Aposense Molecular NanoMotors (MNMs)The first platform, energized by the membrane

dipole potential, for systemic delivery of Nucleic Acids

Aposense Ltd. 5-7 Odem St., P.O.Box 7119, Petach Tikva 49170, Israel Tel: 972-73-2397-600 Fax: 972-3-9215714 www.aposense.com

September 2017

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CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

The following is a presentation of our Company’s business and operations. This presentation does not constitute an offer to sell or

the solicitation of an offer to subscribe for or buy or sell any of our securities. The information contained in this presentation does

not constitute a basis for making an investment decision and does not constitute a recommendation or opinion, nor is it a

substitute for the discretion of a potential investor. Readers are urged to carefully review and consider the various disclosures

made throughout our immediate and interim reports as filed with the distribution systems of the Israeli Securities Authority

(https://www.magna.isa.gov.il) and with the Tel Aviv Stock Exchange Ltd. (http://maya.tase.co.il/reports/company), which are

designed to advise interested parties of the risks and factors that may affect our business, financial condition, results of operations

and prospects. Certain information included or incorporated by reference in the following presentation may be deemed to be

“forward-looking statements” within the meaning of the Israeli Securities Law, 5728-1968. Forward-looking statements are often

characterized by the use of forward-looking terminology such as “may,” “will,” “expect,” “anticipate,” “estimate,” “continue,”

“believe,” “should,” “intend,” “project” or other similar words, but are not the only way these statements are identified. The following

presentation may contain forward-looking statements that include, but are not limited to, projections about our business and

operations and/or our future revenues, expenses and profitability. These statements are only current predictions and are subject to

known and unknown risks, uncertainties, and other factors that may cause our or our industry’s actual results, events, levels of

activity, circumstances, performance and/or achievements to be materially different from those anticipated expressed or implied by

such the forward-looking statements, due to factors that include, but are not limited to: (-) local and areal political and economic

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products; (-) our ability to successfully complete any necessary or required pre-clinical and/or clinical studies with our pre-clinically

and/or clinically developed products; (-) our ability to receive regulatory clearance or approval to market our products and/or

changes in regulatory, legislative and/or international standards environment; (-) our success in implementing our business-

development, sales, marketing and/or manufacturing plans; (-) the level of adoption of our future products by medical practitioners;

(-) the emergence or existence of other products that may make our products obsolete; (-) protection and validity of our patents

and other intellectual property rights; (-) the effect of competition by other companies and technologies; (-) the ability to obtain

reimbursement for our products from government and commercial payers; and (-) our ability to raise sufficient funds for completion

of products research and development and/or our ability to partner with strategic partners and/or investors. You should not rely

upon forward-looking statements as predictions of future events. We cannot guarantee future results, levels of activity,

performance, or achievements reflected in the forward-looking statements. You should not put undue reliance on any forward-

looking statements. Any forward-looking statements in this presentation are made as of the date hereof, and we undertake no

obligation to report events or to report the occurrence of unanticipated events that may lead to the actual events, results,

performance, circumstances or achievements concerning our business and operations being different than as envisaged by such

forward looking statements and/or to publicly update or revise any forward-looking statements, whether as a result of new

information, future events or otherwise, except as required by law. Date of presentation: September 2017.

Milestones in the Evolution of siRNA Therapeutics: From Discovery to the Systemic Delivery Barrier

Discovery of gene silencing through injection of dsRNA to worms1998

Discovery of the RNA Induced Silencing Complex (RISC)2000

Discovery of the Dicer endonuclease2001

The Power of siRNA is demonstrated in numerous applications across

numerous fields of medicine; Huge investments in the field by Pharma

Companies

2001-2006

Nobel Prize to Andrew Z. Fire and Craig C. Mello; "for their discovery of RNA

interference - gene silencing by double-stranded RNA”

2006

The Systemic Delivery Barrier: Large withdrawal from the field: “siRNA is

probably non-druggable”

2006 - 2014

First demonstration of clinical benefit of siRNA targeted to the liver (ATTR

amyloidosis)

2014

Renewed interest in siRNA; Strategic alliances

Only for liver-related indications; or for topical administration

2014 -

• Recognition that siRNA may hold a great therapeutic promise

• Pending on solving The Systemic Delivery Barrier

2014 -

Lack of efficacious and Universal Tools for Systemic Delivery of siRNA; Widely-Recognized as The Major Factor that Holds-Back Clinical Implementation of siRNA

“The most intractable problem with RNAi therapeutics has to do with systemic delivery. Nucleic acids such as RNAi are relatively large and carry a negative charge, preventing absorption through the cell membrane….

Considerable efforts have been expended breaking down the delivery barrier. Yet even the combined resources of both Big Pharma and small biotechs have not been enough to solve the problem, at least not yet”.

Pfizer

siRNA therapeutics; The promise and the unmet need

“The siRNA Technology is quite amazing, to be sure. These small pieces of nucleic acid are capable of knocking down genes with extremely high selectivity”

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siRNA: Molecular weight 14,000 Daltons42 negative charges

Classical drug

Genetic drugAspirin: Molecular weight

180 Daltons

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siRNA: The delivery challenge

Delivery of siRNA across cell membranes into cells requires a very large activation energy

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Apo-Si Molecular Nanomotor PlatformA disruptive technology

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A novel internal

powerhouse

Innovative

Molecular

NanoMotors

Breaking-down the membrane delivery

barrier

• Electric voltage measured between:Membrane / water interface (-) membrane center (+)

• Generated by the ordered carbonyl groups of the phospholipids

• Environment: very hydrophobic

• Dielectric constant: 2-4

• Due to hydrophobic environment, results in an enormously strong intra-membrane electric field of 108-109 V/m !!!

The membrane dipole potential

ΔΨ = the trans-membrane potentialΨs = the surface potential

Ψd = the dipole potentialε = the dielectric constant

8Wang L. Annual Review of Biochemistry 81: 615-635, 2012

A novel internal

powerhouse

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Transmission Unit

Detachment Unit

Electrical Unit

Point for “click attachment” to any Oligonucleotide sequence

(DNA or RNA)

The Apo-Si Molecular NanoMotor (MNM):Optimized molecular structure for utilizing

the membrane dipole potential for drug delivery

• Small-chemical Entity

• Proprietary; All in-house IP

• Non Toxic

• Modular

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Innovative

Molecular

NanoMotors

The MNM attachment module

• Standard building block of any oligonucleotide synthesis • The locations and number of moieties can be tailored per the

specific application

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Detachment Module

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MNM; MW ≈700 Daltons

dsiRNA; MW ≈14,000 Daltons

The dsiRNA-MNM construct

Prolonged residence

in body fluids

Trans-membrane

delivery to reach the

cytoplasm

Membrane

surface

Breaking-down the membrane delivery

barrier

Direct entryEndosome-mediatedentry Flip-flop

Endocytosis; Flip-flop; RNA detachment

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MNM:

• Detachment from RNA

• Excretion: Kidneys / Liver

RNA: Interaction with Dicer & RISC

Gene Silencing

Cytoplasm

Robust trans-membrane delivery of Apo-Si-MNM Conjugates; B16 melanoma cells

X 20

Cy3= Red fluorophore

Control: fluorescently-labeled dsiRNA without MNMs

Fluorescently-labeled dsiRNA, conjugated to MNMs

Control MNM-dsiRNA Conjugate

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1

64

78

90

97

0

10

20

30

40

50

60

70

80

90

100

control 15min 30min 1hour 2hours

% P

osit

ive E

ven

ts,

Cy3

Delivery of dsDNA, Attached to Two Apo-Si-MNMs

3T3 cells; Time course; 40nM; FACS

N=3; n=6

Mean±SE

Uptake of Apo-Si-MNM Conjugate is rapid and efficient; 3T3 Cells

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FACS analysis; Phloretin 750µM 3hr, Apo-Si-MNMs Conjugate 40nM, 2hr

Shutting-down the internal membrane electrical field inhibits delivery of Apo-Si-MNMs Conjugate

Complete inhibition by Phloretin

0%

EGFP fluorescence

Field ONNo MNMs

Apo-Si-MNMs

Conjugate

Field ON+ MNMs

Apo-Si-MNMs Conjugate +

Phloretin

1%

Ap

o-S

i D

elive

ry;

(Cy3

)

EGFP fluorescence

Field OFF+ MNMs

95%

EGFP fluorescence

Ap

o-S

i D

elive

ry;

(Cy3

)Control

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Ap

o-S

i D

elive

ry;

(Cy3

)

Shutting-down the membrane dipole potential inhibits delivery of Apo-Si-MNMs Conjugate; dose-related

N=3; n=6

Mean±SE

FACS analysis; 3T3 cells; Phloretin 3hr, Apo-Si-MNMs Conjugate 40nM 2hr

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Deletion of the Apo-Si-MNM negative pole blocked the delivery of oligonucleotides into 3T3-EGFP cells

40nM, 24hr, FACS Analysis

Increased fluorescence

Apo-Si Uptake; Cy3 fluorescence

Apo-Si-MNMControl;

Apo-Si-MNM; deletion

of negative pole

Control

Ce

ll C

ou

nts

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Robust down-regulation of EGFP expression, induced by Apo-Si-MNM-dsiRNA Conjugates

EGFP-3T3

X20

MNM-dsiRNAConjugate

Control:dsiRNA alone

Control:MNM+DNA

Bright Field

High level of gene expression

High level of gene expression

Robust gene silencing (90%) 3T3 cells

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100

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1512

9

0

20

40

60

80

100

120

Untreated 10 nM 40 nM 150 nM 300 nM

% G

FP

IC50= 4.86 nM

Apo-Si-G dsiRNA, nM

% E

GF

P

0 50 100 150 200 250 3000

20

40

60

80

100

Robust down-regulation of EGFP expression, induced by Apo-Si-MNM Conjugates in HeLa cells; ELISA,72 h

N=3; n=9Mean±SE

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MNM-dsiRNA

MNM-dsiRNA; nM

Apo-Si-MNM: Systemic bio-distribution of siRNAupon intravenous administration

SPECT imaging of I125- labeled MNM-dsiRNAConstruct ; 80-90 minutes after iv administration

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Heart Lung Liver Spleen Kidney Small intestine Large intestine Lymph nodes

SU

V

20

Apo-Si Molecular Nanomotor Platform;performance profile

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Favorable bio-distribution upon systemic administration in vivo rapid and robust distribution of siRNA into various organs (e.g., liver, heart, lung, spleen, kidneys, lymph nodes)

Gene Silencing

• Robust (>80%)

• Nanomolar concentrations

• Dose-responsive manner

• Silencing of both reporter and disease-related genes

• Cytoplasmatic enrichment mechanism

Delivery: • Energized by the membrane dipole

potential

• Universal

• Nanomolar concentrations

• Efficient, into all treated cells

• Rapid

• Dose-dependent manner

• Safe

• PCT and world-wide patent applications

• Novel Compounds, Conjugates & related formulations

• Mechanism of action

• Methods utilizing said Compounds and Conjugates for delivery of molecules and macromolecules, across biological membranes into cells.

• Methods for utilizing said Compounds and Conjugates, for the treatment of medical disorders

Patent Coverage:

• US Patent Application No. 14/830,799 was allowed on April 11, 2017.

• 5 Provisional Patent application were consolidated into a PCT Application, which is now in the National Phase, world-

wide.

• Corresponding applications are now pending in

Israel, Japan, Europe, Canada, China, India, Australia, Korea, Brazil, Mexico, Russia (filing date: 29-March-2015).

• 5 additional Continuation-In-Part applications (CIPs) are now pending in the United States.

• PCT (international) patent application No. PCT/IL2016/050893 is pending (filed: 17-August-2016) covering the same

aspects of the CIPs.

• A new US-patent, covering additional recent developments in the Project is now being submitted.

Patent Applications and status:

Apo-Si: Intellectual Property

Scientific Leadership

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Professor Roger Kornberg, Scientific President:, Nobel Prize Laureate in Chemistry for the year 2006, for his research and discoveries of the molecular basis of eukaryotic transcription (synthesis of RNA from a DNA template).

Professor Ilan Ziv, MD, CEO & CSO. Ilan is a co-founder of Aposense, and the Chief Scientist of the Company. He is an associate professor in Neurology at the SacklerSchool of Medicine, Tel-Aviv University. Ilan is the Inventor of the AposenseTechnology.

Dr. Hagit Grimberg, Ph.D, Senior VP for R&D, has been with Aposense for over 16 years. Hagit has an M.Sc. in Biochemistry, and Ph.D in Physiology & Pharmacology. Hagit has strong background in innovation, research and new product development.

Multiple, Parallel Joint ventures with Pharma Companies

Synergy: Apo-Si delivery platform disease-specific genetic drugs

Delivery modules for siRNA, ASO and beyond

Gene delivery beyond the liver

Potential Income: Upfront payments; milestone payments, profit sharing

MNM

Gene

Delivery

Platform

A Huge, Multi-billion $ profit potential

Apo-Si; Business Model as a Platform Technology Company

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The Vision To introduce an industry standard

for the trans-membrane delivery of genetic drugs

• The opportunityBoth the unmet need (delivery) and the source of energy(dipole potential) are co-localized in the cell membrane

• The solution

• Molecular NanoMotors, internally-energized, for efficacious delivery of genetic drugs

• Small-molecule “chip”, modular, versatile and “click-attached” to any Oligonucleotide sequence

Translating genetic therapeutics into a “druggable” reality 25

Thank you!