Because Response to Interferon is Personal

GenefronPersonalized Medicine DiagnosticJuly 2013

Genefron LTD Team Genefron Ltd. is an Israeli based, privately held company

company that specializes in the development of in-vitro diagnostic kits for personalized medicine.

Our Team: CEO Yaniv Kotler, MSC, LLB Bioinformatics Management – Yoav Smith, PhD (Genomic

Data Analysis Unit, Hebrew University, Jerusalem)

Business Development – Jack Lahav, Livingston NJ. CFO - Orit Kotler, MBA. Project Manager - Shlomo Pundak, PhD

Clinical trials – conducted at : Sheba Medical Center, Tel Aviv, and Shaare Zedek Medical center, Jerusalem.

Innate immune response: RNAase, Ubiquitin etc

Direct Antiviral AgentsPi’s, Pol-i.

INF signal

INF induced genes personal gene expression

Hepatitis C virus (HCV)

INF treatment

INF induced genes - PGE (personal gene expression)

Nucleus

mRNA

Proteins – virus degradation

INF signal

Personal gene expression signature

The Problem and the Technology

Genefron’ s qRT PCR Diagnostic kit, IFR10, from liver tissue or blood samples measuring INF personal gene expression (PGE) signature can identify responders /non responders with ~ 96% accuracy will have an immediate and profound influence on MDs' decision of a specific patient optimal treatment, feasible outcome and cost.

1.5% of WW population is infected with HCV.Currently only about 50% of the Caucasians, 30% of Asians and 80% of the Afro-Americans a HCV patients are non responders to the PEGylated IFNa treatment.Non-responders and relapsed patients report severe adverse effects and incur long and expensive treatments with minimal clinical results.

IFR10 Diagnostics kit

Massive Data-Methylation, DNA, RNA,MICRO-ARRAY, SNP …It’s for Giants

Bioinformatics

Genefron’s breakthrough discovery is a verifiable and highly accurate platform algorithm for scanning extremely large databases that can be applied into various fields. This algorithm is designed to find mathematical connections and characters allowing identifying the desired group within the tested large databases.

Using our algorithm, we examined results from microarray data experiments by comparing responders to non responders and searching for a small list of genes and their particular importance within the liver tissue to the IFN responsiveness and consequently the treatment’s ultimate outcome.

Team Race

Algorithm outcome

Top 10 genesGene race

Results of gene expression analysis

0100200300400500600

gene expression level

3 situations: Healthy - No infection = no Personal Gene Signature (PGE)After Infection = “natural” PGE:

non responders = high genes expression Responders = low gene expression

After Infection + INF treatment = max PGE

HCV Test Validation & Verification

The personal genomic expression (PGE) signature was verified on data from more than 160 HCV type 1 patients studies from Canada, USA, EU and Japan.

The PGE signature has been verified on FFPE liver tissue (23 samples).

Proof of concept has been achieved on the actual qRT-PCR procedure 36 Swiss patients.

Diagnostic kit ingredients and PGE signature have been verified on frozen tissue samples for FDA and CE certification

95%

89%

95%

95%

Example 1: We have used our algorithm on published RT PCR data (Dill et. al. Lausanne SW, 2011) which included 27 patients (X axis), RT-PCR – liver tissue, HCV Type 1 prior to PEG INF treatment. The patients presents various PGE signature (Y axis). The results identified 2 major groups responders (red) and non responders (blue) in 96% accuracy.

HCV Responders vs. Non responders Identification using PGE

R1 R2 R3 R4 R5 R6 R7 NR1 NR2 NR3 NR4NR5 NR6 NR7 NR8 NR9

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9NR20

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Personal Gene Expression .

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ROC curve

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Mirrored ROC curve

ROC curveRandom classifierCut-off point

ROC curveRandom classifierCut-off point

Example 1: Dill et.al. Lausanne SW, 2011. data after analysis ROC curve

Genefron invention in HCV treatment – Liver Biopsy

Genefron diagnostic TEST I: kit used

prior to treatment

Responder IFNα protocol

Personal treatment protocol per PGE

with IFNα (low cost)

Non responder

DAA+ IFNα

Personal treatment protocol per PGE

Genefron Diagnosis test II for non responders for

Treatment prediction with a defined treatment

Identified PGE signature by qRT PCR about 95% accuracy + cost

efficiency

Diagnosed HCV patient

Personal Treatment Adjustment

Personal Treatment AdjustmentUsing the PGE of a patient and a second novel algorithm we are developing a new method for adjustment of Personal Treatment (PT) including Interferon with/without combination of the new DAA medications. This approach will give the physician a new tool to tailor a specific treatment course base on the genomic information of the patient.

Cost efficiency – Israel (example)

SOC in Israel: IFN treatment (estimated 2000- 2500 patient per year), Budget

~$30M If negative IFN+DAA (512 patient per year), Budget ~$12M

Potential saving: We estimate that at least 96% of the non responders can skip

IFN treatment . ~ 1200 patients X $15K =$18M Test cost ~$600. ($1.5M).

Saving of $16.5M

Global market

$2.9 B is INFα (mostly for HCV) WW market. $1.3 B saving today USA +EU can save today ~$1B$.

$20B global market for hepatitis C therapies expected to be by the end of the decade – meaning $17.3B expense on DAA (nature)

Using our technology can reduce dramatically the market to ~$11B.

More PGE Signature Implications

Multiple sclerosis (MS) patients may be treated by IFN-b. We have identified the responders and non-responders patient populations correlates to MD diagnosis.

WW market $5.6B. Estimated saving: $1.2B

MS patients- the graph represent 15 patients (X axis) PGE Signature Genes (Y axis) before and 24h after IFN-b treatment. Notice the expression “shutdown” in the non responders:

nr_1 nr_2 nr_3 nr_4 nr_5 nr_6 nr_7 r_1 r_2 r_3 r_4 r_5 r_6 r_7 r_8

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Algorithm implications

Boxplot of 3 genes (g1-g3, X axis) expression (QRT-PCR units) in PBMC samples of 9 patients, 4 days post infection comparing uncomplicated cases vs. Dengue syndrome shock patients. The red line resemble the average expression of the group

7 healthy volunteers (X- axis) donated PBMC samples before treatment with Poly C adjuvant and PBMC samples were taken 24 h post treatment. The change (delta E) in expression (Y axis) was measured in 4 genes (g1-g4). Note i307, i308 as non responders for future IFN treatment.

Dengue Healthy volunteers

Genefron LTD overview

Genefron Intellectual property (IP) includes:1 granted patent

2 PCT applications 3 patent application in various stages

All granted exclusively to Genefron by the Hebrew University in Jerusalem, Israel.

CE: Genefron has passed BSI (Notified body) for obtaining CE mark. Expected date 1/9/13FDA: Pre IDE meeting was held with the FDA. The company intends to begin its PMA route in 07/13, in full cooperation with the FDA CLIA : Genefron intends to market its product using CLIA route in the second half of 2013