Selected collaborators: Dr. David Gurwitz; Dr. Segev Barak; Dr. Metsada Pasmanik-Chor and Adva Yeheskel, Dr. Galila Agam, Dr. Brian Dean, Dr. Annie Andrieux; Dr. Nikolaos Grigoriadis, Dr. Frank Kooy, Dr. Anke Van Dijck -The Antwerp Cognitive Genetics Group, Dr. Pierre-Luc Germain, Dr. Christopher Pearson. Dr. Anne McKinney, McGill. Profs. Drs. Christiane Richrer-Landsberg &Hans Grabe, Mrs. Angela Zawacki Downing, Mrs. Sandra Bedrosian Sermone

The Story of Tony and Alexi: Combatting Autism-Associated Mutations

Professor Illana Gozes, Ph.D. The Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head, the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology; Bloomfield Supported McGill-Tel Aviv University Brain Collaboration, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, , Israel (www.brain.tau.ac.il);

Laboratory Members: Ph.D. students: Yanina Ivashco-Pachima, Adva Hadar, Iris Grigg, Gal Hacohen-Kleiman, Oxana Kapitansky, Shlomi Sragovich and Gideon Karmon (MD/PhD student). Master Students: Evgenia Maryanovsky, Yarden Ziv, Livnat Bacal and Yael Toren. Project Students: Adi Linovitz and Adi Zaslavsky. Dr. Eliezer Giladi, Ph.D., Laboratory Manager.

AMN Foundation Canadian & Spanish Friends of Tel Aviv University

Thanks!

COMPANY OVERVIEW

January 2017

3

www.coronisns.com

About Coronis Neurosciences

Coronis Neurosciences is a specialty

bio-pharmaceutical company,

focused on the development of

innovative therapeutics for

neurological, neurodegenerative and

neuropsychiatric diseases

4

The Science

5

Our Innovation: Activity-Dependent Neuroprotective Protein (ADNP):

• Activity-Dependent Neuroprotective Protein (ADNP): essential for brain formation and function: No ADNP no brain

– ADNP was discovered by Prof. Illana Gozes, Coronis CSO, in 1999

– ADNP mutations in children result in autism spectrum disorder: ADNP-related syndrome

• In mice: half the content of ADNP results in severe cognitive and social impairments

6

Pinhasov A, Mandel S, Torchinsky A, Giladi E, Pittel Z, Goldsweig AM, Servoss SJ, Brenneman DE, Gozes I. Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res. 2003 Aug 12;144(1):83-90.

How Does ADNP Work ? Increases Nerve Cell Plasticity

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The ADNP-Related Syndrome (ARS)

ADNP-related syndrome: one of the most frequent non-

inherited mutations within the autism spectrum

http://www.adnpkids.com/

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bioRxiv preprint first posted online Apr. 20, 2016 Larsen E, Menashe I, et al., Mol Autism. 2016 Oct 21;7:44.

Helsmoortel et al., Nature Genetics, 2014; 46: 380–384 Gozes I, Helsmoortel C, Vandeweyer G, Van der Aa N, Kooy F, Sermone SB.The Compassionate Side of Neuroscience: Tony Sermone's Undiagnosed Genetic Journey-ADNP Mutation. J Mol Neurosci. 2015 Aug;56(4):751-7.

ADNP Case Report I

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Symptoms noted for Genetic Testing: Heart Defects; Brain Abnormalities; Developmental Delays; GI Issues; Multiple Congenital Anomalies; Hypotonia (Low Muscle Tone) upper/lower as infant, upper body only as toddler; Unusual chest shape “Dysmorphic” facial features including: Eyes – wide spaced and down sloping Ears – posteriorly rotated Relative macrocephaly Long flat philtrum Thin upper lip Narrow vermillion boarder to upper lip Flat nasal bridge Hypertoloric Large head / prominent forehead Wide spaced inner canthi with inner distance of 2.5cm and outer 7.5cm Chubby Small hands / small feet; Deep creases on hands and feet; Short stature; Small penis, scrotum underdeveloped; Failure to grow in length; Teeth (full set of teeth including molars by age 1) AROM at time of delivery was clear fluid. Delivered via repeat C-Section. Apgar scores were 8 @1 & 9 @5 minutes. The infant was bulb suctioned on the perineum and cried spontaneously. Twin brother cried MUCH louder and was much more active. GENETICS TESTING: ADNP Mutation found by Duke University RESULTS: Heterozygous heterozygousc.1046_1047delTGL349RfsX49

Gozes I, Helsmoortel C, Vandeweyer G, Van der Aa N, Kooy F, Sermone SB. The Compassionate Side of Neuroscience: Tony Sermone's Undiagnosed Genetic Journey-ADNP Mutation. J Mol Neurosci. 2015 Aug;56(4):751-7.

ADNP Case Report I

10

NEUROLOGY: Delayed Myelination pattern with poor Arborization Prominent left cerebral extra-axial space Frontal extra-axial space Extra axial fluid noted for almost all brain scans Mild widening of sagittal suture accompanied with fontanelle bulging White matter delay and generous normal vents Macrocephalus, Relative (head circumference) Central Nervous System Disorder (Casey) Hydrocephalus Monitored in 2008/2009 by Neuro Surgery for excessive fluid in the brain Cerebral Palsy noted by Dr. Morrison 4/25/08 and also Cerebral Palsy Spectrum at CDRC Neuro Small strokes noted during last open heart surgery, degree of effect unknown Cerebral Atrophy noted 2014 Regression of skills – unknown cause Sensory Processing Disorder

DEVELOPEMENTAL DELAYS: Pervasive Development Disorder Otherwise Unspecified - SEVERE Delayed Milestones Intellectual Deficits, SEVERE Mixed Receptive-Expressive Language Disorder Phonological Disorder Speech Disorder – (NONVERBAL) Presumed “Absent” Motor Skills Disorder Hypotonia

CARDIOLOGY: Congenital Heart Disease VSD Type 2 Perimembranous, Paramenbranous, Conoventricular (repaired in Sept 2011) -Postcardiac Injury Syndrome – Pericarditis complications lasting 4 months Right Aortic Arch Vascular Compression of Esophagus by Aberrant Artery Vascular Ring (repaired in April 2008) ASD (repaired in Sept 2011)

GASTROLOGY: GERD Gastroesophageal Reflux Disease Hyperactive Gag Reflux Frenulum Linguae Oropharyngeal Dysphagia with frank silent aspiration Barium Swallow Studies Feeding Difficulties G-Tube (Mickey) (Surgically in Oct. 2008 and removed in July 2009) Additional Surgery for G-Tube(Surgery in Feb 2009) -Incision and Drainage of Superficial Abdominal Wall Abscess

UROLOGY: Un-descended Testicles (Surgically repaired (both) in April 2009) Bilateral Cryptorchidism Congenital Hernia (Left Hernia surgically repaired in April 2009) Penoplasty (Surgery in April 2009) Unspecified Constipation

VISION: Cortical Vision Impairment (CVI) Unspecified Visual Delay Disorder of Visual Cortex Associated with Cortical Blindness Delayed Visual Maturation Irregular Astigmatism Hyperopia (farsightedness) Unspecified Disorder of Refraction and Accommodation Strabismus (off and on)

ADNP Case Report II

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Alexi's Fight and Triumphs over Walking and Cognitive Disabilities: A Stop Mutation in ADNP The eight and a half year journey of undiagnosed Alexi: gene sequencing and funding of advanced genetic testing has led to hope and new beginnings Illana Gozes, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Director, Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Adams Super Center for Brain Studies and Sagol School for Neuroscience, Tel Aviv University, Israel. Marc C. Patterson Chair, Division of Child and Adolescent Neurology, Professor of Neurology, Pediatrics and Medical Genetics, Mayo Clinic Children's Center Rochester MN, USA. Anke Van Dijck, R. Frank Kooy Cognitive Genetics Group, Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. Joseph N. Peeden Director, Diagnostic Clinic, East Tennessee Children's Hospital and Clinical Assistant Professor of Medicine at the University of Tennessee, Knoxville TN, USA Jacob A. Eichenberger Assistant Professor of Pediatrics, Physician Informaticist, Children's Hospital of Georgia at Augusta University, Augusta, GA 30912, USA Angela Zawacki Downing Sandra Bedrosian Sermone ADNP kids Research Foundation, Brush Prairie, WA, USA.

Submitted revision

• CP201 (NAP): a small fragment of

ADNP, developed by Prof. Gozes,

is an important nerve cell protecting

site that enhances ADNP activity.

– CP201 formulation was named

davunetide in previous clinical

studies

– CP201 protected by new

formulation (2016)

• CP102 (SKIP): a second

generation snippet

Our Innovation: From Protein Discovery to Peptide Drug

Candidates

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CP201

NAP

ADNP

CP102

SKIP

How Does CP201 (NAP) Work ? Increases Nerve Cell Plasticity

Mechanism of Action:

• Stabilizes and protects cell skeleton/transport system

• Promotes formation of site for contacts between nerve cells (green dots)

Oz S, Kapitansky O, Ivashco-Pachima Y, Malishkevich A, Giladi E, Skalka N, Rosin-Arbesfeld R, Mittelman L, Sege O, Hirsch JA and Gozes I. The NAP-Motif of Activity-Dependent Neuroprotective Protein (ADNP) Regulates Dendritic Spines through Microtubule End Binding Proteins Mol Psychiatry. 2014 Oct;19(10):1115-24.

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+ CP201 –more points for nerve connections (green)

No - CP201 – making less nerve connections (green)

14

0

10

20

30

40

50

60

70

80

90

100

day1 day2 day3 day4 day5

late

ncy (

se

c)

ADNP+/+ ADNP+/- ADNP+/- CP201

##

* # ##

ADNP deficient mice

How Does CP201 (NAP) Work? Enhances Learning and Memory

Impairment (green line) is significantly

reversed by treatment with CP201 (dark blue

line) and resembles normal mice behavior

(light blue line)

ADNP-deficient mice display

impaired learning and memory in

the water maze (latency to reach

the hidden platform is not

reduced after training) compared

to normal mice

Water maze test of

learning and

memory

ADNP-Deficient Normal Deficient mice Normal mice

Vulih-Shultzman I, Pinhasov A, Mandel S, Grigoriadis N, Touloumi O, Pittel Z, Gozes I. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther. 2007 Nov;323(2):438-49.

CP201 (NAP): Our Lead Drug

Candidate • CP201 enhances learning and memory

• CP201 extensively studied in more than 20 cell assays and 25 animal models for:

– Autism

– Schizophrenia

– Alzheimer’s disease

– Frontotemporal dementia

• More than 100 papers published in leading scientific journals:

– Examples: Molecular Psychiatry (Nature press); Proceedings of the National Academy of Science (US); J Neuroscience; Translational Psychiatry (Nature press); Scientific Reports (Nature press); J Neurochemistry; J Molecular Neuroscience (Springer-Nature press); Science online

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CP102 (SKIP)

• CP102 (SKIP) is a small analogue of CP201

(NAP)

• CP102 Protects axonal transport

• CP102’s New formulation enables direct

delivery to the brain circumventing BBB

• Protected by a new published composition of

matter patent (application date 2013) and by a

new formulation patent application (2016).

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How Does CP102 (SKIP) Work?

Ref: Mol Psychiatry. 2016 Oct;21(10):1467-76.

Protects Axonal

Transport

Protects Learning and Memory

State of the art measurements of nerve

cell transport termed “axonal transport”

using MRI technology: Measurements of

contrasting agent progression in the

olfactory bulb (region of interest = ROI),

CP102 protects against toxic disruption.

-0.500

-0.300

-0.100

0.100

0.300

0.500

0.700

0.900

Adnp+/+ Adnp+/+SKIP

Adnp+/- Adnp+/-SKIP

D2 (

b-a

)/(b

+a)

CP102 (SKIP) reverses social memory

impairments in a rodent model:

Differentiation between familiar and novel

mouse

ADNP-Deficient Normal

With SKIP

treatment

Mouse brain MRI scan with

contrasting agent (white)

Relative

time

spent

with the

new

mouse

Clinical Results

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CP201 (NAP) Safety Studies

• Safety shown in adults up to 60mg/day

• Single dose of intranasal delivery (effective dose 5-

15mg/day) provides efficacy for a period of 24 hours

• Bioavailability studies demonstrated presence in blood

and cerebral spinal fluid (CSF)

• 710 patients treated with no significant adverse

events

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CP201 (NAP) aMCI Phase IIa

Clinical Study Results

Amnestic Mild Cognitive Impairment (aMCI)

• Performed by Allon Therapeutics 2007–2008

– 144 people with aMCI, frequently prodromal to Alzheimer's disease.

– This was a three-month, with a one month follow up, multicenter U.S. study.

– Compared the effect on memory outcomes

• The trial was reported to show a statistically significant improvement in test performance compared with placebo at 8 weeks and 16 weeks

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CP201 (NAP) CIAS Phase IIa

Clinical Study Results

Cognitive Impairment Associated with Schizophrenia

• Performed and funded under the TURNS / NIMH

project in 2007-2009

– Performed in 7 academic institutions

– Double blind, placebo controlled

– 66 patients on anti-psychotic medications,

– Clinical endpoints: safety, cognition,

function

• Significant effects were demonstrated on:

• Cognitive domains (working memory,

verbal memory and visual memory)

• Functional ability (UPSA)

• NNT (number needed to treat) equals

to 4, similar to industry standards

acceptable to drugs for treatment of

phobia, mania, depression, PTSD etc.

• Brain protection (MRI sub study)

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CP201 (NAP) Development (2008-

2016)

22

2008 2009 ----- 2012 2014 2015 2016

Effect on aMCI Cognitive - Working

Memory

Effect on CIAS Cognitive - Working Memory,

Visual Learning

Functional Capacity

Brain protection (MRI sub study)

CP201 MOA Mechanism

resolved

ARS

characterized

First 10 patients

Effect on PSP Brain atrophy

precedes clinical

outcome - no effect

Allon Therapeutics Inc. (Former Company) Coronis NS

100 ARS

patients - rapid

diagnosis

Our First Target Market

• ADNP-Related Syndrome (ARS) is a newly discovered rare neuro-genetic

disease caused by de novo (non-inherited) mutations in the ADNP gene

• ARS is thought to be one of the most common causes of non-inherited Autism

Spectrum Disorder (ASD).

• Symptoms manifest early and include abnormalities in a wide range of sensory,

motor and cognitive functions:

– Intellectual disability

– Severe speech delay

– Motor development delay

– Sensory processing disorder

– Insensitivity to pain

– Sleep disorders

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Management Team

Dr. Eric Messika, Ph.D, MBA - Founder, President & CEO

Over 15 years of experience in the Israeli Biotech industry as analyst, lead investor, Director and

entrepreneur. Dr. Messika served as a research associate at the Howard Hughes Medical Institute

at Stanford University, CA. Holds a Ph.D. from the Lautenberg Center for General and Tumor

Immunology at the Hadassah Medical School, Hebrew University in Jerusalem and an MBA from

Herriot-Watt University, Edinburgh.

Prof. Illana Gozes, Ph.D - CSO

Professor of Clinical Biochemistry and the Lily and Avraham Gildor Chair for the Investigation of

Growth Factors, Sackler Faculty of Medicine, Tel Aviv University. Former Director, the Adams Super

Center for Brain Studies. Director the Edersheim Levie-Gitter Institute for Functional Brain Imaging,

Head of the Elton Laboratory for Molecular Neuroendocrinology. Serves as Editor-in-Chief of the

Journal of Molecular Neuroscience. Former President, Israel Society for Neuroscience. Founder,

Former Chief Scientific Officer and Director, Allon Therapeutics Inc.

Dr. Saar Oz, Ph.D - VP R&D

Dr. Oz is an experienced R&D expert. Prior to joining Coronis Neurosciences, Dr. Oz served as

CTO at Orsan Medical Technologies. Dr. Oz is a former Israeli Air Force (IAF) pilot and formerly

held R&D positions at Elisra (Elbit Systems). Former Head of airborne electronic warfare systems

section at the IAF. Holds a Ph.D in neuroscience from the Tel Aviv University faculty of medicine

and a B.Sc. in bio-informatics from Bar-Ilan University.

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Over 350 individuals and organizations worldwide were nominated by

their peers for a RARE Champion of Hope award for their notable efforts

in rare disease advocacy, science, collaborative sciences, and medical

care and treatment. From the extraordinary list of nominees, members

from the Global Genes Board of Directors, Medical and Science Advisory

Board, and other key partners selected the recipients to be honored at

the 5th annual Tribute events.

Global Genes is pleased to announce the 2016 RARE Champion of Hope

Honorees:

RARE Champion of Hope – Science International: Dr. Illana

Gozes, Professor, The Lily and Avraham Gildor Chair, Former Director,

Adams Super Center for Brain Studies

Dr. Illana Gozes discovered the ADNP gene that mutations in it lead to a

genetic syndrome known as the ADNP syndrome/the Helsmoortal-Van Der AA

syndrome. Activity-dependent neuroprotective protein (ADNP) is deregulated

in Alzheimer’s disease (AD) and in schizophrenia and mutated in autism. With

her commitment to research and new therapies, Dr. Gozes continues to help

many undiagnosed patients receive the therapies and tests needed to be

happy, healthy, and diagnosed.

Champion of Hope – Science International

Thank you

27 www.coronisns.com