Transcript INF induced genes personal gene expression

Genefron
Personalized Medicine Diagnostic
July 2013
Because Response to Interferon is Personal
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.
Hepatitis C virus (HCV)
INF signal
INF treatment
Direct Antiviral Agents
Pi’s, Pol-i.
INF induced genes
personal gene expression
Innate immune response:
RNAase, Ubiquitin etc
INF induced genes - PGE (personal
gene expression)
INF signal
Nucleus
Personal gene
expression signature
mRNA
Proteins – virus degradation
The Problem and the Technology
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.
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.
IFR10 Diagnostics kit
Massive Data-Methylation, DNA, RNA,MICROARRAY, 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
Gene race
Top 10 genes
Results of gene expression analysis
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
600
500
gene expression level
400
300
200
100
0
INF
Non
Responders healthy
responders
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%
HCV Responders vs. Non responders
Identification using PGE
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.
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Personal Gene Expression
.
ROC curve
Random classifier
Cut-off point
ROC curve
Random classifier
Cut-off point
1
0.8
0.6
0.4
0.2
0
0
0.5
1
False positive rate (1-Specificity)
Mirrored ROC curve
True positive rate (Sensitivity)
True positive rate (Sensitivity)
ROC curve
1
0.8
0.6
0.4
0.2
0
0
0.5
1
True negative rate (Specificity)
Example 1: Dill et.al. Lausanne SW, 2011. data after analysis ROC curve
Genefron invention in HCV
treatment – Liver Biopsy
Identified PGE signature by qRT
PCR about 95% accuracy + cost
efficiency
Genefron Diagnosis test II
for non responders for
Treatment prediction with
a defined treatment
Genefron diagnostic
TEST I: kit used
prior to treatment
Diagnosed
HCV patient
Responder
IFNα protocol
Non
responder
DAA+ IFNα
Personal treatment
protocol per PGE
with IFNα (low cost)
Personal treatment
protocol per PGE
Personal Treatment Adjustment

Personal Treatment Adjustment
Using 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 nonresponders patient populations
correlates to MD diagnosis.14
before
24hr after
12
10


WW market $5.6B.
Estimated saving: $1.2B
8
6
4
2
0
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
before
r_7
r_8
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:
Algorithm implications
Dengue

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
Healthy volunteers

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.
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 1/9/13
FDA: 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