NEW TREATMENTS IN

HUNTINGTON’S DISEASE

Clinical Professor Peter K PanegyresMD PhD FRACP

www.ndr.org.au

HSG NDR NDR 2005 : to conduct research into the

neurobiology of neurodegenerative disorders:

EARLY ONSET DEMENTIA

HUNTINGTON’S DISEASE

NDR joined HSG in 2008:• Horizon• CREST-E• Reach-2HD• Juvenile HD• Intermediate CAG repeat length• Pride-HD

Huntington’s Disease (HD) Expanded CAG repeat length Mutant protein – Huntingtin Polyglutamine strand (PolyQ-Htt) at N-

terminal

C N

TOXIC

DISEASE

Intervention Model for HD

HD Research Study

Dimebon: cognition and global function in mild to moderate HD

Horizon Study Dimebon: cognition and global function

in mild to moderate HD

Randomized, double-blind, placebo-controlled

64 centres: Australia, Europe and North America

403 research participants: mild to moderate HD and baseline cognitive impairment (MMSE: 10-26)

Dimebon = 20mg tablets or placebo

Horizon Study : Change in MMSE

HD Research Study

Effects of creatine monohydrate on progression of functional decline

CREST-E Study Largest clinical trial for HD First definitive efficacy for creatine One of first Phase III trials for slowing HD First compound for HD based on biomarker

data First trial in which biomarkers are a major

component: correlate efficacy and usefulness Most extensive and controlled high-quality

safety about creatine at higher doses : potential neurodegeneration.

Funding: NIH and NCCAM

CREST-E Study : Phase III 44 HSG sites Ongoing Randomized double-blind control : up to

40g/day Primary objective

• Effects of creatine monohydrate on progression of functional decline (TFC)

Secondary objectives• Long-term safety and tolerability• Compare placebo : clinical• Compare placebo : biological

Stages I or II (TFC ≥ 7)

CREST-E : Creatine in Humans Generally safe and well tolerated

Evidence of Creatine use in 100’s of subjects with dose of ≤ 25 g with no substantiating safety concerns

Widespread use by athletes with no suggestion of toxicity

Expected issues:• GI upset, nausea, diarrhea (individually dose limiting)• Oedema, weight gain• Elevated Creatinine but no organ toxicity

Parallel developmental studies in ALS and PD to assess higher doses

Early Clinical Experience of Creatine Safe and tolerable a 3-10g/day for up

to a year (Verbessem, Tbrizi, Kieburtz, Hersch)

No evident symptomatic response or deterioration during study periods

Studies not powered to detect disease modification

Partial reduction of plasma 80H2’dG, marker of oxidative damage to DNA in brain (Hersch)

Is more creatine better?

Neuronal Degeneration in HD

CREST-E Study : Synopsis

Important goal is to develop viable biomarkers of disease state and possibility of disease modification

Current goal is to validate these biomarkers

Biomarkers – their importance Objective lab measures to track disease onset or

progression

Improve clinical measures

Help test more treatments and test them quicker

If there were biomarkers that made it easier to perform neuroprotection trials, there would be greater incentive for industry to develop neuroprotective treatments

New Assessments in CREST-E Transcriptomics:• To determine if creatine affects the way that

DNA is expressed Metabolomics:• To explore more fully how creatine affects the

metabolome 8OH2’dG MRI:• To determine to what degree creatine affects

brain atrophy Additional neuropsychological assessments:• To evaluate function of other cortical regions

CREST-E Study : Goal 650

538

Ju

ly 1

4

International goal:

NDR recruitments:• Enrolled – 11 subjects• Withdrawn – 3 subjects• Ongoing – 7 subjects• Last patient to complete in December 2014

HD Research Study

Effects of PBT2 in patients with early to mid-stage HD

Reach2HD Study MRI : progressive increases in –• Fe, Cu (transition metals) in basal

ganglia and cerebral cortex in symptomatic HD

Iron oxidative damage

Copper catalyzes oxidation + oligomerization of poly Q-Htt

Oligomerization of Peptides

Reach2HD Study

COPPER [polyQ-

Htt]n

[ polyQ ]n

removal from intracellular pool

+

Sites of intervention

Reach2HD : PBT2PBT2 modifies HD major actions: Prevent aggregation mutant Htt

protein fragments and promote their clearance from the brain.

Prevent neuronal atrophy due to aggregated Htt fragments

Improve the functionality and health of neurons affected by toxic Htt aggregates

Suppress glutamate excitotoxicity due to loss of inhibitory synapses.

Reach2HD Study

Randomized double-blind placebo-controlled study to assess safety and tolerability and efficacy of PBT2 in patients with early to mid-stage HD

Parallel group

Multicentre (Phase IIa)

Reach2HD : ObjectivesPRIMARY: Safety tolerability two-dose levels of PBT2

when given orally once daily over 26 weeks

SECONDARY: The effect of PBT2 after 26 weeks:

• Cognition• Motor function• Functional abilities• Global function • Plasma and urine biomarkers• Brain volumes/function• Pharmacokinetics

N = 100

Reach2HD : Study Schematic

Reach2HD Findings

Primary endpoints of safety and tolerability were met.

Secondary endpoint: Statistically significant improvement in a measure of executive function (cognition) in research participants administered 250mg PBT2 daily (p=0.042).

PBT2 250mg was also associated with a favourable signal in functional capacity.

Preliminary evidence suggests PBT2 250mg reduced atrophy of brain tissue in areas affected in Huntington disease.

HD Research Study

Pridopidine as symptomatic treatment for Huntington’s disease

PRIDE-HD (Pridopidine) : Aim Phase II:• Dose finding• Safety• Efficacy• Randomised• Parallel Group• Double blind• Placebo controlled

PRIDE-HD : Inclusion Criteria Diagnosis of HD

CAG ≥ 36

Age ≥ 21 years

Onset > 18 years of age

Body weight ≥ 50 kg

Able to take oral medication

PRIDE-HD : Participation

Duration = 30 weeks

Screening = 2 weeks

Randomisation – double-blind treatment• 4 week titration• 22 week full dose• 2 week safety follow-up following

last dose

Clinic visits = 9

PRIDE-HD : Study designFlow chart of patient flow

PRIDE-HD : Measures

Q-Motor assessments

+ UHDRS, CIBIC-Plus, CGI-S/C, ECG, bloods and urine

PRIDE-HD : Status

NOW ENROLLING

research@ndr.org.au

Ph: 9481 6293

HD Research Oligonucleotide

therapeutic approaches• Htt gene silencing

Molecular chaperones• Suppress aggregation of

Htt complex

Metabolic, transcriptional, post-translational changes

Cell-replacement strategies

Cellular mechanisms implicated in HD

pathogenesis

GOOD CLINICAL PRACTICE IN

RESEARCH

Essential to Conduct of Study

Proper care and follow up of study

subjects

Effective trial

management

Clean and valid trial

results

Compliance with

regulations

NDR Research StaffProfessor Peter K

Panegyres (Director)

Pat Castledine

(Office Manager)

Cheryl MacFarlane

(Research Manager)

Vicki LorrimarPaula Mather

(Project Managers)

Nicola LewisVicki LorrimarPaula Mather

Cheryl MacFarlane

(Trial Coordinators)

Nicola LewisVicki LorrimarPaula Mather

(Cognitive Raters)

Matthew Faull(Research Assistant)