1. Ataxia research update Ataxia Ireland conference 28 Sep 2013 Dr Alison Stevenson

2. Overview Research developments in: Diagnosis Finding treatments in Friedreich’s ataxia Finding treatments in the cerebellar ataxias Moving from basic research to trials Funding research collaboratively

3. Ataxia UK and Ataxia Ireland joining forces Funding from

4. Developments in diagnosis Ataxia has many causes Correct diagnosis is important – for prognosis, management and to identify rare TREATABLE forms Examples of treatable forms: Gluten ataxia Ataxia with CoQ10 deficiency Ataxia with Vitamin E deficiency

5. Improving diagnosis – genetic testing Many people do not have a specific diagnosis; idiopathic, no known cause Genetic ataxias can be diagnosed by genetic tests eg spinocerebellar ataxias (SCAs); >36 types But tests for all are not available and are performed on single genes at a time

6. Next generation sequencing for diagnosing inherited ataxias New genetic techniques developed that screen more genes than was possible eg: NGS of ataxia genes (Oxford) eg: exon sequencing (Newcastle, London) More accurate diagnoses

7. Gluten ataxia One year trial showed improvements in ataxia with gluten-free diet Important to get early diagnosis Research from Sheffield Ataxia Centre identified a new more sensitive test Could lead to more people with a diagnosis of gluten ataxia

8. Friedreich’s ataxia research developments

9. Energy production Free radical damage Iron mis-localisation Iron mis-localisation What happens in Friedreich’s ataxia? Ataxia ? MutatedFrataxinGeneMutatedFrataxinGene FrataxinProteinFrataxinProtein Cell structural changes

10. A new pathway for Friedreich’s ataxia Investigating new pathways in Friedreich’s ataxia Changes in cell structure were seen – could this be caused by something other than low frataxin protein? PIP5K1-beta gene is ‘turned off’ Encodes a protein that regulates cytoskeleton More studies required to fully understand this discovery Funding from

11. Energy production Free radical damage Iron mis-localisation Iron mis-localisation Tackling Friedreich’s ataxia MutatedFrataxinGeneMutatedFrataxinGene FrataxinProteinFrataxinProtein Antioxidants Iron Chelators Iron Chelators Protein Therapy Drugs to  frataxin Gene Therapy Drugs to turn frataxin gene on Drugs to turn frataxin gene on

12. Antioxidants ‘Mop up’ free radicals Prevent damage from free radicals Improve energy production in cell MutatedFrataxinGeneMutatedFrataxinGene FrataxinProteinFrataxinProtein Energy production Free radical damage Iron mis-localisation Iron mis-localisation Antioxidants

13. Idebenone Similar to CoQ10 A powerful antioxidant Clinical trials in USA and Europe showed trends towards improvements but no significant changes Data is insufficient to licence idebenone for Friedreich’s ataxia Will PROTI study show that taking idebenone can be beneficial?

14. Future of idebenone? Awaiting results of PROTI study In Canada, sale of idebenone (Catena) has been discontinued Available on a named patient basis in the UK

15. Other antioxidants Vitamin E and CoQ10 Possibly beneficial to people who have low levels A0001 Well tolerated; some neurological symptoms improved More studies needed EPI-743 Recruiting in the USA for a Phase II trial (Edison) OX-1 Phase II clinical trial? (Viropharma) EGb761 No published data

16. Other antioxidants (contd) Pioglitazone (Actos) Prescribed for type II diabetes Enhances antioxidant response; improves energy production; may influence frataxin levels 2 year trial; on-going Resveratrol Neuroprotective; increases frataxin levels Pilot study; 2 different doses for 12 weeks, open label Measuring frataxin levels, oxidative stress, ataxia and heart function Results show some promise so other trial planned

17. Iron chelators Iron chelators ‘mop up’ excess iron Hypothesis: iron chelators will mop up excess iron from mitochondria and improve energy production Caution: not to deplete iron from other parts of the cell MutatedFrataxinGeneMutatedFrataxinGene FrataxinProteinFrataxinProtein Energy production Free radical damage Iron mis-localisation Iron mis-localisation Iron Chelators Iron Chelators

18. Deferiprone clinical trials Deferiprone Long-term safety, tolerability and efficacy Awaiting results Deferiprone & idebenone Generally well-tolerated Mixed results for efficacy Deferiprone, idebenone & riboflavin Possibly some neurological and heart benefits; inconclusive results 4 of 13 participants withdrew (adverse effects) More studies needed; monitoring and regular health checks important

19. Drugs to increase frataxin: EPO-alpha Erythropoietin (EPO) - hormone that promotes red blood cell production EPO-alpha – for anaemia, cancer and other critical illnesses Neuroprotective; increases frataxin protein – mode of action is unknown Drugs to  frataxin AtaxiaMutatedFrataxinGeneMutatedFrataxinGeneFrataxinProteinFrataxinProtein

20. EPO-alpha clinical trial Phase II randomised double-blind placebo-controlled trial Long term effects; exercise capacity, safety and tolerability Recruiting in Italy Caution with EPO; it can: Increase red blood cell production Lower iron levels

21. Interferon gamma Naturally occurring molecule; involved in the body’s immune response Licensed for two other rare conditions Increases frataxin in cells and mice Two human clinical trials: Italy – safety of 3 escalating doses (adults) USA – identifying safe dose for children Orphan drug status registered

22. HDAC inhibitors Histone deacetylase inhibitors (HDCAi) Switch frataxin gene back on Ataxia MutatedFrataxinGeneMutatedFrataxinGene FrataxinProteinFrataxinProtein HDACi

23. RG2833 Developed by researchers at Scripps Research Institute and Repligen Phase I pilot study in Turin completed; some preliminary results: –Well tolerated; no severe adverse events –All participants completed the trial –Increased frataxin gene activity –Proof of concept achieved; HDACi can ‘switch on’ the frataxin gene Developing a better version of RG2833 Funding from

24. Nicotinamide / Vitamin B3 Increases frataxin levels in cells from people with Friedreich’s ataxia Good safety profile Trial is looking at safety of the compound and its ability to increase frataxin levels Trial is on-going Funding from

25. Summary of Friedreich’s ataxia clinical trials Awaiting results Idebenone, pioglitazone, resveratrol, EGb761 Deferiprone RG2883 On-going trials EPI-743 EPO-alpha, interferon-gamma, nicotinamide Future trials OX-1

26. Cerebellar ataxia research developments

27. The cerebellum is a processing centre Receives input from and send messages to other parts of the brain and central nervous system. Important in the control of balance, coordination and movement. Compromised function = cerebellar ataxia cerebellum

28. Causes of cerebellar ataxia Over 60 types of cerebellar ataxia Many have a genetic cause These are classified according to the gene that is mutated eg >36 SCAs

29. Finding treatments: a drug screen for SCA3 Genetically modified worms (C elegans) develop symptoms of SCA3 Used to screen 2,800 FDA-approved and off-patent drugs 30 ‘hits’ 2 most promising ‘hits’ being tested in a mouse model of SCA3

30. Exon-skipping for the ataxias A new technique to eliminate the effects of mutated parts of genes and prevent toxicity Tested for SCAs 3, 7, 17 and DRPLA SCA3: Good skipping of faulty part of gene Non-toxic protein produced More testing in SCA3 animal models required Clinical trials for Duchenne muscular dystrophy

31. Clinical trials: Riluzole Approved treatment for amyotrophic lateral sclerosis Rationale – riluzole will regulate nerve impulses in the cerebellum Small 8 week trial showed some improvements in neurological symptoms Follow-up study: 60 people with hereditary ataxia 12 months Double-blind, placebo-controlled trial Recruiting in Italy

32. Varenicline Anti-smoking medication (Champix) Small, 8 week trial showed some cautiously positive results in people with SCA3 Some walking and standing improvements but overall not significantly better than the placebo group More studies over longer time periods are required

33. CoQ10 Naturally occurring antioxidant Deficiency can cause ataxia Inconclusive results from clinical trials New diagnostic test developed; will also be useful for measuring levels in trials CoQ10 testing is available

34. Other drugs in clinical trials Dalfampridine (4-aminopyridine, Ampyra) For EA2; USA, invitation only For gait in SCA; USA, recruiting Lithium for SCAs 1, 2, 3 Trials completed Awaiting results High dose immunoglobulin For spinocerebellar degeneration KP-0373 For spinocerebellar degeneration

35. Summary of cerebellar ataxia research developments Clinical trials - awaiting results Lithium for SCAs 1, 2, 3 Clinical trials - on-going Riluzole for hereditary CA Dalfampridine for EA2 Dalfampridine for SCAs Alleviating symptoms Move ‘n’ fun Finding treatments - research continues

36. Alleviating symptoms: Move ‘n’ fun Aim: to assess coordinative training in children with ataxia Based on benefits from similar training in adults Training will use videogames controlled by full body movements and can be done at home Funding from

38. Results are promising Tested 10 children with progressive ataxias 8 week programme Assessed before and after treatment Found improvements in ataxia ataxia rating scale (SARA –especially posture) Quantitative movement analysis (decrease in step variability, lateral sway and errors in goal directed leg placements)

39. Challenges for clinical trials Ataxia is not a stable condition Measuring changes is difficult No change can be an improvement for a progressive condition Numbers of people to recruit to clinical trials is limited Treatment may be effective for a subset of people Intellectual property Developing a new drug, even if everything goes well, take a long time

40. In our favour… More drugs in trials than ever before Strong, collaborative research community Large European research consortia working on Friedreich’s ataxia and the cerebellum Dedicated supporters Fundraising Participating in research projects Collaborations with other ataxia organisations Pharmaceutical companies eg Pfizer

41. Thank-you for listening!