March 18, 2011NAF AMM LA CA Bringing the Ataxia World Together The LA Experience and an Ataxia Medical Update Susan L. Perlman M.D. Clinical Professor

March 18, 2011 NAF AMM LA CA Bringing the Ataxia World Together

The LA Experience and an Ataxia Medical Update

Susan L. Perlman M.D.Clinical Professor of NeurologyDirector, UCLA Ataxia CenterMedical Director, NAF


Los Angeles is much more than Hollywood and the Beach Boys

• It started with a seafaring culture in Southern California in 8,000 B.C.;

• Incorporated Native Americans of the Hokan and Uto-Aztecan cultures, the Spanish, and ultimately all the rest of us;

• And will end when THE BIG ONE drops us back into the sea.


And I believe it is home to the first Ataxia Center West of the Mississippi


And home to some pretty nice weather most of the time


UCLA ATAXIA/NEUROGENETICS CENTER

• Founded--mid-1970’s as a research clinic for Friedreich’s Ataxia.

• Has a database of over 3000 neurogenetics patients, most with ataxic disorders, as well as a DNA bank. Works with two tissue banks.

• Evaluates about 75 new ataxia patients each year.• Evaluates asymptomatic individuals at-risk for ataxia.• Provides continuity care for many of these individuals.

• Multidisciplinary model (multi-specialty Physician, Nursing, Social Work, Psychology, PT, OT, Orthotics, Speech, Nutrition, Genetics).

• Is a member of the Cooperative Ataxia Group (www.cooperative-ataxia-group.org) and the Collaborative Clinical Research Network for FA, and collaborates with other “ataxologists” across the USA and around the world.

• Provides educational programs and inservice training, as well as community outreach through the National Ataxia Foundation (www.ataxia.org) and Friedreich’s Ataxia Research Alliance (www.curefa.org).

http://www.cooperative-ataxia-group.org/

http://www.ataxia.org/


UCLA ATAXIA CENTER DEMOGRAPHICS

• Catchment area—southwestern US, remaining US, Mexico, Canada, Pacific Rim, providing great ethnic and cultural diversity (but few large pedigrees).

• 40% of cases have either Friedreich’s ataxia or a known SCA

• 60% of cases have unknown genotype or sporadic presentation, spurring the search for new genes and epidemiologic factors

Ethnic Distribution

Middle East / Mediterr

3% Hispanic

17%

Caucasian / NW Europ

52%

Asian 14%

African- American

14%

Distribution of Ataxia Syndromes

Known SCA 18%

Other 61%

Friedreich’s Ataxia 21%

Distribution of Dominant Cases

SCA6 11%

SCA7 5%

Other55%

SCA1 5%

SCA2 10%

SCA3 14%

SCA6

SCA7

Other

SCA1

SCA2

SCA3


UCLA ATAXIA CENTER 1562 PATIENTS SEEN BETWEEN 1995 AND 2005

(CURRENTLY BEING UPDATED)

• GENETIC (Total 656)• Dominant (329) SCA1 15 Cadasil 7 SCA2 32 DRPLA 2SCA3 68 GSS 8SCA6 34 SPG4 2SCA7 14 FXTAS 2SCA8 6SCA10 2 SCA13 2 SCA14 2SCA17 3 Known mutation 196 Unknown mutation 129No one yet with SCA 12• Recessive (250)A-T 26EOCARR 6 (AOA1 1, AOA2 5)Friedreich’s Ataxia 75 (looks like FA but isn’t 112)LOFA 14Confirmed inborn errors 6Late-onset Tay Sachs 11• X-linked or Mitochondrial (80)AMN 10Rett 2Pedigree suggests X-linked 8Confirmed mitochondrial point mutation 6Looks like mitochondrial but isn’t 54

• UNKNOWN GENE/SPORADIC (Total 904)Adult Arnold-Chiari, CP, other congenital 30Combined cortical atrophy 14HSA/HSP 76Immune-mediated 12 MSA 72NPH 7Paraneoplastic 11Post-infectious 17PSP 20Pure cerebellar (ILOCA) 219SOPCA 97Retroviral 7Vascular, post-anoxic, post-trauma 52With known nutritional/toxic cause 16With dementia 11With diabetes insipidus 1With dizziness, vertigo, episodic 71With dystonia 17With myoclonus 32With neuropathy 51With spasticity 53With tremor 14 With white matter changes (not MS or Cadasil) 4


OUR GOALS HAVE BEEN TO ANSWER THE QUESTIONS ASKED BY OUR ATAXIA PATIENTS

TO MAXIMIZE THEIR QUALITY OF LIFEAND TO GET THEM INVOLVED IN RESEARCH

• WHAT DO I HAVE? • WHAT IS THE CAUSE? • ARE MY CHILDREN AT RISK? • WILL IT GET WORSE?

• HOW BAD WILL IT GET? HOW SOON?

• CAN IT BE TREATED?

• CAN IT BE CURED?

• IS THERE ANY RESEARCH BEING DONE? CAN I GET INVOLVED?


HOW FAR HAVE WE COME?

QUESTION 1977 2011

What do I have? 10% known >50% known

Can it be cured? No No

Can it be treated? No drugs tested Rehab helps

18 drugs tested (more on the way) Rehab helps

Is there research? 223 articles 1342 articles

Are my children at risk?

No gene tests available

21 gene tests available($17K), more on the way


1. Diagnosis—Is this Ataxia?• What are we actually seeing?• It is important to nail down a phenotype that can be

retrieved (with the patient) as advances are made in diagnosis and treatment of progressive ataxia.

• The launch of the National Ataxia Registry and Database will make this easier.

• Patient self-registration at: https://www.nationalataxiaregistry.org/• Dr. Subramony is here helping people sign up in the

National Ataxia Registry.


2. Proper Evaluation—Everyone Deserves a Screen For

• Neural localization (MRI, ENG, EPs, EMG/NCV)• Acquired factors--prior illnesses, toxic exposures

or medication (Dilantin, amiodorone)• Other medical problems— thyroid dysfunction

low B12 or E syphilis, EBV, Lyme, HTLV1, HIV rheumatologic factors

• Immune/paraneoplastic— anti-GAD, anti-gliadin, anti-thyroid

anti-Yo, Hu, Ri, others; imaging for hidden Ca• Possible genetic factors—why? Are they treatable? Not yet. But can aid in prognosis and family counseling if found.


Our Approach to the Adult-onset, Predominantly Cerebellar Syndromes

• Assign a phenotype by H & P, imaging, electrodx, LP• Obtain a detailed family and environmental history• Rule out known acquired causes.• Consider genetic testing— Screening for FXTAS, SCA6, FRDA, as well as

SCA1,2, and 3 will identify over 50% of possible inherited causes and cost less than $3000.

2-5% of sporadic cases turn out to be genetic.

• Establish a treatment plan that includes symptomatic medication and rehabilitation.

• Help patients find resources and get involved in research.


Growth of Clinical Research at UCLA (1)the 1980’s

• 1980-82—4 unfortunate publications looking for the cause of Friedreich’s ataxia before we had molecular genetic technologies to help us

• The rest of the 1980’s not so bad, as we focused on the clinical aspects of FA and related ataxias:• Evoked potential abnormalities in the various inherited ataxias.• Nuwer MR, Perlman SL, Packwood JW, Kark RA.• Ann Neurol. 1983 Jan;13(1):20-7.• Eye movements in Friedreich's ataxia.• Furman JM, Perlman S, Baloh RW.• Arch Neurol. 1983 Jun;40(6):343-6.• Cardiac involvement in Friedreich's ataxia: a clinical study of 75 patients.• Child JS, Perloff JK, Bach PM, Wolfe AD, Perlman S, Kark RA.• J Am Coll Cardiol. 1986 Jun;7(6):1370-8.• The mental status of patients with Friedreich's ataxia.• Flood MK, Perlman SL.• J Neurosci Nurs. 1987 Oct;19(5):251-5• Idiopathic central diabetes insipidus followed by progressive spastic cerebral ataxia. Report of four cases.• Birnbaum DC, Shields D, Lippe B, Perlman S, Phillipart M.• Arch Neurol. 1989 Sep;46(9):1001-3.

• And were able to run early pilot studies of physostigmine as a symptomatic treatment for ataxia:• Double-blind, triple-crossover trial of low doses of oral physostigmine in inherited ataxias.• Kark RA, Budelli MM, Wachsner R.• Neurology. 1981 Mar;31(3):288-92.


Growth of Clinical Research at UCLA (2)the 1990’s

• The 1990’s:• Saw the beginning of our ongoing collaboration with the Ataxia Telangiectasia

Research Laboratory at UCLA (Dr. Richard Gatti).

• We continued work with neuro-otology and neuro-opthalmology:• Comparison of oculomotor findings in the progressive ataxia syndromes.• Moschner C, Perlman S, Baloh RW.• Brain. 1994 Feb;117 ( Pt 1):15-25.• Ophthalmologic findings in patients with ataxia.• Rabiah PK, Bateman JB, Demer JL, Perlman S.• Am J Ophthalmol. 1997 Jan;123(1):108-17.• Oculomotor phenotypes in autosomal dominant ataxias.• Buttner N, Geschwind D, Jen JC, Perlman S, Pulst SM, Baloh RW.• Arch Neurol. 1998 Oct;55(10):1353-7.


• And finally the scientific revolution, brought about by molecular genetic technology, opened up the first multi-center collaborations, with Dr. Gomez at U Minn (after his stint at UCLA), as well as our own UCLA-based phenotype/genotype studies.

• The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

• Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM.• Am J Hum Genet. 1997 Apr;60(4):842-50.• Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic

ataxia.• Geschwind DH, Perlman S, Grody WW, Telatar M, Montermini L, Pandolfo M, Gatti

RA.• Neurology. 1997 Oct;49(4):1004-9.• Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype

correlations.• Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM.• Neurology. 1997 Nov;49(5):1247-51.


Growth of Clinical Research at UCLA (3)2000-2010

• In the new millennium:

• We published our first review of symptomatic treatment for ataxia, based on our experiences as well as the published experiences of other “ataxologists”.

• Cerebellar Ataxia.• Perlman SL.• Curr Treat Options Neurol. 2000 May;2(3):215-224.

• Joined Dr. Dave Lynch’s Collaborative Clinical Research Network for FA.• As well as the Cooperative Ataxia Group under Drs. Ashizawa and Subramony.

• And were finally able to get back into drug trials:• A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia.• Lynch DR, Perlman SL, Meier T.• Arch Neurol. 2010 Aug;67(8):941-7.

• And the pilot study of Varenicline in SCA3 under Dr. Theresa Zesiewicz


• Began our collaboration with the neuroimaging groups at UCLA:• Analysis of the brain-stem white-matter tracts with diffusion tensor imaging.• Salamon N, Sicotte N, Alger J, Shattuck D, Perlman S, Sinha U, Schultze-Haakh H,

Salamon G.• Neuroradiology. 2005 Dec;47(12):895-902. Epub 2005 Sep 13.• Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings,

and review of the literature.• Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH.• Arch Neurol. 2005 Dec;62(12):1865-9.• Pontine and cerebellar atrophy correlate with clinical disability in SCA2.• Ying SH, Choi SI, Perlman SL, Baloh RW, Zee DS, Toga AW.• Neurology. 2006 Feb 14;66(3):424-6.• White matter fiber tractography and color mapping of the normal human cerebellum with

diffusion tensor imaging.• Salamon N, Sicotte N, Drain A, Frew A, Alger JR, Jen J, Perlman S, Salamon G.• J Neuroradiol. 2007 May;34(2):115-28.• Patterns of fractional anisotropy changes in white matter of cerebellar peduncles

distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia syndromes.

• Prakash N, Hageman N, Hua X, Toga AW, Perlman SL, Salamon N.• Neuroimage. 2009 Aug;47 Suppl 2:T72-81. Epub 2009 May 14


• Continued our work with genotype/phenotype:• SCA8 repeat expansions in ataxia: a controversial association.• Sobrido MJ, Cholfin JA, Perlman S, Pulst SM, Geschwind DH.• Neurology. 2001 Oct 9;57(7):1310-2.• Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia.• Figueroa KP, Chan P, Schöls L, Tanner C, Riess O, Perlman SL, Geschwind DH, Pulst SM.• Arch Neurol. 2001 Oct;58(10):1649-53.• The SCA12 mutation as a rare cause of spinocerebellar ataxia.• Cholfin JA, Sobrido MJ, Perlman S, Pulst SM, Geschwind DH.• Arch Neurol. 2001 Nov;58(11):1833-5.• Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations.• Kerber KA, Jen JC, Perlman S, Baloh RW.• J Neurol Sci. 2005 Nov 15;238(1-2):41-5. Epub 2005 Aug 16. Review.• Depressive and memory symptoms as presenting features of spinocerebellar ataxia.• McMurtray AM, Clark DG, Flood MK, Perlman S, Mendez MF.• J Neuropsychiatry Clin Neurosci. 2006 Summer;18(3):420-2.• Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.• Fogel BL, Perlman S.• Neurology. 2006 Dec 12;67(11):2083-4. • A family with combined mutations of the hemophilia A and X-linked adrenoleukodystrophy genes.• Fogel BL, Young P, Thompson AR, Perlman S.• Neurogenetics. 2008 Jul;9(3):215-8. Epub 2008 May 15.• Aberrant splicing of the senataxin gene in a patient with ataxia with oculomotor apraxia type 2.• Fogel BL, Lee JY, Perlman S.• Cerebellum. 2009 Dec;8(4):448-53.• Candidate Screening of the TRPC3 Gene in Cerebellar Ataxia.• Becker EB, Fogel BL, Rajakulendran S, Dulneva A, Hanna MG, Perlman SL, Geschwind DH, Davies KE.• Cerebellum. 2011 Feb 16.


Clinical Studies We are Currently Doing at UCLA

1. Clinical Research Consortium for Spinocerebellar Ataxias [CRC-SCA] to Study Natural History and Genetic Modifiers in Spinocerebellar Ataxias [SCA]--Natural History Study for SCA1, 2, 3, and 6 only.

Not a drug trial. All ages and levels of disability. Visits every 6 months for 2 years. No travel reimbursement.

2. Clinical Outcome Measures in Friedreich Ataxia--Natural History Study for Friedreich's Ataxia.

Not a drug trial. All ages and levels of disability. Visits once a year. Some travel reimbursement.

3. Molecular Genetic Studies in Diseases of the Brain Affecting Movement and Balance--one visit for anyone with any type of ataxia, all ages and levels of disability. Not a drug trial. A neurological history and exam plus blood draw will be done. No travel reimbursement.

4. Benefits of Hydrotherapy Versus Conventional Physical Therapy in the Treatment of Friedreich Ataxia--open to Friedreich's ataxia patients 18 years of age and older who are still ambulatory (with or without assistive devices) and can come in for physical therapy 3 mornings per week for 1 to 3 months. No travel reimbursement.


The Geschwind Lab for Basic Research

• Dr. Daniel Geschwind is the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and is a professor of neurology and psychiatry at the UCLA School of Medicine. He is director of the Neurogenetics Program and the Center for Autism Research and Treatment (CART) and co-director of the Center for Neurobehavioral Genetics at UCLA.

• The Geschwind laboratory is working to improve our understanding of human neuropsychiatric diseases, such as autism and neurodegenerative diseases, and their relationship to the range of normal human higher cognitive function. We use a combination of genetic, functional genomic and neurobiological methods in our work--frequently in collaboration with other laboratories or disciplines. Our methodological focus involves the application of network analyses and systems biology, which offer the promise of integration of multiple levels of data, connecting molecular pathways to nervous system function in health and disease.


Partners in Clinical Neurogenetics Research at UCLA

• Daniel Geschwind, M.D., Ph.D., Neurogenetics Program Director (Molecular Genetics, DNA bank)• Susan Perlman, M.D., Ataxia Clinic Director (Ataxia Database, Drug Trials)• Robert Baloh, M.D. (Neuro-Otology)• George Bartzokis, M.D. (Neuroimaging, Biomarkers)• Yvette Bordelon, M.D., Ph.D. (Huntington’s disease, Biomarkers, Drug Trials)• Stephen Cederbaum, M.D. (Medical Genetics, Metabolic Disorders)• Giovanni Coppola, M.D. (Molecular Genetics)• Brent Fogel, M.D., Ph.D. (Molecular Genetics, DNA bank)• Ming Guo, M.D., Ph.D. (Drosophila)• Michelle Hamilton, M.D., Juan Alejos, M.D. (Cardiology)• Joanna Jen, M.D., Ph.D. (Episodic Ataxias, Drug Trials)• Arik Johnson, Psy.D. (Psychology)• Catherine Mamah, M.D. (Molecular Genetics)• William Oppenheim, M.D. (Orthopedics)• Noriko Salamon, M.D. (Neuroradiology)• Eric Wexler, M.D., Ph.D. (Psychiatry)• Ernest Wright D.Sc., Ph.D, Vladimir Kepe Ph.D,, Jorge Barrio Ph.D. (Neuroimaging, Biomarkers)

• GlennyJane Gabriel — Clinic Coordinator (310) 825-3370• Tarshiah Nulliah— Ataxia Research Coordinator (310) 206-8153• Barbara Fallick, MSW — Social Work Coordinator (310) 794-1225 • Michelle Fox, M.S. — Genetic Counselor (310) 206-6581

• New Patient Appointments — (310) 794-1195 and follow the menu


Goals for Future Clinical Trials at UCLA

• A longitudinal natural history study for people with non-genetic ataxia or less common genetic ataxias.

• An epidemiologic study of environmental and lifestyle factors that can influence the cerebellum and progression of ataxia.

• More Drug trials—pilot or Phase I, II, or III for the SCAs for Friedreich’s ataxia for Ataxia Telangiectasia for other recessive ataxias for non-genetic ataxia for Multiple System Atrophy

• Our clinical neurogenetic research team is eager to push forward with these important projects, together with all our colleagues here and around the world. We need each other and WE NEED YOU.



Upcoming Ataxia Medical UpdateDiagnosis, Symptomatic Treatment, Disease-Modifying Therapy, Resources

• You will be hearing a lot more about advances in all areas of ataxia over the rest of the convention and in the Birds of a Feather sessions:

• The rest of Friday morning:9:45 a.m. ............ Melinda Guttry, PT & Jacquelyn Glenn, OTR ......OT/PT for Ataxia

• 10:40 a.m. .......... Anne Lefton, CCC-SLP ......................................... Speech & Swallowing• 11:20 a.m. ........... Al LaSpada, MD, PhD, FACMG ............................ Poly Q SCAs/SCA7

• Saturday• 8:30 a.m. ............ Jamie Hoffman, CTRS ............................ Adaptive Recreation, What You CAN DO!• 8:55 a.m. ............ Richard Ivry, PhD .................... How Cerebellar Dysfn Affects Motor Control• 9:20 a.m. ............ Joel Gottesfeld, PhD ............................... HDAC Inhibitors in FRDA• 9:45 a.m. ............ Vikram Shakkottai, MD, PhD .................. Clinical Trials and Natural History Study• 10:10 a.m. .......... Theresa Zesiewicz, MD, FAAN ............... Analysis of Chantix Clinical Trial• 10:35 a.m. .......... Clive Svendsen, PhD .............................. Stem Cell Research for Ataxia• 11:00 a.m. .......... Henry Paulson, MD, PhD ........................ Research Update• 2:00 p.m. ............ Christopher Gomez, MD, PhD ................ Medication for Ataxia Symptoms• 2:25 p.m. ............ S.H. Subramony, MD .............................. National Ataxia Registry• 2:50 p.m. ............ Ralph Miller .............................................. Wheelchair Yoga• 3:15 p.m. ............ Arnie Gruetzmacher, CFP ....................... Financial Planning

• Sunday• 9:00 a.m. ............ Sid Gilman, MD .......................................Sporadic Ataxia and MSA Research• 9:25 a.m. ............ Una Lee, MD ........................................... Management of Neurogenic Bladder• 9:50 a.m. ............ Joanna Jen, MD, PhD ............................. Management of Dizziness in Ataxia• 10:15 a.m. .......... Jon Rodis, MBA .......................................Applying for Social Security Disability• 10:40 a.m. .......... Brent Fogel, MD, PhD ............................. Recessive & Paraneoplastic Ataxia


And with the Internet, you can become the teachers

• http://www.ncbi.nlm.nih.gov for PubMed and OMIM

• http://www.neuro.wustl.edu/neuromuscular• http://www.geneclinics.org• http://www.curefa.org• http://www.ataxia.org• http://cooperative-ataxia-group.org/• http://www.eurosca.org/


A Brief Literature Search for the past 10 years in humans (double the numbers if you include animal studies)

http://www.ncbi.nlm.nih.gov for PubMed and www.clinicaltrials.gov for Clinical Trials

• Spinocerebellar ataxia—--2486 articles• Multiple system atrophy--1903 articles• Friedreich’s ataxia-------- 619 articles• Sporadic ataxia------------ 375 articles ____________________________________________________• Spinocerebellar ataxia—----44 clinical studies• Multiple system atrophy—-35 clinical studies (fluoxetine, lithium, IVIG, stem cells, riluzole, rasagiline, minocycline)

(14 dealing with low blood pressure)

• Friedreich’s ataxia------------19 clinical studies• Sporadic ataxia------------------4 clinical studies (coQ10, Riluzole, IVIG-all completed)

______________________________________________________________________ ______________________________________________________________________

• Parkinson’s disease--------30,022 articles 746 clinical studies


First Thing To Remember

• Everything we are doing with the genetic and non-genetic ataxias can be applied to the other genetic and non-genetic brain diseases and vice versa.

• This includes research about normal nerve

cell functioning, nerve cell sensitivities, nerve cell death, “normal aging”, and environmental and lifestyle factors that influence the brain.

COOPERATIVE ATAXIA GROUPfounded in 2002 for the development of natural history studies and therapeutic trials in ataxia

Sue Perlman_______________________

Kathleen Poston

UCLA_______________________

Stanford University

*Louis Ptacek SCA7Gail Kang

University of San Francisco

Stefan PulstSCA2

University of Utah

(Bernard Ravina)

* Andrew McGarry

University of Rochester NY

* Jeremy SchmahmannMSA

Mass General

Lew Sudarsky Brigham and Womens

George Wilmot Emory

* Joseph Savitt Sarah Ying

Johns Hopkins

Theresa Zesiewicz University of South Florida

Huda ZoghbiSCA1

Baylor East Coast 13 Middle America 4 West Coast 6

* T Ashizawa, S H Subramony

Laura Ranum, Mike WatersSCA10

University of Florida, Gainesville

Thomas Bird________________________

Thomas CrawfordAT

University of Washington________________________

Johns Hopkins University

John Day, Khalif BusharaSCA5, 8; Gluten Ataxia

University of Minnesota

Kurt Fischbeck NINCDS

Sid Gilman MSAHank Paulson SCA3

University of Michigan

Chris GomezSCA6

University of Chicago

Mark Hallett NINCDS

Robert Herndon Univ of Mississippi

Al La Spada SCA7________________________

Ja-Shin Lou

UCSD________________________

University of Oregon

Dave Lynch, Rob WilsonFriedreich’s ataxia

University of Pennsylvania

* Pietro Mazzoni Columbia University




We need enough sites to run all the clinical trials barreling toward us

• Clinical Trials


NECESSARY COMPONENTS FOR A SUCCESSFUL CLINICAL TRIAL (besides $)

• Disease mechanism understood• Candidate drugs• Natural history baseline• Rating scales, QOL measures• Biomarkers to speed up the trials• Research centers to do the trials • Patient Registries to find the subjects• Database to keep it all in


WHAT WE ALREADY HAVE

• Disease mechanism understood--somewhat

• Candidate drugs— some ideas, need more

• Natural history baseline— being collected

X Rating scales, QOL measures• Biomarkers — being developed

X Research centers – telemedicine would help X Patient RegistriesX Database to keep it all in


“18 Drugs Tested”(But Almost None in Controlled Trials)

Some Commonly Used Off-Label Ataxia Treatments

• 1. ImmunoRx—Corticosteroids Mycophenolate

mofetil (CellCept), Rituximab (Rituxan)

IVIG, plasmapheresis

• 2. Anti-Oxidants Alpha lipoic acid Coenzyme Q10 Creatine L-carnitine N-acetylcysteine Omega 3 fish oil/EPA (eicosapentanoic acid) Selenium Vitamin E (d-alpha tocopherol succinate)

• 3. Ataxia Acetazolamide Amantadine Buspirone Gabapentin L-5-OH tryptophan Thyrotropin releasing hormone Varenicline Several others in very small trials based on

animal or in vitro studies

• 4. Action tremor Carbamazepine Clonazepam Gabapentin Isoniazid Levetiracetam Ondansetron Primidone Propranolol Topiramate Valproate Zonisamide

• 5. Nystagmus Dizziness Acetazolamide Baclofen 3,4-diaminopyridine Carbamazepine Clonazepam Gabapentin Meclizine Ondansetron Promethazine Valproate


Brain Stimulation Rather than Drugsagain, very few and small studies

• Deep brain stimulation with implanted electrodes—used mainly for tremor.

• rTMS—repetitive transcranial magnetic stimulation over motor cortex and over cerebellum.


Exercise Always Helps AtaxiaBrain Aerobics


Treatment Trial Retrospective

• Mov Disord. 2009 Jun 15;24(8):1111-24.• Effectiveness and safety of treatments for degenerative ataxias: a systematic

review.• Trujillo-Martín MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R.• Canary Islands Research and Health Foundation (Fundación Canaria de

Investigación y Salud-FUNCIS), Santa Cruz de Tenerife, Canary Islands, Spain. [email protected]

• The aim of this study was to determine the effectiveness and safety of available treatment alternatives for degenerative ataxias (DA). We systematically reviewed studies that assess pharmacological, rehabilitative, or psychological treatments in patients with DA. Twenty-five studies were included

• Most studies were of small sample sizes, wide age variations, and low scientific validity.

• Availability of quality studies to evaluate the safety and efficacy of treatments for most DA is scarce. Further investigations with improved trial designs are necessary.

• BUT THE PROCESS CAN SEEM OVERWHELMING.

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Trujillo-Mart%C3%ADn%20MM%22%5BAuthor%5D



http://www.ncbi.nlm.nih.gov/pubmed?term=%22Serrano-Aguilar%20P%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Monton-Alvarez%20F%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Monton-Alvarez%20F%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carrillo-Fumero%20R%22%5BAuthor%5D



mailto:[email protected]


TYPES OF CLINICAL TRIALSTYPE # SUBJECTS LENGTH AIM OF STUDY

N of 1 1 Ongoing Do I get better or stop getting worse on this drug?

Pilot Up to 20

All get drug

Weeks to months

Is a larger study worth doing, will there be problems?

Phase 1 20-80 normal or patient

in groups of 3

2 years Escalating doses to learn side effects, safety, best dose

Phase 2 20-300

Placebo and drug groups

2 years To assess potential for good effects, as well as side effects.

Also designed as “futility” study—to show a drug doesn’t not work(fewer subjects, less$)

Phase 3 300-3000

Placebo and drug groups

3-5 years To prove efficacy

May include crossover design, open extension trial

Phase 4 100’s-1000’s

Open drug use

Ongoing To find out more about the effects of an approved drug.


OFFICIAL PIPELINE FOR NEW DRUGS

Up to 15 years and $500-700million to get to market

• Discovery—clinicians and scientists working out the cause of the disease, the “dominos” that fall over, and targeted candidate drugs.

• Preclinical testing—test tube and animal studies.

• Phase I—dosing, safety

• Phase II—safety, possible efficacy

• Phase III—efficacy• FDA Approval• Phase IV--Post-marketing studies

for long-term side-effects and good effects.

• To help with promising drugs for serious diseases with unmet needs:

• NIH—Rapid Access to Intervention Development (RAID)

• FDA—Orphan Drug Status


FUNDINGA PUBLIC-PRIVATE PARTNERSHIP

• Discovery—clinicians and scientists working out the cause of the disease, the “dominos” that fall over, and targeted candidate drugs.

$25-80,000 per yr over many years

• Preclinical testing—test tube and animal studies.

$100,000 per year for at least 2 yr

• Phase I and Phase II-- $500-700,000 per year for 4 yr$2-4 million to get to this point

• Phase III—$4-5 million ($10K/subject)

• FDA Approval• Post-marketing studies for long-

term side-effects and good effects and possible other uses of the drug.

• Government Private research foundations

• Government Private research foundations Pharmaceutical companies

• Government Private research foundations Pharmaceutical companies

• Pharmaceutical companies


The Bottom Line

• Every ataxia patient must participate in clinical trials.

• Every researcher designing a clinical trial must make it accessible to all ataxia patients.

• There will be exceptions to both of these fiats, but they must be justified.


Every Ataxia Patient Must Participate in Clinical Trials

1. Registries will enable you to be found.

These are rare diseases with very small numbers of patients who can participate. Every person counts.

2. Be knowledgeable about what makes a good clinical trial—don’t make bad investments.

3. Speak up about the roadblocks to participation. Become involved in planning the trials.

4. Be prepared to make sacrifices.


Sacrifices

• Time

• Money

• Confidentiality

• Giving up one drug trial to participate in another.

• Risking receiving a placebo.


DO WE REALLY NEED PLACEBOS?• Gold Standard for Phase III clinical trials is the double–blind, placebo-controlled,

randomized study.

• The “placebo effect” is very real and ideally accounts for all the other effects not related to the drug directly.

• Dramatic differences between the placebo and drug groups will usually result in all subjects being placed on drug before the end of the trial.

• If it would be dangerous for a potential subject to end up on placebo, that subject would not be enrolled in the study. This includes the subject having to stop other medications to enter the study.

• Active placebos may be used.

• Use of historical controls or subject acting as own control may require a longer study to prove benefit of drug.


Every Researcher Designing A Clinical Trial Must Make It Accessible To All

Ataxia Patients.• Design trials that can use the fewest patients over the

shortest period of time (this usually means testing better drugs and using biomarkers).

• What is the rationale for excluding certain patients? Can those excluded be used in other ways? Parallel or compassionate studies?

But remember that a patient can participate in only one trial at a time and that participation in some trials may permanently disqualify participation in others.

• Reimbursing travel costs is essential for recruitment and compliance. Telemedicine?

• Don’t expect the patients to make unreasonable sacrifices.


Roadblocks for Clinical Researchers

• Picking the right drugs.• Designing the trial properly—number of patients,

measures/biomarkers, length of study, placebo, how many sites.

• Getting the FDA to agree.• Getting funding.• Finding sites and getting them approved.• Finding subjects.• Doing the work in a timely fashion.


WHAT WE HAVE DONE IN SPITE OF ALL THIS October 2007----------------------------------------------------Today


THANK YOU• National Ataxia Foundation— sponsor of grants for our internal database, our DNA bank, our web-based

database project, and the SCA3 Chantix study.

• The Cooperative Ataxia Group— sponsor of the grant for the SCA Natural History Study. NINDS RC1 NS68897 and NIH Office of Rare Diseases Research

• Muscular Dystrophy Association and • Friedreich’s Ataxia Research Alliance— sponsors of the grant for the collaborative project on “Clinical Outcome

Measures in Friedreich’s Ataxia”. http://www.curefa.org/registry.html EVERYONE REGISTER!

• The Smith Family Foundation• The Bettencourt Family Foundation• The Norman Lapin Fund• The Mariette Monnier Fund

• And to our patients and their families for their willingness to work with us and to share with us their ideas and hopes.

http://www.curefa.org/registry.html

Documents

March 18, 2011NAF AMM LA CA Bringing the Ataxia World Together The LA Experience and an Ataxia Medical Update Susan L. Perlman M.D. Clinical Professor