BritModis What s new in PSP and CBD - the PROSPECT for clinical trials BRITMODIS Huw Morris UCL Institute of Neurology Queen Square

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1 What s new in PSP and CBD - the PROSPECT for clinical trials BRITMODIS 2016 Huw Morris UCL Institute of Neurology Queen Square

2 What s do we know and what s new in PSP? What are the challenges? How will the PSP Research Network/PROSPECT longitudinal study help? What will be the outcomes and benefits for patients?

3 1) Supportive care 2) Palliative care What is research? 3) Disease mechanisms 4) Disease treatments building understanding and evidence

4 What have we learnt so far about PSP? 50 years since description of PSP 1) Description of the prototypic disease 2) 1991 Tau neurofibrillary tangles in PSP 3) 1997 Tau gene association 4) 1998 Tau mutations in FTDP-17 and tau haplotypes 5) 2001 Prevalence of PSP

6 What s new in PSP? 6) 2005 Different phenotypes related to PSP pathology 7) 2011 five genetic variants related to PSP 8) large scale drug trials in PSP riluzole, davunetide, tideglusib, valproate 9) Transmission and tau strains in PSP

7 6) 2005 Different phenotypes related to PSP pathology PSP-Richardson syndrome PSP-Parkinsonism PSP-Pure akinesia with gait freezing Early stage diagnosis may be difficult delayed diagnosis is common Falls, hemiparesis, Behavioural change, Non-specific visual symptoms

8 CBD Limb apraxia Asymmetric stiffness, dystonia Action myoclonus Cortical sensory loss Eye movement apraxia Eye lid apraxia Oro-buccal apraxia Misdiagnosis PD; Stroke

9 Different pathologies related to CBS TDP-43 FUS <9 years <2 years Alzheimer CBS <9 years Tau/CBD Prion <9 years <6 months

10 What s new in PSP? 6) 2005 Different phenotypes related to PSP pathology 7) 2011 five genetic variants related to PSP 8) large scale drug trials in PSP riluzole, davunetide, tideglusib, valproate 9) Transmission and tau strains in PSP

11 MAPT splicing 4R (X10) (X3) PERK PSP/CBD MOBP Age Activation of UPS STX6 Mitochondrial failure Spread MAPT aggregation MAPT deposition MAPT clearance FTDP-17 MAPT splicing, Coding mutation Age Neuronal and glial tau accumulation Microtubule destabilization

12 What s new in PSP? 6) 2005 Different phenotypes related to PSP pathology 7) 2011 five genetic variants related to PSP 8) large scale drug trials in PSP riluzole, davunetide, tideglusib, valproate 9) Transmission and tau strains in PSP

13 Therapeutic trials 10% mortality 1 year Riluzole approaching 50% mortality/3 years

14 What s new in PSP? 6) 2005 Different phenotypes related to PSP pathology 7) 2011 five genetic variants related to PSP 8) large scale drug trials in PSP riluzole, davunetide, tideglusib, valproate 9) Transmission and tau strains in PSP

16 What are the targets? Reduction in tau levels - ASO Alteration in 4R:3R tau ratio Splicing factors Anti-tau aggregation therapy: Grape seed extract, Methylene blue Kinase inhibitors; Phosphatase enhancer: SVP, Lithium, Tideglusib ve Autophagy stimulation: Trehalose Microtubule stabilizing agents: Davuentide ve; EpothiloneD Anti-tau propagation therapies: Immunization

17 What are the challenges? 1) Ascertaining patients with rare disease at an early stage 2) Firm diagnosis at an early stage for PSP and CBD 3) Monitoring the disease progress 4) Understanding disease biology 5) Research Infrastructure

18 Research Network/ PROSPECT STUDY

19 Research Network: PROSPECT STUDY

21 PROSPECT PSP Research questions include 1) Clinical and biomarker progression of PSP 2) Early diagnosis 3) Heterogeneous phenotypes 4) Progression in PSP

22 PROSPECT PSP Aims Longitudinal cohort up to 7 years Clinical Assessment/MRI/CSF/Blood biomarkers/psychology/consent to recontact 98 PSP; 98 up to Atypical parkinsonism; 98 MSA; 98 controls Cross-sectional ( one-stop ) Clinical Assessment / DNA / Consent to recontact

23 PROSPECT PSP - PROGRESS Study set-up 6M ethics, protocol at UCL, initiate recruitment Site set-up 6M 6M activate and coordinate 7 UK centres: local ethics, contracts, additional funding to cover biomarkers Recruitment: Longitudinal Recruitment: Crosssectional Follow-up 2Y 7Y 7Y

24 PROSPECT PSP - PROGRESS Study set-up 6M ethics, protocol at UCL, initiate recruitment Site set-up (5 complete) 6M 6M activate and coordinate 7 UK centres: local ethics, contracts, additional funding to cover biomarkers Recruitment: Longitudinal Recruitment: Crosssectional Follow-up 2Y 7Y 7Y

26 Update 28/1/ complete

27 Longitudinal PSP Research Study / Network Sub-groups and Add-ons 1) Clinical progression 2) Genetics 3) Imaging 4) Cell biology 5) Pathology

29 CBD SOLUTIONS CLINICAL FELLOW Dr. Ruth Lamb

30 Outcomes Building a research infrastructure in the UK Enabling clinical trials in UK Maintaining a clinical and biosamples database for research by bona fide investigators Add-on studies

32 HJ8.5 antibody Phase 1 complete RCT DB 4 sites 32PSP patients Ipierian BMS Completed 2 phase 1 studies Plan RCT 48 PSP patients at 12 sites

33 How can patients be involved? Longitudinal study sites Cross-sectional study sites Remote contact

34 What have we learnt so far about PSP and what s new? What are the challenges? How will the PSP Research Network/PROSPECT longitudinal study help? What will be the outcomes and benefits for patients?

35 Acknowledgements Patients Carers

36 PSP - Research Overview, Research Network and PSP Longitudinal Research Study (PROSPECT) Huw Morris UCL Institute of Neurology Queen Square

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