Ataxia research updateAtaxia Ireland conference 28 Sep 2013

Dr Alison Stevenson

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

Ataxia UK and Ataxia Ireland joining forces

Funding from

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

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

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

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

Friedreich’s ataxia research developments

Energy production

Free radical damage

Iron mis-localisation

What happens in Friedreich’s ataxia?

Ataxia?Mutated

FrataxinGene

FrataxinProtein

Cell structural changes

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

Energy production

Free radical damage

Iron mis-localisation

Tackling Friedreich’s ataxia

MutatedFrataxin

Gene

FrataxinProtein

Antioxidants

IronChelators

Protein Therapy

Drugs to frataxin

Gene Therapy

Drugs to turnfrataxin gene on

Antioxidants

• ‘Mop up’ free radicals• Prevent damage from free radicals• Improve energy production in cell

MutatedFrataxin

Gene

FrataxinProtein

Energy production

Free radical damage

Iron mis-localisation

Antioxidants

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?

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

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

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

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

MutatedFrataxin

Gene

FrataxinProtein

Energy production

Free radical damage

Iron mis-localisation

IronChelators

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

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

AtaxiaMutatedFrataxin

Gene

FrataxinProtein

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

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

HDAC inhibitors• Histone deacetylase inhibitors (HDCAi)• Switch frataxin gene back on

AtaxiaMutatedFrataxin

Gene

FrataxinProtein

HDACi

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

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

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

Cerebellar ataxia research developments

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

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

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

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

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

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

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

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

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

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

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)

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

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

Thank-you for listening!