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

Increase in Incidence with Aging of Population

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 450139 G-secretase inhibitor BMS 708163 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

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.

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

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

Alzheimer’s Disease

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

Peter Davies, Hofstra University – Unpublished data AD - Posiphen Lowers Levels of Aggregated Tau in Transgenic humanTau Mice Peter Davies, Hofstra University – Unpublished data

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

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

Parkinson’s Disease

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

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

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

Human Data

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

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

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

Posiphen Mechanism of Action

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

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

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

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

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

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

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