CLINICAL TRIALS AND NATURAL HISTORY STUDY Vikram Shakkottai, MD, PhD University of Michigan

Ataxia trials  82 listed studies on Phase ISmall group (20-100). Assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug Phase IILarger group (20-300). Designed to assess efficacy, as well as to continue Phase I safety assessments Phase IIIRandomized controlled multicenter trials on larger groups (300–3,000). Aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment.

Sporadic ataxia StudyAimLocationPIResults RiluzolePhase IIS. Andrea Hospital (Italy) Giovanni RistoriRiluzole reduces ICARS score by > 5 points Coenzyme Q10 Phase IUT Galveston UF H SubramonyCompleted/ Unpublished Rifampicin (MSA) Phase IIIMulti-centerPhillip Low David Robertson Sid Gilman Not yet recruiting Lithium (MSA) Phase IIUniversity Federico II (Italy) Alessandro FillaOngoing

Friedreich Ataxia  20 studies StudyAimLocationPIResults IdebenonePhase IIIUCLA CHOP Susan Perlman David Lynch No significant alteration in neurological function at 6- months (Arch Neurol :941-7) DeferipronePhase IIBelgium France Italy Spain Massimo Pandolfo Arnold Munnich Franco Taroni Javier Arpa Completed/ Unpublished Epoetin alfaPhase IIFederico II University (Italy) Alessandro FillaOngoing Carbamylated Erythropoietin Phase IIAustria Germany Italy H. Lundbeck A/S (company) Ongoing

Dominant ataxias StudyAimLocationPIResults Lithium (SCA1) Phase INIHCompleted/ Unpublished RiluzolePhase II/III S. Andrea Hospital Silvia RomanoOngoing Varenicline (SCA3) Phase IIUSF UCLA Theresa ZesiewiczOngoing

Riluzole in ataxia  In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks.  Outcome measure: 5 points in the International Cooperative Ataxia Rating Scale (ICARS).  The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 8 weeks (13/19 vs 1/19). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score vs  Sporadic, mild adverse events occurred. Ristori et. Al., Neurology. 2010;74:

Riluzole in ataxia Ristori et. Al., Neurology. 2010;74:

Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias  To establish a new multidisciplinary consortium that provides the infrastructure for future clinical trials to test safety and efficacy of therapeutic interventions for spinocerebellar ataxias.  Rare Disease = # of Patient <200,000 in US

Participating Sites of SCA-CRC Original Sites ( )  University of Florida: Ashizawa, Subramony  UCLA: Perlman  University of Chicago: Gomez  Emory University: Wilmot  University of Michigan: Paulson  University of Minnesota: Bushara  University of South Florida: Zesiewicz  University of Utah: Pulst Voluntary Participants ( )  Johns Hopkins University: Ying  Harvard University: Schmarmann  UCSF: Kang  Columbia University: Kuo/Fahn  NIH, NINDS: Galpern, ORDR: Ferguson  EuroSCA, Brazil, Japan Patient Support Organizations  National Ataxia Foundation: S. Hagan  Sparkman Fund

Specific Aims of SCA-CRC  Aim 1. Establish the organizational foundations for the CRC- SCA  Aim 2. Recruit patients, obtain longitudinal clinical data for future clinical trials, and develop novel methods for clinical trials for a small sample size.  Aim 3. Initiate a pilot study to determine genetic modifiers of SCA 1, 2, 3 and 6  Aim 4. Establish a training program for cultivating physician- scientist investigators for clinical and translational research of SCA

Aim 1. Establish the organizational foundations for the CRC-SCA  Participating institutions  12 US institutions  NINDS  NAF  DMCC  EuroSCA, Brazil, other countries

Aim 2. Recruit patients and obtain longitudinal clinical data for future clinical trials  Natural History Database: Patients with SCA 1, 2, 3 & 6  Quantitative measures of ataxia  Keyboard Click Test  SARA scale  Pegboard test  Stepwatch activity monitor

Stepwatch Activity Monitor Logitech Media Keyboard (39 cm between “~” and “-”)

 Determine ataxia mutations  All patients in the Natural History Database  SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and DRPLA.  Identify genetic modifiers of the age of disease onset  Variation in normal polyQ length in genes associated with neurodegeneration  Candidate genes (hSKCa3, RAI1, and ApoE)  Collaborations with EuroSCA Aim 3. Initiate a pilot study to determine genetic modifiers of SCA 1,2,3 and 6

 Develop a comprehensive Training Program  Recruit candidates and select trainees Aim 4. Training

Current enrollment Type of SCANMean age ± SDAge rangeAge at onset SARA SCA ± SCA ± SCA ± SCA ± Total ±

Future directions Spin-off clinical trials:  Varenicline for SCA3  Lithium for SCA1  CoQ10 for SAOA  Riluzole for SCAs

Acknowledgements  Tetsuo Ashizawa  H. Subramony  National Ataxia Foundation  NIH 5RC1NS (PI Ashizawa)  Training component of the NIH 5RC1NS068897