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NEW TREATMENTS IN HUNTINGTON’S DISEASE Clinical Professor Peter K Panegyres MD PhD FRACP www.ndr.org.au.

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Presentation on theme: "NEW TREATMENTS IN HUNTINGTON’S DISEASE Clinical Professor Peter K Panegyres MD PhD FRACP www.ndr.org.au."— Presentation transcript:

1 NEW TREATMENTS IN HUNTINGTON’S DISEASE Clinical Professor Peter K Panegyres MD PhD FRACP

2 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

3 Huntington’s Disease (HD)  Expanded CAG repeat length  Mutant protein – Huntingtin  Polyglutamine strand (PolyQ-Htt) at N-terminal CN TOXIC DISEASE

4 Intervention Model for HD

5 HD Research Study Dimebon: cognition and global function in mild to moderate HD

6 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

7 Horizon Study : Change in MMSE

8 HD Research Study Effects of creatine monohydrate on progression of functional decline

9 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

10 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)

11 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

12 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?

13 Neuronal Degeneration in HD

14 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

15 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

16 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

17 CREST-E Study : Goal July 14 International goal: NDR recruitments: Enrolled – 11 subjects Withdrawn – 3 subjects Ongoing – 7 subjects Last patient to complete in December 2014

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

19 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

20 Oligomerization of Peptides

21 Reach2HD Study COPPER [polyQ-Htt] n [ polyQ ] n  removal from intracellular pool + Sites of intervention

22 Reach2HD : PBT2 PBT2 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.

23 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)

24 Reach2HD : Objectives PRIMARY:  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

25 Reach2HD : Study Schematic

26 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.

27 HD Research Study Pridopidine as symptomatic treatment for Huntington’s disease

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

29 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

30 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

31 PRIDE-HD : Study design Flow chart of patient flow Follow up one follow-up visit after trial is completed 6 months taking study medication 9 visits to monitor progress Randomisation to study drug (80%) or placebo (20%) 45 mg67.5 mg90 mg112.5 mgPlacebo Screening Determination of eligibility

32 PRIDE-HD : Measures Q-Motor assessments + UHDRS, CIBIC-Plus, CGI-S/C, ECG, bloods and urine

33 PRIDE-HD : Status NOW ENROLLING Ph:

34 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

35 GOOD CLINICAL PRACTICE IN RESEARCH

36 Essential to Conduct of Study Proper care and follow up of study subjects Effective trial management Clean and valid trial results Compliance with regulations

37 NDR Research Staff Professor Peter K Panegyres (Director) Pat Castledine (Office Manager) Cheryl MacFarlane (Research Manager) Vicki Lorrimar Paula Mather (Project Managers) Nicola Lewis Vicki Lorrimar Paula Mather Cheryl MacFarlane (Trial Coordinators) Nicola Lewis Vicki Lorrimar Paula Mather (Cognitive Raters) Matthew Faull (Research Assistant)


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