S.I.S

Venoms For Humanity

S.I.S Shulov Innovative Science Ltd.A biopharmaceutical company focused on the discovery and development of novel human therapeutics.

April 2013

Presentation’s Agenda• Who we are?

– Scientific Board

• What do we do?• Our products• How do we do it?• IP• The Market• Company’s snap shot• Milestones and Finance• Company’s History• Contact info

Who we are?

S.I.S Shulov Innovative Science Ltd. was founded by the late Prof. Aharon Shulov and

Mr. Aviv Marx

•Prof. Aharon Shulov (1907-1997) – Dept. of Zoology at the Hebrew University of Jerusalem, Founder and General

Manager of The Jerusalem Biblical Zoo for over 40 years.– Proposed a research program to identify the analgesic components of snake

venom

•Mr. Aviv Marx - President and CEO– Entrepreneur and family friend provides funding.

Founders

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• Dr. Naftali Primor – VP of R&D– Dr. Primor is a world renowned expert in the toxicology and chemistry of snake

venoms. – He has featured in the National Geographic Film entitled "Snakes in The Holy

Land", and is constantly sought for his expertise and skills in the handling and toxicology of venomous reptiles and scorpions.

• Dr. Avigdor Levanon – VP of Business Development– Formerly VP, Research at BioTechnology General (Israel) Ltd.(BTG), Chairman of

the Board at Target-In Ltd. and Director at the Israel Oceanographic and Limnological Research Ltd. with over 31 years in the biotech industry.

• Prof. Israel Steiner (M.D.) – Board Member – Head of Dep. of Neurology, Beilinson Hospital Petach-Tikva, Israel. Head of

Neurology Sciences Unit, Hadassah University Hospital, Jerusalem and a world expert in molecular basis of HSV1 latency and HSV1 infectivity.

Scientific Board

Who we are?

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• Prof. Elka Touito - Board Member – Dep. of Pharmacy, the Hebrew University Hadassah Medical School, Jerusalem. Head of

Innovative Dermal, Trasdermal and Transmucosal Delivery Group and a world expert in enhancement of dermal drug delivery for systemic action.

• Prof. Amos Panet - Board Member – Dep. of Biochemistry and the Chanock Center for Virology – IMRIC, the Hebrew

University Hadassah Medical School, Jerusalem. – Prof. Emeritus of Cancer Research, Virus replication and viral diseases, a world expert in

HSV1 molecular biology.

• Prof. Yechiel Shai - Board Member – Dep. of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel– World expert in protein-membrane interaction and protein-protein recognition within

the cell membrane

Scientific Board (Cont’)

Who we are?

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What do we do?

Developing new and innovative products based on snakes’

venom by isolating novel non-toxic short peptides.

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Our products• Treatment for skin psoriasis

– Psoriasis is a chronic skin disease that is the most prevalent autoimmune disease in the U.S., with as many as 7.5 million Americans affected (2.45% of the population). It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells.

• Treatment for Genital and simplex Herpes– Herpes is the most common form of infection. Herpes viruses cycle between

periods of active disease presenting as blisters containing infectious virus particles that last 4–21 days, followed by a remission period. Unfortunately, a cure for herpes has not yet been developed. Once infected, the virus remains in the body for life

– Globally, about 4.0 billion people are estimated to be infected with Herpes Viruses.

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Novel non-toxic short peptide has been isolated from snake venom based on its highly potent in-vivo analgesic activity upon topical application.

Based on the above novel molecule a whole family of relatedcompounds has been identified in various snake venoms.

One of the naturally occurring peptides (coded Zep-4) and its chemically modified version coded Zep-3, were chemically synthesized in gram quantities.

These peptides were formulated as a cream and assessed for their analgesic and anti-viral activities and for the treating of psoriasis symptoms upon topical application on the skin. (Based on histological observations and specific psoriasis bio- Markers.)

How do we do it? (innovation)

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Intelectual Property

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As of February 2013 the European Patent Examiner has approved our claims in a new PCT patent (PCT/IL2012/050105 – "method for treating disorders of the skin") including the therapeutic use of the peptides astreatment for viral induced clinicalsymptoms, such as HSV1 Cold Sores, HSV2 Genital Herpes and psoriasis.

The total skin disorders market is estimated to be $28 Billion annually (for 2011), about 1/3 of which is due to viral

infections, most of these being the Herpes virus (HSV1, HSV2 and Herpes Zoster)

By the age of 40, nearly 90% of adults, have been exposed to HSV1, 15% of those exposed to HSV1 may develop symptoms (blisters, cold sores) every year.

In the Western World (U.S., Europe and Japan) the potential market is over 100 Million patients, these patients develop clinical symptoms every year. A large percentage of them have several episodes annually.

HSV1 - The Market

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Globally, about 4.0 billion people are estimated to be infected with Herpes Virus

The incidence rate of cold sores, caused by the HSV1 virus, is the second largest worldwide, trailing only behind common cold

About 79% of the U.S. population is infected with HSV1, with about 25-35% of the adults enduring recurrent spate of cold Sores

in recent years HSV1 has become the most common cause of newly diagnosed genital herpes infections

”The need for innovative therapies for the treatment of herpes simplex infection, and the search for novel antiviral drugs continues. This presents a huge potential for the growth of herpes simplex therapeutics market in future”.

(Global Industry Analysts, Inc.)

HSV1 – The Market (cont’)

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> Above 40% of genital Herpes is caused by HSV1 and Zep-3 presents a possible prevention as well as cure.

HSV1 - The Market (Cont’.)

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Psoriasis - MarketPsoriasis is a chronic skin disease that is the most prevalent autoimmune disease in the U.S., with as many as 7.5 million Americans affected (2.45% of the population). Psoriasis Market Info™ captures all the relevant data on this disease. The overall market value is $1.8+ billion in 2010 in the U.S alone and $3.4 billion world-wide. This market is expected to grow significantly in the future, largely due to the chronic nature of the disease, the high unmet and continued need for topical therapies which will make this market approachable for any new therapy that is both effective and safe.

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Company’s snap shot• Development Studies• Current status of SIS's products• Inhibition of HSV1 replication and spreading

in tissue culture• Safety and Toxicology• Trans Dermal Permeability

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• Phase I Clinical Study

Analytical and bio-analytical assays to trace the products in buffers and

in body fluids have been developed.

The % of trans-dermal permeability has been determined in a Franz cell

model (permeability via pig’s ear skin is less than 0.1%) Intra vaginal permeability in rabbits as a model for mucosal endothelial cells rich in blood vessels. A 90 days sub-chronic toxicity study in rates

Anti viral activity was established In- vitro and In- vivo. Determination of product stability Intra vaginal permeability in rabbits

as a model for mucosal endothelial cells rich in blood vessels was performed.

A 90 days sub-chronic toxicity study in rats is being performed

Development Studies

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Current status of SIS's productsS.I.S has conducted a large variety of pre-clinical studies in accordance with the requirements of the health regulatory authorities and in order to support the development processes of Zep-3 and Zep-4 cream as a product and to establish its safety and efficacy. S.I.S has completed all essential toxicology and safety studies required for the submission of a file for Phase I Clinical Study. Safety Parameters: The drug permeation studies reviled that during the 24 hrs experiment, Zep-3 and Zep-4 have a very low absorption profile across the skin (less than 1%) while significant amount of drug is accumulated in the skin. Identical results were obtained upon intra vaginal application (3 times per day for 7 days) in rabbits as a model to blood vessel rich tissue . Phase I Clinical Study: A Helsinki approved Phase I Clinical Study was performed at the Dep. Of Dermatology at Shiba hospital (Israel). All the 22 (100%) healthy volunteers enrolled into the study were subjected to Zep-3 cream treatment administrated topically 4 times daily during 5 consecutive treatment days at either 0.1% or 1.0% in dose escalating area size 1cm; 10cm and 20cm.Zep-3 was found in this clinical study to be well tolerated, safe to use and didn't present any undue risks to the study participants. 16

Inhibition of HSV1 replication and spreading in tissue culture

The anti HSV1 activity of Zep-3 is determined by measuring plaque forming unit, using tissue culture vero cells in vitro.

The results depicted below are representative of one out of six repeated experiments using two different batches of Zep - 3

Infected HSV1 treated with Zep-3 (4mg/ml or 8mg/ml)

Infected HSV1 treated with “Scrambled” peptide (4mg/ml or 8mg/ml).

“Scrambled” refers to the identical amino acids such as Zep-3 but in altered sequence

The anti-viral effect was induced without causing Cell Toxicity in the Control Vero Cells 17

Inhibition of HSV1 Replication by Zep-3

Zep – 3 (4mg/ml)

Zep – 3 (8mg/ml)

Scramble (4mg/ml)

Scramble (8mg/ml)

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Zep-3 inhibits virus replication and spreading in tissue culture.

Control - No Peptide Zep-3

Zep-3 inhibits in dose dependent manner the replication of HSV1 in Vero cells

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Inhibition of HSV1 Replication by Zep-3 in Organ Skin Culture

Control - None InfectedHSV1 - Infected

HSV1 – Infected + Scramble (8mg/ml)HSV1 – Infected + ZEP-3 (8mg/ml)

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Zep-4 for Treating Psoriasis

Anecdotal data indicates that Zep-4 upon topical application is efficient for treating psoriasis in patients.

Zep-4 reduce the expression of psoriasis specific biomarkers in human skin organ culture stimulated by EGF and LPS.

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Safety and Toxicology of Zep-3 and Zep-4

Safety studies were carried out in rats in which the following end points were recorded:

•body weight•Vitality •blood picture•Internal organs histopathology

No adverse side effects were observed at twice a week administration (topical or I.V.) of high dosages for 200 days

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Trans Dermal Permeability of Zep-3 and Zep-4

Dermal Permeability was tested using the ear-skin pig model.Zep-3 and Zep-4 show permeability profile below 1% after 24 hrs. Significant amount of drug accumulated in the skin. Identical results were obtained upon intra vaginal application (3 times per day for 7 days) in rabbits as a model to endothelial membrane rich in blood vessels. 23

Summary of Zep-3 Zep -3 upon topical application inhibits/prevents

within less than 5 minutes the itching and pain induced by Herpes Simplex Virus Type I (HSV1) and eliminates swelling and blister formation in less than 36 hours

Zep-3 inhibits in a dose dependent manner the replication and spreading of HSV1 and HSV2 in Vero cells infected by the viruses.

In a Phase I Clinical Study (22 healthy volunteers), Zep-3 cream was found to be well tolerated, safe to use and didn't present any undue risks to the study participants. 24

Summary of Zep-3

Zep – 3 inhibits in a dose dependent manner the replication of HSV1 in Vero cell line infected by the virus

Zep-3, demonstrates analgesic properties in acute and chronic pain animal models

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Milestones and Finance

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Cash Flow

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Income The Company has annual income of NIS 1.8M from

selling snakes’ serum to the Israeli Ministry of HealthHard Expenses The Company has annual hard expenses as follows:

Salaries – NIS 726K Legal, Accounting and general – NIS 150K Patents – NIS 100K

Total annual hard expenses – NIS 3.1 M (245K monthly) The Company has additional soft expenses that are

varied according with the R&D requirements (next slide).

201120122013

Snakes' serum income

2,000,0002,000,0002,000,000

Salaries

(685,000)

(685,000)(726,000)Legal, Accounting &General

(150,000)

(150,000)(150,000)

Patents & IP

(100,000)

(100,000)(100,000)

R&D

(1,428,000)

(1,500,000)(3,200,000)

Total(363,000)

(435,000)(2,076,000)

Cash Flow- NIS

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Gant & Capital Requirements

29* Self funded

201320142015

TaskCost(M$)Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4

Phase I - Safty*0.4

Phase II- HSV1 Cold Sores 1.60

Phase II- Genital Herpes2.30

Phase I/Iia - Psoriasis 2.90

Mode of Action0.25

Long Term Stability0.15

Degradation Pattern0.25

Mucosal Tissue Permeability & Toxicity0.05

ADME0.80

Anti Viral Specificity0.05

New Formulation0.15

Unpredictable0.89

TOTAL9.79

Company History

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Founded in 1985,

S.I.S targeted the development

of innovative pharmaceutical

products based on properties

of snake venom

History1985 -

The founding of S.I.S pharmaceutical Ltd. by Prof Aharon Shulov and Mr. Aviv Marx.

1989 -

Developing a pain model using HCl for efficacy testing using topical application.

1990 -

Viper venom is separated into 5 fractions while the analgesic activity is attributed to the fraction.

1992 -

The viper venom in the above non toxic fraction was further fractionated on a size exclusion chromatography column

1993 -

S.I.S applies for first patent based on viper venom following the discovery of the analgesic fraction.

1996 -

S.I.S reveals the existence of an uniform analgesic fraction in three families of venomous snakes. 31

History1998 -S.I.S applies for a second patent after

discovering that the analgesic fraction is identified as common, among all venomous snakes.

2000 - The structure of the analgesic peptides was identified chemically.

2001 - The peptides and a chemically modified version of one of them, Zep, were chemically synthesized and assessed for their analgesic activity relative to the natural snake venom derived molecules.

2002 -Third Patent is filed. Composition comprising an analgesic peptide (Zep) and its therapeutic use.

Zep is successfully formulated as cream and tested to confirm its efficacy.

2003 - Conformation of the anti-pain activity in various in-vivo animal models for several clinical indications.

2007 - 2011

Continuation of Pre-clinical studies, validation of efficacy in several animal models and accumulating safety toxicology data.

2011 -S.I.S focuses on the development of one of its products for the treatment of Herpes Simplex Virus (HSV1) induced symptoms, such as Cold Sores, preventing itching, lesion and scab formation.

2011 - A new patent was filed claiming the efficacy of the product(s) for various skin disorders including those induced by HSV1 infection.

2012 -Performing safety toxicology studies for the submission of an IND file for Phase I clinical trial to the end of the year.

2013 -Phase I Clinical Study and approval of the claims in the new PCT patent.

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Contact information

Mr. Aviv MarxPresident and CEO

Tel: +972 (8) 931-4114Mail: aviv@sis-shulov.com

Dr. Naftali PrimorVP R&D

Tel: +972 (50) 536-3748Mail: naftali@sis-shulov.com

Dr. Avigdor LevanonExecutive VP,Business Development

Tel: + 972(50)724-4287Mail: alevano@bezeqint.net 33

THANK YOU

Venoms For Humanity

S.I.S Shulov Innovative Science Ltd.

April 2013

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