1. Treating Chronic and Acute Neurodegeneration by Inhibiting Neurotoxic Aggregating Proteins AP/PD Conference April 2, 2017

2. Increase in Incidence with Aging of Population

3. Because Targeting Abeta or just one Toxic Protein doesn’t work
Drug
Class
Company
Phase
Status
AAB-001
A-beta antibody
JNJ/Wyeth/Elan
III
Failed
Solenuzumab
Eli Lilly LY
G-secretase inhibitor
BMS
Bristol Myers II
Gammagard
Baxter
ELND 005
Ab aggregation inhibitor
Elan/Transition
A-beta antibody, early
Verubecestat
B-secretase inhibitor
Merck
II/III
B-secretase inhibitor, very early
May Fail
A-beta antibody, very early
Amaranth
AstraZeneca/Lilly
Mission AD1
Biogen/Esai
CNP520
Amgen/Novartis
Aducanumab
Biogen
Crenezumab
Genentech/Roche
various
A-beta and tau
many
I or preclin

4. AD Requires a New Approach
Brain insults lead to neurodegeneration
Posiphen
Attacking one neurotoxic aggregating protein results in minimal effect; Posiphen is the only drug to attack multiple neurotoxic proteins
Amyloid β
Alzheimer’s
Parkinson’s
Tau
Tauopathies
Synuclein
Aβ Targeting Compounds
Tau Targeting Compounds
Lewy Bodies
PD-specific
SYN Targeting Compounds
Increase in aggregating neurotoxic proteins
Clean up. Lose “Co overview” from each slide.

5. Posiphen: Compelling NCE
Orally bioavailable with good blood brain-barrier
permeability
Lead asset, Posiphen, has unique paradigm-shifting mechanism of action in neurodegeneration
Posiphen inhibits more than one neurotoxic aggregating protein

6. What we will Cover Posiphen for Alzheimer’s disease
Posiphen for Parkinson’s disease
Other:
Huntington's
Frontotemporal dementia
Down Syndrome
Traumatic brain injury
Acute glaucoma
Human Data
Mechanism of Action

7. Alzheimer’s Disease

8. Lilja AL et al. PLOS One, March 2013 | Volume8
AD - Posiphen Lowers Levels of Soluble and Aggregated Aβ in Brains of APP/PS1 Mice
Lilja AL et al. PLOS One, March 2013 | Volume8

9. Peter Davies, Hofstra University – Unpublished data
AD - Posiphen Lowers Levels of Aggregated Tau in Transgenic humanTau Mice
Peter Davies, Hofstra University – Unpublished data

10. AD - Posiphen Improves Spatial Memory in APPswe/PS1 Mice
Posiphen significantly (p=0.0033) improves spatial memory of double transgenic mice in radial water maze test
Ottavio Arancio, Columbia University

11. AD - Posiphen Rescues Synaptic Dysfunction (LTP) in Hippocampal Slices from APP/PS1 Mice
Treatment with oral Posiphen rescues long-term potentiation
Ottavio Arancio, Columbia University

12. Parkinson’s Disease

13. Parkinson Mice: Posiphen Improves Gut Motility in transgenic αSYN A30T Mice
Consider alternative dual slide for these experiments as in PPM.
Dbl-PAC-Tg(SNCA A30P); Snca -/- and control mice treated with 0, 3 or 10mg/kg IP daily from 6 to 28 weeks of age
Colonic motility significantly increased with Posiphen treatment

14. Parkinson Mice: Posiphen Improves Gut Motility in transgenic αSYN A53T Mice
Transgenic PD PAC A53T mice and controls were treated with 10mg/kg ip daily from 2 months to 4 and 7 months of age. Colonic motility was measured and compared to control treated and untreated animals
UCSF, sponsored by Michael J Fox Foundation

15. Parkinson’s Mice: Posiphen Lowers aSYN Levels in Animals with Restored Gut Motility
Decrease in aSYN in Gut of tg PAC A53T Treated with Posiphen
Preliminary Data
Treatment Time in Weeks 3 10 21
% Decrease Compared to Control
9.6
29.4
37.9
Statistical Significance p
0.4857
0.0342
0.0286
Posiphen dose in mg/kg
0 10
Sample Western Blot
UCSF, sponsored by Michael J Fox Foundation

16. Human Data

17. Safety in Phase 1 Clinical Trials
Maccecchini ML, et al. JNNP 2012

18. Maccecchini ML, et al. JNNP 2012
Posiphen Lowers Neurotoxic Proteins in 5 MCI Patients to Levels of Healthy Volunteers
Human Biomarker
CSF % of Time 0
Standard Error
P-Value
Assay
sAPP α
-34.1%
0.659
0.0661
MSD
-59.9%
0.231
0.0006
AlphaLisa
sAPP β
-34%
1.516
0.0901
-57.7%
0.361
0.0001
Tau
-46.2%
0.538
0.0020
-74.1%
0.259
0.0150
Innogenetics
pTau
-61%
0.195
0.0039
Maccecchini ML, et al. JNNP 2012

19. New Phase 2 Biomarker Trial in Early AD
Multi-center, randomized, double-blind, placebo- controlled trial
Subjects with diagnosis of early AD
Proof of mechanism, proof of concept and identify dose range for efficacy
Trial to obtain optimal information to proceed to pivotal, large scale cognition study
Endpoints:
Safety and tolerability
PK in plasma and CSF
Effects on Aβ40 in CSF using SILK
Effects on Aβ38/40/42, sAPP, sAPPβ, T-tau, AChE and inflammatory markers
ADAS-Cog12, MMSE and NPI

20. Posiphen Mechanism of Action

21. Common Behavior of Neurotoxic Aggregating Proteins
AD: plaques and tangles
PD: Lewy bodies
HD: Huntingtin inclusions
TSE: prion amyloid plaque
ALS: superoxide dismutase inclusions
Claudio Soto, Nature Reviews Neuroscience, 2004

22. present in most neurodegenerative disorders
Neurotoxic Aggregating Proteins and Associated Diseases
Disease
Old Knowledge
New Knowledge AD
Aβ, tau
Aβ, tau, aSYN, prions PD
SNCA
aSYN, Aβ, tau DS
Aβ, tau, SOD, prions
CJD
Prions
Prions, Aβ
ALS
SOD
SOD, TDP43 HD
Htt
Htt, Aβ, tau
many
tau
present in most neurodegenerative disorders

23. Posiphen Inhibits Translation of Neurotoxic Aggregating Proteins
Commonalities of Neurotoxic Protein Regulation
Neurotoxic aggregating proteins display similar features from gene activation, to protein synthesis to folding, misfolding, toxicity and aggregation:
Transcription is regulated by Cu/Zn
Translation is regulated by Fe
At low concentrations they have a normal function
At high concentrations they form toxic oligomers
Oligomers can infect other cells in the brain and spread
They are degraded by the proteasome
The cell sequesters these toxic oligomers into aggregates to neutralize them
Posiphen Inhibits Translation of Neurotoxic Aggregating Proteins

24. 5’ UTR IRE Stem Loop Homology of Neurotoxic Aggregating Protein mRNAs
Highly Preserved Consensus Loop in 5’UTR of Neurotoxic Aggregating Proteins
>50% homology between 5’UTRs of mRNAs

25. Posiphen Mechanism of Action
IRP-1 binding to APP IRE inhibits APP, tau and aSYN translation 3’
APP/aSYN/tau/SOD1/ Prp/Htt
IRP-1
IRE RNA stem loop
AUG 5’
IRE
+ Posiphen (PS) PS
APP/aSYN/tau/SOD1/ Prp/Htt
IRE – iron responsive element
IRP – iron binding protein
Posiphen potentiates the binding of IRE to IRP-1
thus further inhibiting translation

26. Posiphen’s Novel MOA Combats Multiple Molecular Pathologies
High Levels of neurotoxic aggregating proteins…
Cause disturbances in vesicle maturation and transport - Posiphen normalizes vesicle transport
human neuronal cells : Bill Mobley, UCSD
Impair synaptic transmission – Posiphen normalizes it
rat striatum: Marie-Francoise Chesselet, UCLA
mouse hippocampus: Ottavio Arancio, Columbia U.
Cause inflammation - Posiphen lowers inflammation in
human CSF: QR Pharma
rat brain: Marie-Francoise Chesselet, UCLA
Kill nerve cells - Posiphen protects nerve cells from dying in
rat substantia nigra: Marie-Francoise Chesselet, UCLA
rat retina : Jeff Sundstrom, Hershey Medical Center
mouse enteric nerves: Bob Nussbaum, UCSF

27. Scientific Advisory Board
Peter Davies, PhD, Hofstra University
Director and Professor, Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research
Jeff Cummings, MD, Cleveland Clinic, is Director, Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada and Cleveland, Ohio.
Bill Mobley, MD, PhD, UCSD
Department Chair , Distinguished Professor and Executive Director of UCSD's Down Syndrome Center and the Florence Riford Chair of Alzheimer Disease Research
Greg Petsko, PhD, Weill Cornell
Professor of Neurology and Neuroscience and Director, Alzheimer’s Disease Research Institute at and adjunct professor of Biomedical Engineering at Cornell University.
Sid Strickland, PhD, The Rockefeller University Vice President, Dean and Professor, Patricia and John Rosenwald Laboratory of Neurobiology and Genetics
Rudy Tanzi, PhD, Massachusetts General Hospital
Vice-Chair and Director of Neurology, Genetics and Aging, Joseph and Rose Kennedy Professor of Neurology