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Fp1 public summary_giovannoni1-yr5_gg1
Fp1 public summary_giovannoni1-yr5_gg1
Fp1 public summary_giovannoni1-yr5_gg1
Fp1 public summary_giovannoni1-yr5_gg1
Fp1 public summary_giovannoni1-yr5_gg1
Fp1 public summary_giovannoni1-yr5_gg1
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Fp1 public summary_giovannoni1-yr5_gg1

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  • 1. NATIONAL MULTIPLE SCLEROSIS SOCIETY 733 Third Avenue New York, NY 10017-3288 (212)986-3240 TRANSLATIONAL RESEARCH PARTNERSHIP PROGRESS REPORT Principal Investigator's Name (Last, First, MI, Position and Title: Professor of Neurology Degree[s]): Giovannoni, Gavin, MBBCh, Phd, FCP (S.A. Neurol.), FRCP, FRCPath. Address: Tele Number: +44 20 7882 8954 Department: Neurology School: Blizard Institute, Queen Mary University London Institution: Barts and The London School of Medicine FAX number: +44 20 7882 2180 Street: 4 Newark Street, Whitechapel City: London Postal Code: E1 1BB Email: g.giovannoni@qmul.ac.uk Country: United Kingdom Public Summary of Major Accomplishments Introduction We made substantial contributions with regard to all five components of our Promise 2010 Programme. Importantly, in collaboration with the UK MS Clinical Trials Network, we have started a neuroprotective clinical trial and are awaiting decision regarding funding for two other studies. Our research 5 aims: 1. To develop and validate effective experimental models for studying the intricate relationship between inflammation, neuroprotection and neurorestoration. 2. To use these models to study specific neuroprotective and neurorestorative therapeutic strategies. 3. To develop novel clinical trial designs aimed at studying focal nervous system repair and more global neuroprotection strategies in people with MS. 4. To identify biomarkers for non-invasive monitoring of nervous system repair and protection. 5. To design a phase2b/3a neuroprotective trial for testing the efficacy of a small molecule or combination therapy in progressive MS. NMSS TRP 5th Year Progress Report Page 1 of 8 July 2012
  • 2. Aim 1: Experimental Models - David Baker, Larry Steinman & Sam Jackson 1. We have explored combination therapy experiments in our animal model of progressive MS. This has informed and underpinned our strategy that to effectively delay disease progression in MS (primary and secondary) we will need to combine therapies targeting several pathways involved in progressive MS. This is why we are promoting an anti-inflammatory combined with a neuroprotective drug in our proposed SPMS trial. 2. Animal studies screening several compounds have provided evidence for their neuroprotective effects and support our ongoing clinical trials in progressive MS. 3. Work done on drugs from the family of sphingosine-1-phosphate modulators has produced very promising results in our animal model. It suggests that this group of compounds has neuroprotective properties, in addition to their well-known anti-inflammatory properties. Fingolimod is currently being tested in PPMS (we are a clinical site) and one of the new sphingosine-1-phosphate modulators will be tested in SPMS. 4. We have identified several new therapeutic targets that we are taking forward with additional grant funding; these grants involve novel drugs and hence are a long way off being tested in human subjects. The main target of these drugs are a specific channel on nerve cells and a group of drugs that target the mitochondria; the latter are the energy factories of the cell. 5. We have developed an animal model of optic neuritis with the means to measure and assess the function of the optic nerve function in live animals. This has allowed us to use this model to test neuro-protective and restorative therapies. Data from this animal model has led to the design of a clinical study that is currently been funded by the NMSS. Aim 2: Neuroprotective and neurorestorative strategies – Yuti Chernajovsky 1. We extended the work on reprogramming cells to produce specific growth factors in the brain of animals with MS-like disease. As a result of this Prof. Chernajovsky has obtained additional funding to take work forward, in collaboration with Professor Charles, ffrench-Constant, in Edinburgh. 2. We successfully created several novel carrier proteins with the ability to release cytokines (immune messengers) into inflamed lesions in animals NMSS TRP 5th Year Progress Report Page 2 of 8 July 2012
  • 3. with an MS-like disease. At present Amgen, the large US Biotech Company, are doing due diligence on one family of these compounds. Aim 3: Novel trial design - Gavin Giovannoni 1. As you are aware we have been involved in two exploratory neuroprotective monotherapy placebo-controlled clinical trials in the United Kingdom. a. Lamotrigine, a drug used in epilepsy that has been shown to protect nerves, was assessed in a phase 2 study to see if it could slow the development of progressive brain shrinkage in subjects with SPMS. The principal investigator of this study is Dr Raj Kapoor at the National Hospital for Neurology and Neurosurgery, Queen Square, London. Unfortunately, this study was negative, but has provided us with some interesting insights into how to do SPMS trials. We have also used the samples collected in this study for some innovative biomarker work. b. The second study was a large multi-centre study investigating whether the active compound in cannabis, THC (Tetrahydrocannabinol), could slow the progressive phase of the disease. This was being coordinated by Prof. John Zajicek from the Peninsula Medical School in Plymouth (see http://www.pms.ac.uk/cnrg/cupid.php). Unfortunately, this study was negative (results were presented at the British Association of Neurologists meeting in April 2012). Although this study was negative, a post-hoc analysis showed that in MSers with lower levels of disability on entering the study, EDSS <5.5, derived benefit from THC. Therefore we should aim to target MSers with lower levels of disability when doing progressive studies. 2. As part of the UK MS Clinical Trial Network we completed several commissioned tasks that have been used to inform clinical trial design. The commissioned work included: a. An analysis of published neuroprotective studies in animal models of MS (due to be published by the Edinburgh Group). b. The development of an adaptive trial, to see if it is feasible to perform a multi-arm trial in patients with progressive disease. The study designs from this component have been published: NMSS TRP 5th Year Progress Report Page 3 of 8 July 2012
  • 4. (1) Friede T, Parsons N, Stallard N, Todd S, Valdes Marquez E, Chataway J, Nicholas R. Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis. Stat Med. 2011 Jun 15;30(13):1528-40. (2) Chataway J, Nicholas R, Todd S, Miller DH, Parsons N, ValdésMárquez E, Stallard N, Friede T. A novel adaptive design strategy increases the efficiency of clinical trials in secondary progressive multiple sclerosis. Mult Scler. 2011 Jan;17(1):81-8. c. An in-depth clinical outcome measures analysis to define the most appropriate set of clinical outcomes to be used in phase 2b/3a neuroprotective studies. This is being led by Prof. Jeremy Hobarts (Plymouth) and is ongoing and will be completed in the next 12-18 months. d. A biomarker validation study to make sure that the assays that we plan to use in the clinical trial have been appropriately validated. This report has been completed. e. Animal studies in independent laboratories to check whether or not compounds that have been claimed to be neuroprotective in the secondary progressive disease are in fact neuroprotective. Several drugs were re-tested by two independent laboratories, including our own. The results were used to inform drug choices for our proposed progressive MS trial. f. We have submitted a large grant to the NIHR (National Institute of Health Research) to perform a phase 2 study (screening part of the adaptive design) to test 4 putative neuroprotective compounds in progressive MS. This study includes an add-on spinal substudy to assess the utility of CSF neurofilament levels in progressive trials. We will know if we have been successful with our application in October 2012. 3. In collaboration with Dr Peter Dabnichki, Engineering QMUL, and Grass Roots, a private IT company, we developed a web-based test for assessing upper-limb motor function in people with MS. This has been validated in a cross-sectional study and correlates with the 9-hole peg test, the most commonly used upper limb motor test. The aim is to include this test in a NMSS TRP 5th Year Progress Report Page 4 of 8 July 2012
  • 5. battery of web-based tests in future MS neuroprotection studies. 4. We completed a cross-sectional study showing that motor activity as detected using the Actiwatch system correlated with EDSS, 9-hole peg test and timed 25-foot walk. This data has been presented at the ECTRIMS meeting in 2011 and will be submitted for publication shortly. We would therefore recommend that motor activity is measured using this device in future exploratory progressive MS trials so that it can be validated longitudinally as a potential outcome measure in neuroprotective MS studies. This is a competitive field and several other groups have competing devices. 5. We have successfully applied for and received funding from the NMSS to perform a trial of Phenytoin (a sodium channel blocker) in acute optic neuritis. This trial has started recruiting subjects (see Appendix). 6. We have prepared and submitted a grant application to the NMSS to perform a neuroprotective study to assess the impact of oxcarbazepine on CSF neurofilament levels in SPMS. We will hear in August 2012 whether or not this study will be funded. Aim 4: Biomarker studies – Gavin Giovannoni & Sam Jackson 1. We have confirmed that blood levels of the neuronal protein, neurofilament, is a good marker of nerve cell loss in an animal model of motor neurone disease and that you can impact on the amount of NF released with a neuroprotective therapy. We have shown a similar effect in our animal model of MS. Gnanapavan S, Grant D, Pryce G, Jackson S, Baker D, Giovannoni G. Neurofilament a biomarker of neurodegeneration in autoimmune encephalomyelitis. Autoimmunity. 2012 Jun;45(4):298-303. 2. We measured the levels of neurofilament in the samples collected from patients participating in the Phase 2 Lamotrigine Trial in Secondary Progressive MS. Interestingly these levels predicted clinical outcome. A paper has been prepared and will be submitted shortly for publication. 3. One of the difficulties associated with biomarker research remains the scarcity of clinical samples. Therefore any sample should have its potential use maximised. The more analyses which can be performed on single sample the better. This is particularly important when NMSS TRP 5th Year Progress Report Page 5 of 8 July 2012
  • 6. dealing with sample volumes from animals in our studies that are very small. We have therefore successfully converted our neurofilament assay onto a new technology platform called the Mesoscale Discovery (MSD) platform. This technology has allowed us to miniaturize our existing assays, to measure multiple proteins in the same assay and to perform serial studies on animals using very small blood volumes. We are currently using this assay for processing a large number of samples from our sample bank. The data has yet to be analysed. 4. Sharmilee Ganapavan, the clinical research fellow, who worked on the Promise 2010 biomarker programme developed and validated several human assays. Some of her data has recently been published. Gnanapavan S, Grant D, Illes-Toth E, Lakdawala N, Keir G, Giovannoni G. Neural cell adhesion molecule--description of a CSF ELISA method and evidence of reduced levels in selected neurological disorders. J Neuroimmunol. 2010 Aug 25;225(1-2):118-22. Aim 5: To design a phase2b/3a neuroprotective trials – Gavin Giovannoni 1. We have successfully applied for and received funding from the NMSS to perform a neuroprotective trial of Phenytoin (a sodium channel blocker) in acute optic neuritis. This trial has started recruiting subjects (see Appendix). 2. We have prepared and submitted a grant application to the NMSS to perform a neuroprotective study to assess the impact of oxcarbazepine on CSF neurofilament levels in SPMS. We will hear in August 2012 whether or not this study will be funded or not. 3. We have submitted a large grant to the NIHR (National Institute of Health Research) to perform a phase 2 study (screening part of the adaptive design) to test 4 putative neuroprotective compounds in progressive MS. This study includes an add-on spinal substudy to assess the utility of CSF neurofilament levels in progressive trials. We will know if we have been successful with our application in October 2012. Conclusions In the five years of Promise 2010 we made progress in all areas of our programme. Importantly, we identified several small-molecule compounds NMSS TRP 5th Year Progress Report Page 6 of 8 July 2012
  • 7. that are neuroprotective in animal models of MS and are testing these in clinical trials. Some of these molecules are novel and we are in the process of using additional funds to develop these further, for example one project is being funded by FastForward and we have a grant application with the Wellcome Trust for the second class of compounds. We combined several neuroprotective compounds to produce a “neuroprotective cocktail” or “polypill”, unfortunately we have had difficulties taking this forward as the regulatory requirements for testing combination therapies is too complex and pharmaceutical companies are resistant to invest money in combination strategies until there is regulatory clarification. Studies to develop new therapies to deliver growth factors to the sites of inflammation were successful to a point; we have had follow-on funding to take the cell-based strategies forward and a large Biotech has expressed interest in one family of engineered molecules. We have developed a very exciting new animal model of optic neuritis with the ability to monitor visual function in live animals. This animal model has already been useful to test neuroprotective strategies; we are currently using the model to test stem cell therapies that are being developed to promote remyelination and neuro-restoration. Finally, we will continue to be involved in several collaborative initiatives to improve MS neuroprotective clinical trial design. In conclusion the “Promise 2010 Programme” has had a major impact on our careers and has served as a launch pad for numerous collaborative projects. It has also made us realize that progressive MS is the “holy grail” in multiple sclerosis research and that we will need the best talent to overcome this problem. Promise 2010 has invested in that talent. The good news is that since the launch of the Promise 2010 Programme, Big Pharma has reengaged with the field of progressive MS. Novartis started, and have completed recruitment, of a trial of Fingolimod in PPMS, Roche are sponsoring a trial of ocrelizumab (anti-CD20) in PPMS, Biogen-Idec have started a study to assess natalizumab in SPMS and several other companies are planning trials in progressive MS. Progressive MS is clearly uppermost in their minds. Despite these developments the level of expectation from the MS community remains, in my opinion, unrealistic. Despite an active education programme as part of our public engagement in science initiative, a recent survey has shown that, a significant number or MSers (45%) still expect an effective neuroprotective therapy to restore lost function. At this point in time I think this is unrealistic and we should spend more time engaging with the community in such a way so as not to disappoint them. NMSS TRP 5th Year Progress Report Page 7 of 8 July 2012
  • 8. We look forward to a meeting in 2015 when we will be able to assess if the investment in the Promise 2010 programme has delivered tangible results; a treatment for people with progressive MS. The following is the result of a survey completed on our blog (www.msres.org) to assess what MSers expect from a neuroprotective therapy. Clearly we have some way to go. NMSS TRP 5th Year Progress Report Page 8 of 8 July 2012

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