Clinical Trials and Collaborations - ALLFTD IM Adam Boxer on behalf of the FPI Investigators October 6, 2020
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Clinical Trials and
Collaborations
Adam Boxer on behalf of the FPI Investigators
ALLFTD IM
October 6, 2020
Outline
• FTLD clinical trial landscape
– bvFTD/PPA
– 4R Tauopathies
• EOD collaboration LEADS – Blood Biomarkers for EOD
• The FTD Prevention Initiative (FPI)
• Disease Progression Models (DPM) in f-FTLD
• Platform trial possibilities
• ALLFTD-Treatment Unit challengesOngoing and planned FTD Clinical trials
• Genetic (familial) FTLD
– C9orf72 – antisense oligonucleotides Ph1 ALS; 1-2 trials planned in
FTD in 2021
• At least one small molecule program planned in 2021
– GRN – anti-sortilin mAb Ph3; 1-2 gene therapy trials 2020-21
• Multiple other approaches in development
– MAPT– planning through FTD Prevention Initiative
• Sporadic (non-familial) FTLD
– bvFTD & PPA with behavioral problems – intranasal oxytocin
– bvFTD – low dose lithium
– bvFTD or PPA – transcranial AC or DC stimulation
– PPA – Communication bridge remote speech therapy
3Ongoing and planned CBS and PSP trials
• Ph2 Anti-tau mAb (UCB0107) in PSP-Richardson’s Syndrome
– underway in EU; planned start in N. America Q1 2021
• Ph1 MAPT ASO planned for 2021 PSP-RS
– ≥ 2 similar anti-MAPT approaches in development
• Small molecules for PSP-RS possibly in 2021
– OGNi, anti-oxidant, undisclosed target
• Ph1 kinase inhibitor PSP-RS and amyloid (-) CBS likely
• Other anti-tau, novel target approaches in development
4Blood Biomarkers for Early Onset Dementia
• Collaboration with LEADS (non-genetic EOAD) network
• Screen for ALLFTD and/or LEADS participants; partnership with
New IDEAS for recruitment
• Goals:
– Validate blood biomarkers (P-tau, Aꞵ, NfL) collected in community
– Added Value of online, remote neuropsych & clinical assessments?
– Determine EOD etiology in Under Represented Minorities
• Plan: gold standard in person visits at ALLFTD & LEADS sites
• Planned U19 submission 2/2021 (PIs: Rivera-Mindt, Rabinovici,
Boxer)
• Please let us know if you have well developed community
partnerships for URM recruitment
5www.thefpi.org
In contact with
sites in S. America
and Asia to
involve them.
6FPI Goals
Overall aim is to promote clinical trials of new therapies to prevent FTD.
Key goals:
• Promote responsible data sharing within the context of observational studies
and trials in familial FTD.
• Create an international database of familial FTD research participants who
might be eligible for clinical trials.
• Create uniform standards for conduct of clinical trials in familial FTD syndromes
and organize global platform trials.
7Special thanks to:
ALLFTD & GENFI research participants
FPI DPM Team Berry Statistical NfL Data
Adam Staffaroni Consultants Carolin Heller
Jon Rohrer Melanie Quintana Tania Gendron
Howard Rosen Barbara Wendelberger Len Petrucelli
Hilary Heuer
Lucy Russell
Yann Cobigo
8Bayesian Repeated Measures
Disease Progression Models
• Not feasible to conduct a natural history study that follows individuals from
presymptomatic status until death.
• Bayesian DPM leverages natural history data from all mutation carriers, across the
entire disease spectrum
• Estimates a latent “disease age” parameter
– This estimate is a determined by jointly estimating the onset and rate of decline for multi-
modal data.
• Alignment on subject-specific “disease age” allows us to characterize the entire
disease spectrum and make predictions about each subject’s progression.
Quintana et al. 2018, Stats in Medicine 9Comparing and combining longitudinal data
1. Assemble dataset of C9orf72, GRN, and MAPT cases in ALLFTD & GENFI
– Neuropsych, functional, imaging, biofluids
2. Identify common measures across several domains between both cohorts
3. Harmonize measurements using ALLFTD developed statistical tools (Kornak et al., 2019)
4. Build and compare disease progression models in both cohorts
– Determine suitability for a joint dataset
5. Combine into a single DPM
6. Choose most appropriate endpoints
– Prediction of onset
– Enrollment criteria
– Sample size estimates
7. Design trial protocol
10Overview of DPM approach
• Model clinical endpoints & biomarkers jointly as a function latent disease stage
– CDR® + NACC FTLD Module (FTD-CDRSB)
– Neuropsychological tests
– Plasma NfL
– MRI Frontal and Temporal Volumes
• Disease age is defined as years since clinical onset:
– Chronological Age – Age at onset
• Age at onset:
– Prior Expectation:
• If onset observed, sample from Normal with mean of observed value with a SD of 4
• If not observed, sample from Normal with mean for mutation type with a SD of 10
– Update prior expectation given outcome measures
11Endpoints, Sample Size and Follow-up
• Clinical Dementia Rating Scale GENFI Summary Data
plus NACC FTLD Module C9orf72 GRN MAPT
– CDR® + NACC FTLD
– Informant Rating Scale – 8 domains N 172 177 73
N CDR=0 86 119 49
• Neuropsychological Measures N CDR=.5 29 17 7
– Trail Making Test, Parts A & B
– Animal Fluency N CDR>=1 55 38 17
– Benson Figure Copy and Delayed Mean Years Followed 0.7 0.9 1.1
Recall
– Digit (GENFI) vs Number Span
(ALLFTD) Forward & Backward ALLFTD Summary Data
– Confrontation Naming C9orf72 GRN MAPT
• MINT (ALLFTD) vs BNT (GENFI)
N 127 68 80
• Plasma NfL N CDR=0 63 39 45
N CDR=.5 23 7 13
• Volumetric MRI N CDR>=1 41 22 22
– Frontal or temporal lobe volumes
Mean Years Followed 1.4 1.4 1.8
12Clinical Dementia Rating (CDR) plus NACC FTLD
ALLFTDWhat is clinically meaningful?
Endpoints
When isthat are
it too most
late sensitive to change
to treat?
CDR plus NACC FTLD-sb 20
15
10
5
0
-10 -5 0 5 10
Predicted years from disease onset
C9orf72
NfL CDR FTLDsb MINT
Trails B
GRN
NfL CDR FTLDsb Figure copy, recall
Trails A,B MINT, vMRI frontal
MAPT
NfL CDR FTLDsb MINT, Figure recall
vMRI temporal Trails BPlatform Trials: Next Steps
• MAPT: 2 ASOs and or drugs vs. common placebo?
– Stagger start; begin one drug prior to other?
– Preliminary negotiations underway with industry partner
• C9orf72:
– Ph1 (POC) can combine C9-ALS and FTD (FDA guidance)
– C9-FTD platform (Ph2/3): 2 ASOs and/or drugs vs. common placebo
• GRN: consider after current Ph3
– 2 drug or gene tx approaches vs. common placebo
15Where are we with ALLFTD-TU?
• Therapies targeting inflammation, mitochondria, oxidation:
potential to include FTLD-TDP and –tau in single trial
• Which population to prioritize for trial planning?
– C9, GRN, MAPT, bvFTD, svPPA, 4RT ….
• Recruiting trial ready cohorts that meet trial enrollment
criteria and have (?longitudinal) baseline data would like
require future trial commitment with identified therapie(s)
• Start with focused efforts in f-FTLD?
• (Too) Many exciting possibilities
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