clinical research update · clinical research update adam l. boxer, m.d., ph.d. endowed professor...
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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
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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
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Multidisciplinary intensive rehabilitation therapy (MIRT)
4 week intervention
2017
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Tau therapeutic targets
Boxer et al., Lancet Neurology, 2017
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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
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Challenges for PSP therapeutic development
• Late diagnosis (advanced disease)• Clinical heterogeneity• Rare disease (enough patients?)• Narrow pipeline (need more drugs to test)
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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
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Disease progression in PSP
current trials
CBSnfvPPAGait freezingParkinsonism
Prevention Trials
Biomarkers Boxer et al., Lancet Neurology, 2017
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Mov Disord. 2017 Jun;32(6):853-864.
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U01AG045390
U54NS092089
R01AG038791
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18 ARTFL, LEFTDS and 4RTNI sitesClinical Research Networks
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LEFFTDS through 8/2017
Participants
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vMRI change in PSP, CBS
Dutt, et al. Neurology 87, 2016
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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
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Low CSF ptau bad in PSP• Elevated CSF ptau associated with AD pathology
Rojas, et al., Neurology, in press
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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