Brainstorm · 2020. 7. 9. · Brainstorm’s Pipeline 3 Indication Preclinical IND Enabling Phase 1...
Transcript of Brainstorm · 2020. 7. 9. · Brainstorm’s Pipeline 3 Indication Preclinical IND Enabling Phase 1...
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Brainstorm Cell Therapeutics
July 8, 2020
KOL Webinar
Phase 2 trial with NurOwn for
Alzheimer’s Disease
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Agenda – KOL Webinar to Discuss NurOwn for Alzheimer’s
2
8:15-8:25 Chaim Lebovits, CEO Brainstorm
Ralph Kern, M.D., MHSc, President & CMO Brainstorm
o Introduction and overview
8:25-8:40 Pr. Dubois, Salpétrière University Hospital
o High prevalence of the disease worldwide
o Great progress in diagnostic procedures
o Disappointment with current treatment
8:40-9:00 Pr. Scheltens, Amsterdam UMC
o New emerging therapies
o Biomarkers progress
o What’s attractive about Brainstorm approach
9:00-9:10 Stacy Lindborg, Ph.D. EVP & Head of Global Clinical Research
Brainstorm
o Study Protocol
9:10-9:30 Participants
o Q&A
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Brainstorm’s Pipeline
3
Indication Preclinical IND Enabling Phase 1 Phase 2 Phase 3 Next Milestones
NurOwn® MSC-NTF Technology Platform
ALSQ4’20E
Top-line data
Progressive MS Q4’20E
Top-line data
Alzheimer’s DiseaseIND: Q2’20E
Phase 2: 2H’20E
Parkinson’s Disease
Huntington’s Disease
Autism Spectrum Disorder
Peripheral Nerve Injury
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ALS Phase 2 Clinical Trial: Functional Outcomes
4Berry et al Neurology 2019, * for p < 0.05
Single dose NurOwn® slowed the rate of disease progression by improving the ALSFRS-R LS mean change in slope vs. pre-treatment slope
*p<0.05
All n = 46 Rapid progressors n=21
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• Primary safety
endpoint met
• Efficacy
demonstrated in
ALSFRS-R, a
measure of ALS
function
A Change from post-treatment to pre-treatment slope B Change from post-treatment to pre-treatment slope
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NurOwn®
(n = 26)
Placebo(n = 9)
ALS Phase 2: CSF Delivery of NTFs Confirmed
5Berry et al Neurology 2019
CSF Profile 2 Weeks Post Treatment Demonstrates Delivery of NTFs
*p<0.05, **p<0.01, ***p<0.001
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NurOwn®
(n = 26)
Placebo(n = 9)
ALS Phase 2: CSF MCP-1 Reduction
6Berry et al Neurology 2019
MCP-1 (an inflammatory mediator) is Significantly Reduced 2 Weeks Post-Treatment
*p<0.05, **p<0.01, ***p<0.001
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NurOwn’s MOA Demonstrated in ALS- Relevant to Alzheimer’s Disease
7
ALS: Amyotrophic lateral sclerosis; pMS: Progressive multiple sclerosis; AD: Alzheimer’s Disease; MOAs: Mechanisms of action; Sources: Prion. 2013 Jan 1; 7(1): 47–54. Front Immunol. 2018; 9: 217. J Neurosci Res 2017 Dec 95(12):2430-2447. Brain. 2018 Sep 1;141(9):2561-2575. Curr Neuropharmacol. 2011 Dec; 9(4): 559–573. Front Neurosci. 2010; 4: 32. Int J Mol Sci. 2012; 13(10): 13713–13725. Lancet Neurol. 2015 Apr; 14(4): 388–405. Curr Pharm Des. 2017 23(5):693-730. Front Immunol. 2017; 8: 1005. J Neuroinflammation. 2019 Feb 21 16(1):46.
Neuronal Degeneration
Astrocyte Dysfunction and Loss of
Neurotrophic Support (NTFs)
Neuroinflammation and
Microglial Activation
Underlying pathologies
of ALS, MS, and AD
Neuroprotection
↑CSF miR-132, ↓CSF Caspase-3
Enhanced delivery of NTFs
↑CSF VEGF, HGF, LIF, BDNF, GDNF
Immunomodulation
↑CSF miR-146, ↓CSF MCP-1, SDF-1, CHIT-1
NurOwn® MSC-NTF MOA
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French National Coordinator of AD Trial Principal Investigator of AD Trial
Bruno Dubois, M.D., Ph.D.
Professor of Neurology: Salpétrière University Hospital
President: Scientific Committee of France-Alzheimer
President: International Fund Raising for Alzheimer's Disease
Philip Scheltens, M.D., Ph.D.
Professor of Cognitive Neurology: Amsterdam UMC
Director of the Alzheimer Centre: Amsterdam UMC
Extensive experience as PI of international AD trials
Introducing Today’s KOLs
8AD: Alzheimer’s disease PI: Principal investigator
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Agenda
9
8:15-8:25 Chaim Lebovits, Chairman & CEO Brainstorm
Ralph Kern, M.D., MHSc, President & CMO Brainstorm
o Introduction and overview
8:25-8:40 Pr. Dubois, Salpétrière University Hospital
o High prevalence of the disease worldwide
o Great progress in diagnostic procedures
o Disappointment with current treatment
8:40-9:00 Pr. Scheltens, Amsterdam UMC
o New emerging therapies
o Biomarkers progress
o What’s attractive about Brainstorm approach
9:00-9:10 Stacy Lindborg, Ph.D. EVP & Head of Global Clinical Research
Brainstorm
o Study Protocol
9:10-9:30 Participants
o Q&A
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Alzheimer’s Landscape
1) High prevalence of the disease worldwide
2) Great Progress in diagnostic procedures
3) Disappointment with current treatment
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A High Prevalence
$7.9 trillion is the potential cost saving from early AD diagnosis only for current population in U.S.
Every 65 seconds someone in U.S. develops Alzheimer‘sdisease
35% of Americans age ≥60 are most afraid of developing AD or dementia (cancer 23%)
• EU: Projected to grow to 13.1M by 2040
• US: Projected to grow to 13.8M by 2050
Projection
• >7.5M in EU
• >5M patients in the US
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Significant Progress in Diagnostic Procedures
The 2 types of biomarkers
Pathophysiological markers = Diagnostic markers
• Reflect in-vivo pathology (amyloid and tau changes)
• Are present at all stages of the disease
• Observable even in the asymptomatic state
• Might not be correlated with clinical severity
• Indicated for inclusion in protocols of clinical trials
Topographical markers = Progression markers
• Lesser disease specificity
• Indicate clinical severity (staging marker)
• Might not be present in early stages
• Quantify time to disease milestones
• Indicated for disease progression
Dubois et al, Lancet Neurol. 2014
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Clinical Biological
Clinical phenotype
Typical AD:
• aMCI
• Amnestic syndrome
of hippocampal type
Atypical AD:
• Posterior cortical
• Logopenic variant
• Frontal variant
Biomarker positivity
• CSF abeta
• CSF tau
• CSF phosho tau
• amyloid PET
• tau PET
AD Diagnosis Framework
Clinical-biological entity
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Alzheimer’s Disease: “Turning to the left”
Dubois B et al. Alz Dement 2016
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1993-2001 Approvals• 1993: Tacrine (Cognex) first
one approved, now off
market due to safety
• Nov 96: Donepezil approved
• 2000: Rivastigmine
• 2001 Galantamine
2003 Approvals• Memantine
2006-2008 Failures• GSK Serotonin 6
receptor antagonists
halted after Phase 2
• Voyager: Leuprolide
• Neurochem Tramiprosate
• Myriad Flurizan
Other Failures• NSAIDs
• Latrepirdine
• Histamine H3
receptor antagonists
2011-2012 Failures• Gamma secretases Semagacestat,
Avagacestat, Elan: AN1792
• Amyloid immunoRx Bapineuzumab
• Solanezumab (+/-)
• Vaccination Affitope AD02
• H3 receptor antagonist Sanofi:
SAR 110894
2015-2016 Failures• Roche MAO-Bi Sembragiline
failed Phase 2 on primary efficacy
• Lundbeck Idalopirdine Ser 6 rec at
failed Phase 3
• Lilly Solanezumab MoAb failed
Phase 3b
• Merck’s Verubecestat failed in
mild AD, continue in prodromal
2017-2018 Failures• Janssen, Atabecestat (Preclincial A5
trial) discontinued due to safety concerns
• Merck discontinued Verubecestat
prodromal trial
• BI’s PDE9 inh Ph2 negative read out
• Axovant’s intepirdin’s Ph3 failure
• vTv azeliragon missed 2 primary
endpoints in Ph3
AcEiNMDA receptor
antagonists
2018: BAN2401 and Aducanumab showed promise in slowing of cognitive
decline in addition to target engagement
Disappointment with Current Treatment Research
Last 20 years, more than 100 negative trials
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Alzheimer’s Disease:
Cummings et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 272-293
Current Phase 2 and Phase 3 trials
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Agenda
17
8:15-8:25 Chaim Lebovits, Chairman & CEO Brainstorm
Ralph Kern, M.D., MHSc, President & CMO Brainstorm
o Introduction and overview
8:25-8:40 Pr. Dubois, Salpétrière University Hospital
o High prevalence of the disease worldwide
o Great progress in diagnostic procedures
o Disappointment with current treatment
8:40-9:00 Pr. Scheltens, Amsterdam UMC
o New emerging therapies
o Biomarkers progress
o What’s attractive about Brainstorm approach
9:00-9:10 Stacy Lindborg, Ph.D. EVP & Head of Global Clinical Research
Brainstorm
o Study Protocol
9:10-9:30 Participants
o Q&A
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The Use of Biomarkers to Advance NurOwn® in Alzheimer’s Clinical Trials
Prof. dr Philip Scheltens, FAAN, FEAN
Amsterdam UMC
Alzheimer Center Amsterdam
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Contents
o New emerging therapies
o Biomarker progress
o Brainstorm approach
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Beyond amyloid-β targets and approaches
Alzheimer Center Amsterdam
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Yearly increase in number of Alzheimer’s diseaseclinical trials and agents between 2016-2019
93105
112
132
115
139 135
156
20192016 2017 2018
+12%
Agents
Trials
Cummings et al., Alzheimer’s & Dementia: TRCI (2016,
2017, 2018, 2019)
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Issues in drug development
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ATN profiles Biomarker category
A-T-N- Normal AD biomarkers
A+T-N- Alzheimers
pathophysiology
Alzheimer’s
pathophysiological
continuum*
A+T-N+ Alzheimers
pathophysiology
A+T+N- Alzheimers disease
A+T+N+ Alzheimers disease
A-T+N- Non- AD pathophysiology
A-T-N+ Non- AD pathophysiology
A-T+N+ Non- AD pathophysiology
The right patients
Alzheimer Center Amsterdam
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CSF amyloid and tau are linked to cognitive decline in AD
Hansson Scientific Reports 2019
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Amyloid+/Tau+ linked to
neuroinflammation
Amyloid+/Tau+ linked to
neurodegeneration (NfL and Neurogranin)
Nordengen et al. Journal of Neuroinflammation (2019) Mila-Aloma Alzheimer’s & Dementia (2020)
CSF Amyloid/Tau are linked to neuroinflammation and neurodegeneration
MCP-1 NeurograninNfL
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Neuroinflammation plays a key role in AD….
Ising and Heneka Cell Death and Disease (2018) 9:120
Nature | Vol577 | 16January2020 | 399
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…which is mediated by microRNA-132
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miR-132 is
downregulated in
AD1
Decreased miR-
132 correlates
with AD Severity2
NurOwn® delivery of miR-132 addresses AD Pathology
AD: Alzheimer’s disease; NCI: No cognitive impairment; AD-MCI: Mild cognitive impairment due to Alzheimer’s disease; FC: Fold change
NurOwn® MSC-NTF cells express and deliver miR-132, which is downregulated in AD
Lo
g2
F
old
Ch
an
ge
of
mir
-13
2-3
p
NCI AD-MCI AD
miR
-13
2
Ex
pre
ss
ion
(2
-c
t )
ADAS Score
Phase 2 ALS:
Single NurOwn®
treatment
increased CSF
miR-132 in
responders
miR-132 is
upregulated in
MSC-NTF cells3
MSC MSC-
NTF
No
rma
lize
d R
ela
tive
Qu
an
tile
s
miR-132-3p Expression
FC = +4.06
1. Front Neurosci. 2019; 13: 1208;
2. Sci Rep. 2018; 8: 8465.
3. Stem Cell Res Ther. 2017 Nov 7; 8(1):249.
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In conclusion
NurOwn®
• Has shown promising results in ALS by increasing NTFs and micro-RNA 132
• Which is downregulated in AD and is considered the right target in AD
• Which mediates a large array of pathologies in AD
• The upcoming trial includes the right patients, uses the right biomarker and is the right trial to provide important safety information and efficacy signals needed to build the next phase of the development
Alzheimer Center Amsterdam
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Agenda
30
8:15-8:25 Chaim Lebovits, Chairman & CEO Brainstorm
Ralph Kern, M.D., MHSc, President & CMO Brainstorm
o Introduction and overview
8:25-8:40 Pr. Dubois, Salpétrière University Hospital
o High prevalence of the disease worldwide
o Great progress in diagnostic procedures
o Disappointment with current treatment
8:40-9:00 Pr. Scheltens, Amsterdam UMC
o New emerging therapies
o Biomarkers progress
o What’s attractive about Brainstorm approach
9:00-9:10 Stacy Lindborg, Ph.D. EVP & Head of Global Clinical Research
Brainstorm
o Study Protocol
9:10-9:30 Participants
o Q&A
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BCT-201-EU Study Overview
Prodromal to Mild Alzheimer’s Disease Study
Stacy Lindborg, Ph.D.
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Patient Selection:
40 participants with Prodromal to Mild AD at Medical Centers in France and the Netherlands
• Clinical diagnosis of prodromal to mild dementia* at least 6 months prior to enrollment
• MMSE 20-30, CDR global score 0.5-1.0
• CSF profile consistent with AD**
Rationale for Patient Selection Criteria:
Stage of disease where measures important to Alzheimer’s disease exhibit the largest dynamic range
• Clinical measures
• AD biomarkers
• Neuroinflammatory markers linked to Alzheimer’s disease progression
Objective:
Safety and Efficacy of NurOwn® (Mesenchymal stem cells differentiated into neurotrophic factor
secreting cells, MSC-NTF cells)
*IWG-2 (Second International Working Group) and NIA-AA (National Institute on Aging and Alzheimer’s Association)
** aβ42<1000 pm/ml and P-tau>19 pm/ml or ratio >0.024 (Elecsys assay) 32
BCT-201-EU, AD Phase 2a Study
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BCT-201-EU, AD Phase 2a Trial Design
33
52 Week clinical trial
42-week treatment period and post-treatment follow up
R
3
:
110-week run-in
Bone Marrow
Aspiration
• Follow up visits on Week 28 and 42
• CSF collection: pre-treatment, Week 0, 8, 16,
• Serum sample collection: pre-treatment, Weeks 0, 8, 16 and follow-up visits week 28, 42
• Patient phone calls after treatment visits at Weeks 0, 8, 16
• Total Study length 52 weeks, Final visit at Week 42
Collect CSF,
Treatment
N = 40
Open
Label
TreatmentTo evaluate the modulation of
CSF and blood biomarkers
To evaluate clinical outcomes
measures to assess efficacy
(cognition and function)
Primary Objective
Secondary Objectives
To evaluate safety and
tolerability of 3 Intrathecal
administrations of
MSC-NTF cellsCollect CSF,
Treatment
Collect CSF,
Treatment
16-week treatment period,
8 weeks between treatments
In person
Visit
In person
Visit
26-week follow-up period,
12 & 14 weeks apart
treatment with MSC-NTF cells
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Biomarkers: paired serum and CSF samples Interested in biomarker levels over time to explore:
• Neurotropic, neurodegenerative and inflammatory factors (e.g., VEGF, HGF, NfL, NfH, MCP-1, IL-6)
• Markers associated with amyloid deposition (e.g., ab40, ab42)
• Markers of tau protein levels (e.g., p-tau, t-tau)
Clinical outcome measures: cognition* and activities of daily livingInterested in changes from baseline over time in the following tests:
• Clinical Dementia Rating Scaled – Sum of Boxes (CDR-SB)
• Free and Cued Selective Reminding Test (FCSRT)
• Neuropsychological Test Battery (NTB)
• Delis-Kaplan Executive Function System (D-KEFS) subtests
• Mini Mental State Examination (MMSE)
• Amsterdam Instrumental Activities of Daily Living Questionnaire - Short Version (A-IADL-Q-SV)
34* Including memory, executive function, and attention
BCT-201-EU, Phase 2a Study Measurements
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Question & Answer
35
Question & Answer
37
QA