Clinical Research Update

Adam L. Boxer, M.D., Ph.D.

Endowed Professor in Memory and Aging

Director, AD and FTD Clinical Trials Program

Director, Neurosciences Clinical Research Unit

University of California, San Francisco

PSP/CBD Research Update and Practical ConferenceSaturday, October 28, 2017; Foster City

Disclosures

• NIH U54NS092089, R01AG038791, U01AG045390

• University of California Cures AD Program, Tau Research Consortium, Bluefield Project to Cure FTD, Association for Frontotemporal Degeneration, CBD Solutions, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Association

• Industry research support: Avid, Biogen, BMS, C2N, Cortice, Forum, Genentech, Eli Lilly, Roche, TauRx

• Industry consulting: Abbvie, Alector, Asceneuron, Celgene, Delos, Ionis, Janssen, Merck, Novartis

Multidisciplinary intensive rehabilitation therapy (MIRT)

4 week intervention

2017

Tau therapeutic targets

Boxer et al., Lancet Neurology, 2017

Clinical status of PSP therapies• Microtubule stabilizing agents

o Epothilone D (abandoned) -- ADoDavunetide (abandoned) – MCI & PSPo Abeotaxane (TPI-287) Phase 1 – AD, CBD, PSP

• Post-translational modification/aggregationoMethylene blue (LMTM) Phase 3 – AD(-), bvFTD (-)o Tideglusib (GSKi; abandoned) – AD, PSPoO-glc-NACase inhibitors – PSP plannedo Salsalate (acetylation) Phase 1 – PSP, AD

• Anti-sense oligonucleotides (Phase 1, AD)• Immunotherapies to tau or phospho-tau

omAbs: Multiple agents in Phase 1-2 PSP, ADo Active vaccines: Phase 1

• Other approaches o Young plasma infusions – Phase 1 AD, PSPoHypnotics (suvorexant and zolpidem)– remote clinical trial

Challenges for PSP therapeutic development

• Late diagnosis (advanced disease)• Clinical heterogeneity• Rare disease (enough patients?)• Narrow pipeline (need more drugs to test)

Richardson’s (PSP-RS/ NINDS-SPSP)

Richardson’s (PSP-RS/ NINDS-SPSP)

PSP-Parkinson’s (PSP-P)

PSP-Parkinson’s (PSP-P)

Pure akinesia with gait freezing (PSP-PGF)

Pure akinesia with gait freezing (PSP-PGF)

Corticobasal syndrome (PSP-CBS)

Corticobasal syndrome (PSP-CBS)

Variant PSP diagnosis

Richardson’s (PSP-RS/ NINDS-SPSP)

Richardson’s (PSP-RS/ NINDS-SPSP)

PSP neuropathologyPSP neuropathology

• Eye movements• Falls• Axial rigidity• Bulbar

o Cognitiveo Behavior

Progressive nonfluent aphasia (PSP-SL)

Progressive nonfluent aphasia (PSP-SL)

Frontotemporal dementia (PSP-F)Frontotemporal

dementia (PSP-F)

Psychiatric Psychiatric

DysexecutiveDysexecutive

• 4R > 3R tau• Neuronal loss

Mov

emen

tB

ehav

ior

Hoglinger, Mov. Disorders, 2017Boxer, Lancet Neurology, 2017

100%accurateby final visit

Williams and Lees; Lancet Neurol 2009; 8: 270–79

Disease progression in PSP

current trials

CBSnfvPPAGait freezingParkinsonism

Prevention Trials

Biomarkers Boxer et al., Lancet Neurology, 2017

Mov Disord. 2017 Jun;32(6):853-864.

U01AG045390

U54NS092089

R01AG038791

18 ARTFL, LEFTDS and 4RTNI sitesClinical Research Networks

LEFFTDS through 8/2017

Participants

vMRI change in PSP, CBS

Dutt, et al. Neurology 87, 2016

18F-AV1451: 33 PSP-Richardson’s Syndrome > 46 healthy controls

P < 0.001Uncor.

3.2 T 9.4PSP: 10 UCSF/LBL, 4 MGH, 19 Avid A09 study23 males, age 69.6, mean PSP-RS 34.7

Schonhaut et al., Annals of Neurology 2017 82: 622-634

Low CSF ptau bad in PSP• Elevated CSF ptau associated with AD pathology

Rojas, et al., Neurology, in press

InvestigatorsAdam BoxerHoward RosenBrad BoeveBrian ApplebyYvette BordelonBradford DickersonKimiko Domoto-ReillyNupur GhoshalNeill Graff-RadfordMurray GrossmanEdward HueyRobin HsiungDavid IrwinDaniel KauferDiana KerwinDavid KnopmanIrene LitvanIan MackenzieMario MendezAlex PantelyatErik RobersonCarmela TartagliaSandra Weintraub

Fellows: Richard Tsai; Jaya PadmanabhanManagement: Hilary Heuer Anna Karydas Matt Miller

Cate Freyer Caitlin Glennon

Christina CasoGayathri CheranReilly DeverChristina DheelSophia DominguezAnn FishmanBehnaz GhazanfariDana Haley

Amy HalpinElvira JimenezLynne JonesSheila JoshiRuth KraftSamantha KrivenskyDenise LedlowFran Lissemore

Masood ManoochehriTahlee MarianLaura MartindaleEmily McKinleyNamita MultaniPheth SengdyKimberley ThomasJana Windsor

Research Coordinators

BiospecimensTatiana ForoudKelley FaberMadeline Potter

GenotypingGiovanni CoppolaRosa Rademakers

MRIKejal KantarciDenise ReyesKaely Thostenson

Data SharingArt TogaKaren Crawford

Patient Advocacy Group Partners

Funding

Pilot Project PIs: Gil Rabinovici, Ted Huey, Emily Rogalski-Miller