To determine if the innate immune system is a potential target for Selisistat. Methods Cytokine assays were carried out using the MesoScale Discovery (MSD) multiplex platform, as per the manufacturer9s recommendations, and analysed on a SECTOR 2400 instrument. The cytokines of interest included IL-1b, IL-6, IL-8 and TNF-α. The operator was blinded to the disease state of each sample during processing and statistical analysis was performed independently. Results and Conclusions Here we will present comparative analysis of the plasma cytokine profile of Huntington9s disease patients at four time points, screening, baseline, day 14 and day 28, in each of the three treatment arms of the study.