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

Background1

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 > Entrepreneur and family friend provides funding.

> 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 related compounds 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.

Innovation2

Intelectual Property3

S.I.S has been granted a key patent in the US which is in various stages of approval worldwide

> US Patent - 7220725Composition comprising an analgesic peptide and therapeutic use thereof

> As of March 2012, a new PTC patent (#PCT/IL2012/050105) was submitted (U.S. application - # 61/468,212)

“Method for treating disorders of the skin” claiming the therapeutic use of the peptides as a treatment for viral induced clinical symptoms, such as HSV1 induced cold sores, HSV2 induced Genital Herpes and Psoriasis.

> 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%)

> Local Irritation Study is being performed

> Local Sensitization study is being performed

> Gynotoxicity studies are being performed

> A mice model that mimics the clinical symptoms upon infection with HSV1 is being established

> Anti viral activity was established In- vitro and In- situ.

> Determination of product stability

Development Studies4

Current status of SIS's products5

> S.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. > Zep-3:, Zep -3 is in Phase I clinical study (at the Dep. of Dermatology, Shiba Hospital, Israel). After concluding the study (Q2, 2013) we will initiate a Phase II study for HSV1 Cold Sores indication and a Phase II study for the Genital Herpes indication.> In relation to HSV1 infection, Zep -3 is a fast acting drug, which causes an immediate relief from pain and itching within less than 5 minutes and prevents lesion formation within 36 hours. Furthermore, it seems to have no adverse side-effects.

Inhibition of HSV1 replication and spreading in tissue culture

6

> The anti HSV1 activity of Zep-3 is determined by measuring plaque forming, 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 produced without causing Cell Toxicity in the Control Vero Cells

Inhibition of HSV1 Replication by Zep-3

7

Zep – 3 (4mg/ml)

Zep – 3 (8mg/ml)

Scramble (4mg/ml)

Scramble (8mg/ml)

Zep-3 Inhibits Virus Replication in tissue culture8

Control - No Peptide Zep-3

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

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

9

Control - None InfectedHSV1 - Infected

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

Zep-4 for Treating Psoriasis10

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

> Zep-4 relieves itching and redness.

Safety and Toxicology of Zep-3 and Zep-4

11

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

body weightVitality blood pictureInternal organs histopathology

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

Trans Dermal Permeability of Zep-3 and Zep-412

> 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.

> 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.

HSV1 - The Market13

> 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 (continue)14

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

HSV1 - The Market (Contd.)15

Psoriasis - Market16

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). 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.

Summary of Zep-317

> 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 of HSV1 in Vero cell line infected by the virus

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

Summary of Zep-418

> Zep-4 upon topical application is efficient for treating psoriasis in patients.

> Zep-4 relieves itching and redness associate with Psoriasis.

Capital Requirements19

Cost (M$)

Schedule Indication Phase

0.4 Q1 (2013) - Q2 (2013)

Safety Phase I

1.6 Q3 (2013) - Q4 (2014)

HSV1 Cold Sores

Phase II

2.3 Q1 (2014) - Q2 (2015)

Genital Herpes

Phase II

2.9 )Q1 (2014) - Q2 (2015

Psoriasis Phase I / IIa

Gant table20

(Q2ׂ(2013)--------------- Q1 (2015((

Cost (M$)

Task

---------+---------+--------+---- 0.25 Mode of Action

----------------------------------------------------- ----------------- ----------------

0.05 0.15 0.25 0.80

Long term stabilityDegradation PatternADME

------- 0.05 Mucosal Tissue Permeability & Toxicity

---------------

0.05 Anti Viral Specificity

---------------------------- 0.15 Foam Formulation

Founded in 1985,

S.I.S targeted the

development of

innovative

pharmaceutical products

based on properties

of snake venom

History21

1985 -

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.

History22

1998 - 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.

Prof. Israel Steiner (M.D.) 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.

Prof. Amos Panet 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.

Dr. Avigdor Levanon Executive VP, Business Development and CTO at S.I.S 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.

Scientific Board23

Prof. Elka Touito 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. Yechiel Shai 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

Dr. Naftali Primor Executive VP, Research and Development at S.I.S.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.

Capital Requirements24

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) 536-3748Mail: avigdor@sis-shulov.com

THANK YOU

Venoms For Humanity

S.I.S Shulov Innovative Science Ltd.

April 2013