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Paradigm Shift in the Treatment of Alzheimer’s
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NEUROTROPE, INC. (OTCQB: NTRP)
February 2017
Safe Safe HarborHarbor StatementStatement
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Certain statements in this presentation, particularly those pertaining to our strategy, constitute forward-looking statements. Such statements are based upon the current beliefs and expectations of management and are subject to significant risks and uncertainties. Actual results may differ materially from those set forth in the forward-looking statements.
Any statements that are not statements of historical fact (including statements containing the words “believes,” “plans,” “ anticipates, ” “ expects, ” “ estimates ” and similar expressions) should also be considered to be forward-looking statements. There are a number of important factors that could cause actual results or events to differ materially from those indicated by such forward-looking statements. These factors are contained in Neurotrope Inc.’s filings with the SEC, including Neurotrope’s Annual Report on Form 10-K for the year ended December 31, 2015 and its Quarterly Report on Form 10-Q for the quarter ended September 30, 2016 and registration statement on Form S-1 filed on January 14, 2016. We encourage all viewers of this presentation to review the aforementioned filings. All statements contained in this presentation are made only as of the date of this presentation, and we do not undertake any obligation to publicly update any forward looking statements.
THESE MATERIALS DO NOT CONSTITUTE AN OFFER TO SELL, OR THE SOLICITATION OF ANY OFFER TO BUY, ANY SECURITIES OF THE COMPANY OR ANY ENTITY WHATSOEVER. ANY SUCH OFFER MAY ONLY BE MADE BY A PRIVATE PLACEMENT MEMORANDUM OR PROSPECTUS ISSUED BY THE COMPANY. ANY REPRESENTATION TO THE CONTRARY BY ANY PARTY SHOULD BE IGNORED.
The full text of Neurotrope’s SEC filings can be found at the SEC’s website (http://www.sec.gov)
The Neurotrope Difference: Paradigm Shifting Science The Neurotrope Difference: Paradigm Shifting Science In The Treatment of Alzheimer’s In The Treatment of Alzheimer’s
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Clinical-stage biopharmaceutical company developing novel therapies for neuro-degenerative diseases, initially focused on Alzheimer’s
Fundamentally novel understanding on the causes of Alzheimer’s
Focus re-generation of synapses and synaptic networks rather than neuronal loss through beta amyloid plaque and tau tangles
Potential to reverse Alzheimer’s even in advanced patients –
Unique regenerative approach based on molecular understanding of memory and learning based on PKC epsilon activation
Mechanism of action fundamental to other neuro-degenerative disease
Platform technology, fundamental mechanism underlying a larger number of neuro-degenerative diseases (FXS, Rett Syndrome; stroke, TBI, depression)
The Neurotrope Difference: The Neurotrope Difference: Upcoming Phase 2 Data Upcoming Phase 2 Data
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Upcoming Phase 2 topline data in April 2017 in moderate to severe Alzheimer’s – pivotal valuation inflection point:
148 patients, double-blind, placebo-control, 26 sites US sites
Bryostatin, lead compound, well tolerated in 1500 patients
Extensive preclinical data, preliminary clinical and Compassionate Use data
Major Corporate DevelopmentsMajor Corporate Developments
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Neurotrope formed in 2012 out of the Blanchette Rockefeller Institute (BRNI) Dr. Alkon – 30 years at NIH; 15 years at BRNI > 300 publications > $200m funding while at NIH and BRNI > $35 million raised since NTRP inception (2012- 2015)
Major restructuring in August/ September 2016 Closed an additional $24.3 million (Nov 2016) Restructured Board & Management Change Dr. Alkon joined as President in addition to CSO
Dynamic Clinical Program Development, next 12 – 18 months Alzheimer’s disease (AD) program Fragile X Syndrome Program (FXS)
January 2017 announces plans to list on NASDAQ and Neurotrope Completes Licensing Agreement for Accelerated
Synthesis of Alzheimer’s Drug Bryostatin-1
LeadershipLeadership TeamTeam
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Dr. Susanne Wilke, Ph.D , MBA – Chief Executive OfficerSignificant sector, business development. commercial, and investing experience World-wide Director of Commercial Assessment/ In-licensing at Forest Labs
(now Allergan) Venture Capital Investor (SVLS, NGN Capital): - led > 17 investments, Previous leadership positions at Roche, Amgen, The Monitor Group Dual Ph.D, Bio-Chemistry/Drug Development; MBA-Tuck/ Dartmouth,
Kauffman Fellow
Dr. Daniel Alkon, MD – President, Chief Scientific Officer Specializing in memory and neuro-degenerative diseases 30 years at NIH, 15 years at the B.R.N.I > 300 peer reviewed publications Graduate of Cornell Medical School, Mt. Sinai
Dr. Kenneth Gorelick, MD – Interim Chief Medical Officer Managing Director of Zymo Consulting Group LLC Graduate of Cornell Medical School, Mt. Sinai
Robert Weinstein, CPA, MBA – Chief Financial Officer Experienced CFO, Private Equity and Investment Banking
Synaptic Loss – Not amyloid plaques Synaptic Loss – Not amyloid plaques and tangles - Correlates with AD and tangles - Correlates with AD
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Ann Neurol 1991
Molecular Understanding of Memory Molecular Understanding of Memory Key Insights – Molecular Understanding of Memory
Based on Electron/ Confocal Microscopy Studies
Synaptic networks are key to memory
Disruption of synaptic networks leads to cognitive loss, disease; regeneration of synaptic networks lead to memory enhancement > 11 animal models
PKC epsilon a key player in memory and neurodegenerative process. Activation of PKC e acts as a master switch in increase synaptogenesis
Identified Bryostatin, as a highly potent and selective activator of PKC epsilon in the brain
Harvard Study: Fresh Frozen Brain samples of AD patients showed PKC epsilon deficiency
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Dr. Alkon, MD – Pioneer in Memory Research
PKCe: PKCe: Master Master Switch Switch for for MemoryMemory, , DiseaseDisease
Activates Synaptic Growth Factors – BDNF, IGF- 1, NGF and others
Activates All amyloid-β Degrading Enzymes
Increases in BDNF via ApoE3 induced PKCϵ
Increases BDNF via loss of ApoE4 mitigated reduction of BDNF
Activates α-secretase reducing neurotoxic amyloid-β
Bryostatin normalizes GSK3-β, thereby inhibiting pathological Tau
Brain Health• Memory and Learning• Spatial Recognition
Decreased PKCe activation leads to reduced synaptic density
Reduced Synaptic Growth Factors – BDNF, IGF-1, NGF, others
Inactivated amyloid-β degrading enzymes increased neurotoxic amyloid-β
Increasing pathological Tau
Neurodegenerative Diseases:• Alzheimer’s• Fragile X (FXS)• Rett Syndrome• Stroke
Multi- modal effects
NTRP 9
Multi-Modal Multi-Modal Mechanism Mechanism ofof ActionAction
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Acvation of Protein Kinase C epsilon (PKCϵ) Activates Synaptic Growth Factors – BDNF, NGF, IGF, others Activates All amyloid-β Degrading Enzymes (ECE, Neprilysin, IDE,
ect)
Activates α-secretase, which reduces formation of neurotoxic amyloid-β formed by γ-secretase and BACE
ApoE3 induces PKCϵ; by activating PKCϵ, there is an increase in BDNF expression
Bryostatin blocks ApoE4 reduction of BDNF via HDAC inhibition
Bryostatin normalizes GSK3-β, thereby inhibiting pathological Tau protein transformation into neurofibrillary tangles (NFTs)
Bryostatin targets multiple pathways
Snapshot of Bryostatin - Synaptogenesis Snapshot of Bryostatin - Synaptogenesis
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On The Cover: Integrative neurons in the hippocampus show large oval nuclei (blue) and presynaptic axonal boutons. Yellow grains, boutons with brain-derived neurotrophic factor (BDNF); green grains, boutons with no BDNF accumulation; red grains, postsynaptic dendritic spines with BDNF. BDNF is important for synaptic activity and neuron survival. The PKCε activator, bryostatin 1, enhanced the presence of the synaptogenic growth factor, BDNF, as indicated by the yellow dots. For details, see the JBC article by Sen et al., pages 16462–16476.
Pre-clinical Data:
Bryostatin Prevents the Loss of Synapses in AD-transgenic Mice (Tg2576)
Electron microscopy of the stratum radiatum in the hippocampal CA1 area. Red arrows point to all synapses and mushroom spines are highlighted in yellow. **p<.01, ***p<.001; two-tailed t-test. n=3 mice and n=25-35 electron micrographs in each group. Synapse loss was entirely prevented by Bryostatin treatment.
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Bryostatin Bryostatin - Clinical- Clinical DevelopmentDevelopment
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Safety and Clinical Development
Safety 1,500 patients in NCI – well tolerated
Compassionate Use protocols in severe AD patients
❒ Significant improvement in cognition and daily living
❒ Possibility of disease reversal
❒ Three patients treated, longest dosed patient ~followed for one year
• Phase 2a clinical trial completed❒ Bryostatin achieved primary safety endpoint
❒ Demonstrated activation of PKCϵ target engagement ❒ Cognitive enhancement within 3 hours
• Phase 2: last patient dosed , top-line efficacy data April 2017
Bryostatin Compassionate Use Program: Severe Alzheimer’s Disease No other reports have ever shown comparable benefits in such severely
demented patients – albeit in the absence of age-matched controls.
Patient 1 - 95 y/o ♂ (JT) – disoriented, intermittent coma, non-verbal
Course: Became alert, attentive; remembered date, place, time; mind active, engaged, watching TV, requested to return to work
Patient 2 - 38 y/o ♀ (JS) - familial Early-Onset AD due to PSEN1 mutation Non-verbal, drooling, unable to swallow (fed with gastrostomy), attention grossly impaired, spasticity, inability to move
Course: Return of some language and vocalization, swallowing, increased attentiveness to environment & persons, increased range of motion
Patient 3 - 76 y/o white (FC)
Course: MMSE: 2-3 improves to 10 -12; recognizes, vocalizes words
ADCS-ADL-sev score: 18 improves to 33; Hallucinations: reduced;
Return of complex motor skills – e.g. swimming, billiards
Compassionate Use Patients: Overview
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Phase 2 – Ongoing Clinical TrialPhase 2 – Ongoing Clinical Trial Double – Blind, Placebo – controlled, 148 moderate to severe AD patients dosed over 12 weeks
q Dosing initiated in January 2016, trial fully enrolled
q Full data results expected April 2017
qPrimary efficacy endpoint: ◦ Severe Impairment Battery (SIB) possible disease reversal
q Secondary efficacy endpoints: ◦ Mini-Mental State Exam (MMSE)◦ Activities of Daily Living (ADL)◦ Neuropsychiatric Inventory (NPI)
q 20ug and 40ug doses of bryostatin vs. placebo
q26 sites all in the U.S.
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Clock Drawing Test – MMSE 10 - 0
Current Neurotrope Current Neurotrope Phase 2Phase 2::MMSE: Secondary MMSE: Secondary Clinical Endpoints Clinical Endpoints and and
Screening Tool - Severe PatientsScreening Tool - Severe Patients
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Phase Phase 2 - 2 - Clinical AssessmentClinical Assessment MethodsMethods
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Cognition
Behavior
Function
Neuropsychiatric Inventory (NPI)
AD Cooperative Study −Activities of Daily Living, severe
(ADCS-ADL-SIV)Mini Mental State Examination (MMSE)
Severe Impairment Battery (SIB)
Neurotrope Neurotrope Phase 2:Phase 2:
Baseline Baseline Characteristics - EndpointsCharacteristics - Endpoints
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Mean sd Median Range AD-Type
Age 72.2 7.8 73 55 – 85
Gender M/F 49/55
MMSE (screened, N=212) 10.2 4.0 10.5 0 – 20
MMSE (randomized, N=125)* 10.0 3.5 11.0 4 – 15 Severe
<10
SIB (randomized) 76.4 19.1 83.0 11 – 99
NPI (randomized, Freq x Sev) 13.9 14.1 10.0 0 – 77
NPI (randomized, caregiver distress) 7.3 6.4 6.0 0 – 37
ADCS-ADL-SIV (randomized) 35.5 10.8 37.5 6 – 54
MMSE (Mini-Mental State Exam), SIB (Severe Impairment Battery); ADL (Activities of Daily Living); NPI – (Neuropsychiatric Inventory); * Sept. 21, 2016
Memantine Memantine –– Approved Approved IIn Moderate n Moderate –– Severe Patients - Results Severe Patients - Results
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Registration Trial: NEJM, 2003 : SIB (Severe Impairment Battery) - best correlating scale
Biogen (2016): Highest Dose Still Results in Decline in MMSE, No Reversal
Nature. 2016 Aug 31;537(7618):50-6. doi: 10.1038/nature19323.
Aducanumab effect (change from baseline) on MMSE.*P< 0.05 versus placeboThere was over a 30 percent rate of brain edema in Mild Cognitive Impairment patients
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World Class AD Clinical AdvisorsWorld Class AD Clinical Advisors
q Dr. Jeffrey L. Cummings, MD, ScD, CCF - Chairmanq Director of Cleveland Clinic Lou Ruvo Center for Brain Healthq Expert in clinical trial design & analysis, global trial implementation, outcome measuresq Authored or edited 30 books and published 600 peer-reviewed papers
q Dr. Martin R. Farlow, MDq Professor and Vice Chairman of Research, Dept. of Neurology Indiana Universityq Associate Co-Director of the Indiana AD Center and member of gov’t. AD task forceq Published 200 peer-reviewed papers
q Dr. Samuel E. Gandy, MD, PhDq Mount Sinai Chair in AD Research, Professor of Neurology and Psychiatry at Mount Sinaiq Discovered PKC regulation of amyloid precursor phosphorylation and processing
q Dr. Michael Weiner, MDq Professor UCSF School of Medicine in Radiology and Biomedical Imagingq Educated at Mount Sinai and Yale, Assistant Professor of Medicine at Stanfordq Established MRI Unit at the San Francisco VA Medical Center
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Fragile Fragile X X SyndromeSyndrome discussiondiscussion
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Most common inherited cause of mental retardation, genetic cause of autism and single gene cause of intellectual disability
• ~135,000 patients in U.S.• Affects 1 in 3000-4000 boys, 1 in 4000-8000 girls
Subtle physical phenotype with striking neuropsychiatric phenotype
25-30% of full-mutation males meet criteria for a dx of autism, nearly all the rest have Autism Spectrum Disorder/Pervasive Developmental Disorder
20-25% of males have seizures Normal life expectancy True developmental disorder---not neurodegenerative Treatments offer only symptomatic benefit
World World Class FXS ClinicalClass FXS Clinical AdvisorsAdvisors
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Chairperson : Elizabeth Berry-Kravis MD, PhD, Rush Medical
Randy Haberman, Mind Center, UCSD
Craig Erickson, MD, Chief NIH Clinical Advisory Group
Bryan King, MD, UCSF
Sara Jane Webb, MD, U. Washington
Mike Tranfaglia, MD, President of FRAXA
World-Class World-Class ScientificScientific CollaborationsCollaborations
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Trading and Capitalization Trading and Capitalization
Ticker Symbol NTRP
Share Price (02/10/17)$13.35
Common Stock 8 M
~5.7 million warrants $12.80 - $32 per share and .7 million options $10.56 - $71 per share Market Cap $107 M
Pro-rata Cash Balance as of 11/22/16 $30 M
: NTRP 26
Neurotrope AppendixNeurotrope Appendix
A1
A Multi-modal Strategy for Alzheimer’s Disease: A Multi-modal Strategy for Alzheimer’s Disease:
PKC PKC εε Activators Activators
Restore Lost Synapses - Synaptogenesis
Protect against Neuronal Loss - Anti-apoptosis
Treat Cognitive Deficits
Anti-Aβ Oligomers, Prevent Plaques
Anti- τ phosphorylation, Prevent Tangles
A2
Neurotrope Therapeutics for Neurodegeneration
I. Therapeutic Targets for Early, Late Alzheimer’s Disease (AD):
l. Synapse Regeneration 2. Prevention of Neuronal Death 3. Anti-Amyloid 4. Anti-tau
II. Potential Efficacies l. Underlying Disease – prevention, reduction,
reversal 2. Symptomatic Relief 3. Cognitive Enhancement
A3
ApoE - PKC ε : Mechanistic Relevance For Alzheimer’s Disease
• A poE 3: Increases Genetic Expression of PKC ε – BDNF Synaptogenesis - Activated by Bryostatin
• ApoE 4: Genetic Risk Factor for AD - Prevents PKC ε - Synaptogenesis - Blocked by Bryostatin
• PKC ε Degrades A Beta Oligomers, Activates alpha secetase
• PKC ε Deficits in AD Brains at Autopsy (Harvard/BRNI)
• PKC ε Enhances/Mediates Learning and Memory
A4
Snapshot of Bryostatin - Synaptogenesis Snapshot of Bryostatin - Synaptogenesis
A5
On The Cover: Integrative neurons in the hippocampus show large oval nuclei (blue) and presynaptic axonal boutons. Yellow grains, boutons with brain-derived neurotrophic factor (BDNF); green grains, boutons with no BDNF accumulation; red grains, postsynaptic dendritic spines with BDNF. BDNF is important for synaptic activity and neuron survival. The PKCε activator, bryostatin 1, enhanced the presence of the synaptogenic growth factor, BDNF, as indicated by the yellow dots. For details, see the JBC article by Sen et al., pages 16462–16476.
bb
cc400 nm
NaïveNaïve
Maze+BryoMaze+Bryo
aa
T
Perforated PSDPerforated PSD
Macular PSDMacular PSD
150 nm
Nv Sw MzMz/B
r
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Mac
ular
mus
hroo
m/1
00um
2
***
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
***
*
Perfo
rate
d m
ushr
oom
/100
um2
dd
ee
600 nm
MazeMaze+Bryo+Bryo
SwimSwim
MazeMaze
SwimSwim
NaïveNaïve SwimSwim
MazeMaze
Learning Specifically increases:
the number of mushroom spine
synapses
Water maze training - Electron MicroscopyA6
Bryostatin-1 Preserves Synapses (CA1 Neurons)
in Tg2576 AD Transgenic mice
A7
Bryostatin prevents the loss of synapses in AD-transgenic mice (Tg2576)
Electron microscopy of the stratum radiatum in the hippocampal CA1 area. Red arrows point to all synapses and mushroom spines are highlighted in yellow. **p<.01, ***p<.001; two-tailed t-test. n=3 mice and n=25-35 electron micrographs in each group. Synapse loss was entirely prevented by Bryostatin treatment
A8
Prevent Loss of Learning & Memory
In 5XFAD Mice: - Bryostatin-1 or - PKCε activator
Bryostatin-1 at 20 g/m2 (tail i.v., 2 doses/week for 9 weeks); water maze: 3 trials/day
Tar
get Q
uadr
ant R
atio
3
2
1
0
NS
C+ Tg+ Tg+ C+
**
A9
PKCε
Aβ
-
--
-
Amyloid/PKC Metabolism
Progression Targets
A10
Tau/PKC Metabolism
Progression Targets
A11
PKC-ε Activator reduces the formation of amyloid plaques in AD-transgenic mice (5X FAD)
Wild 5X FAD5X FAD+
PKC activator
1 m
Wild
Wild+ activa
tor5x
FAD
5X FA
D+ activa
tor
Am
yloi
d pl
aque
s in
CA
1 ar
ea
0
0.2
0.4
0.6
0.8
1.0
***
A12
Cerebral ischemic rats: anti-apoptosis – Bryostatin
Bryostatin-1 (15 g/kg. iv; 2 doses/ week for 5 weeks) A13
Bryostatin Background
• Purified from marine bryozoan Bugula neritina
• Potent activator of PKC ε
• Reached phase II clinical trials as an anti-tumor agent (metastatic melanoma), but was ineffective
• Well-tolerated at Doses for Neurodegeneration
• Phase II a Trial Safety, Initial Pharmacokinetics (NTRP)
• Phase II b FDA Recently Approved 150 patient trial (NTRP)
Compassionate Use Trials (NTRP) – efficacy in Severe AD A14
Bryostatin Compassionate Use Program: Severe Alzheimer’s Disease No other reports have ever shown comparable benefits in such severely demented patients – albeit in the absence of age-matched controls.
Patient 1 - 95 y/o ♂ (JT) – disoriented, intermittent coma, non-verbal
Course: Became alert, attentive; remembered date, place, time; mind active, engaged, watching TV, requested to return to work
Patient 2 - 38 y/o ♀ (JS) - familial Early-Onset AD due to PSEN1 mutation Non-verbal, drooling, unable to swallow (fed with gastrostomy), attention grossly impaired, spasticity, inability to move
Course: Return of some language and vocalization, swallowing, increased attentiveness to environment & persons, increased range of motion
Patient 3 - 76 y/o white (FC)
Course: MMSE: 2-3 improves to 10 -12; recognizes, vocalizes words
ADCS-ADL-sev score: 18 improves to 33; Hallucinations: reduced;
Return of complex motor skills – e.g. swimming, billiards
A15
Orphan Drugs: Bryostatin Normalizes Fragile X Synapses
A16
Alzheimer’s Disease – early, moderate, severe
Fragile X Disease – Orphan Drug Status
Stroke
Traumatic Brain Injury
Mood Disorders
Niemann-Pick Disease
Potential Indications
A17
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