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NEW TREATMENTS IN HUNTINGTON’S DISEASE

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

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NEW TREATMENTS IN HUNTINGTON’S DISEASE

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

  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) C N TOXIC DISEASE Expanded CAG repeat length Mutant protein – Huntingtin Polyglutamine strand (PolyQ-Htt) at N-terminal

  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 650 International goal: 538 July 14 • 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 Sites of intervention + COPPER [polyQ-Htt]n [ polyQ ]n  removal from intracellular pool

  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

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

  33. PRIDE-HD : Status research@ndr.org.au Ph: 9481 6293 NOW ENROLLING

  34. HD Research Cellular mechanisms implicated in HD pathogenesis • Oligonucleotide therapeutic approaches • Htt gene silencing • Molecular chaperones • Suppress aggregation of Htt complex • Metabolic, transcriptional, post-translational changes • Cell-replacement strategies

  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

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