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2015 Investor/Analyst Breakfast December 3, 2015

Company Update

This presentation contains "forward-looking statements." These statements include words like "may," "expects," "believes," “plans,” “scheduled," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements.

3

Forward Looking Statements

BioLineRx Snapshot

• Drug development company focused on oncology & immunology – Founded in 2003 by Teva and other key players in Israeli Life Sciences industry

• Lead clinical programs:

– BL-8040 for AML and other hematological indications

– BL-7010 for celiac disease

• Strategic collaboration with Novartis for co-development of selected Israeli-sourced programs

• Strong balance sheet

– ~$51 million cash as of September 30, 2015

– Provides operational capital for next three years through 2018

4

Main Pipeline Assets

5

* BL-1040 for the prevention of ventricular remodeling post AMI is currently sub-licensed to Bellerophon, pending decision on future development in light of negative results from CE mark registration study recently reported

*

2016

Major Development Milestones – 2015 and 2016

6

BL-7010 (Celiac) CE pivotal study initiation

BL-8040 (AML) phase 2 completion 2015

BL-8040 (FLT-3) phase 1/2 initiation

BL-8040 (SC Mobilization) phase 1 completion √

BL-8040 (hMDS & AA) phase 1/2 interim results

BL-8040 (SC Mobilization) phase 2 initiation

BL-8040 (SC Mobilization) phase 2 interim results

BL-8040 (AML) – discussions with agencies

BL-8040 (SC Mobilization) phase 1 apheresis data √ BL-8040 (AML) phase 2 partial results √

BL-7010 regulatory pathway determination

BL-8040 (Consolidation) phase 2b initiation √ BL-8040 (SC Mobilization) Meeting with FDA √ BL-5010 (Skin Lesions) CE Mark submission √

BL-5010 (Skin Lesions) CE Mark approval

BL-5010 (Skin Lesions) product launch

BL-8040 (hMDS & AA) phase 1/2 initiation √

Role of the SDF-1/CXCR4 Axis in Stem Cell Trafficking and Cancer

John F. DiPersio MD, PhD Division of Oncology

Siteman Cancer Center Washington University School of Medicine

DiPersioLab.org DiPersio

Lab

Stem Cell Mobilization

- AMD3100 Small molecule CXCR4

antagonist ?

?

Presenter

Presentation Notes

Hematopoietic stem cells are anchored to the bone marrow through several receptor/ligand interactions between the stem cells, bone marrow matrix, and osteoclasts1 These receptor/ligand pairs include CXCR4/SDF-1, CD44/HA, CD62/PSGL, Kit/KL, and VLA-4/VCAM-1 G-CSF treatment facilitates mobilization through unknown mediator cells in protease and non-protease–dependent manners1 G-CSF induces release of several proteases, including neutrophil elastase, cathepsin G, and matrix metalloproteinase-9. These proteases cleave several important adhesion molecules G-CSF also induces transcriptional downregulation of SDF-1 mRNA in bone marrow stroma and osteoblasts Mozobil™ complements the activity of G-CSF by selectively and reversibly blocking the SDF-1/CXCR4 interactions1 The combined activity of these 2 agents helps rapidly mobilize hematopoietic stem cells into the bloodstream1 Reference: Pusic I, DiPersio JF. The use of growth factors in hematopoietic stem cell transplantation. Curr Pharm Des. 2008;14:1950-1961.

G-CSF

G/Chemo Failure Rates (<2M CD34/kg) for MM, NHL and HD First Mobilizers after 5 Apheresis Days.

22.9% 18.20%5.9%

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

MM (n=17) NHL (n=35) HD (n=11)

G/Chemo MobilizationFa

ilure

Rat

e

G/Chemo

G-CSF Failure Rates (<2M CD34/kg) for MM, NHL and HD First Mobilizers after 5 Apheresis

Days.

26.5% 26.20%

6.7%0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

MM (n=387) NHL (n=471) HD (n=130)

G-CSF Mobilization

Failu

re R

ate

Failure Rates of Mobilization

Pusic et al BBMT, 2010

Ferrraro et al Sci Transl. Med, 2011 Fadini et al Diabetes Care 2012 DiPersio, NEJM, 2012 Fandini et al, Diabetes, 2015

Effect of G-CSF and Diabetes on the HSC Niche

Quest for a Rapid and Robust Mobilization Design

• CXCR4 inhibitors Others • VLA4 inhibitors • Groβ, truncated Groβ • proteasome inhibitors • Flt3L, truncated Flt3L • Continous infusion CXCR4 inhibitors

NHL Patients (%)a Achieving ≥ 5 × 106 CD34+ Cells/kg by Apheresis Day – ITT Population

Kap

lan-

Mei

er E

stim

ate

of P

ropo

rtion

of

Patie

nts R

each

ing

≥ 5

× 1

06 CD

34+

cells

/kg HR = 3.64, 95% CI (2.39, 5.45), P <.001

27.9%

49.1%

57.7% 65.6%

4.2% 14.2% 21.6%

24.2%

0

10

20

30

40

50

60

70

1 2 3 4 Apheresis Day

Mozobil™

Placebo

DiPersio et al, JCO, 2009

Presenter

Presentation Notes

Significantly more non-Hodgkin’s lymphoma (NHL) patients receiving Mozobil™ + G-CSF achieved the primary endpoint of collecting ≥ 5 × 106 CD34+ cells/kg than patients receiving placebo + G-CSF1 More NHL patients that received Mozobil™ + G-CSF collected ≥ 5 × 106 CD34+ cells/kg on the first day of apheresis than those that received placebo + G-CSF after 4 days of apheresis (27.9% vs 24.2%)2 This comparison is denoted by the white dotted line The median number of apheresis days for Mozobil™-treated patients to collect ≥ 5 × 106 CD34+ cells/kg was 3 days. Because less than 50% of placebo-treated patients were able to collect ≥ 5 × 106 CD34+ cells/kg within 4 days, the median is not estimable2 On day 1, approximately 6-fold more NHL patients who received �Mozobil™ + G-CSF collected ≥ 5 × 106 CD34+ cells/kg than patients receiving placebo �+ G-CSF1 By day 2, approximately 3.5-fold more NHL patients who received �Mozobil™ + G-CSF collected ≥ 5 × 106 CD34+ cells/kg than patients receiving placebo �+ G-CSF1 By day 3, approximately 2.5-fold more NHL patients who received Mozobil™ + G-CSF collected ≥ 5 × 106 CD34+ cells/kg than patients receiving placebo + G-CSF1 References: Mozobil™ [prescribing information]. Cambridge, MA: Genzyme Corp; 2008. Genzyme Corp. Data on file.

Secondary Efficacy: Patients Achieving ≥ 2 million CD34+ cells/kg in 4 Days of

Apheresis

A Treatment effect estimated using difference in chance of success

* p-value of difference in proportions using Pearson’s Chi-Squared test

Intent-to-Treat Population Outcome Plerixafor

(n=150) Placebo (n=148)

Estimate of Treatment Effect

[95% CI]

p-value*

Success 130 (86.7%) 70 (47.3%) 39.4%A

[29.7%, 49.1%] <0.0001

DiPersio et al JCO, 2009

Presenter

Presentation Notes

Mozobil – 20 failures include 3 pts w/ no study drug and 17 pts <2 million Placebo – failures include 6 patients no GCSF or SD and 72 pts < 2 million

38.1

52.38

9.52 5.68

18.75

75.57

4.77

26.49

68.74

32.5 35

32.5

0

10

20

30

40

50

60

70

80

<2 x 10^6 2-5 x 10^6 >5 x 10^6

% of

Patients

# CD34+ cells collected (cells/kg) first apheresis

Impact of Mobilization Strategies on Normal Allogeneic Donor Stem Cell Yields (n=603)

AMDG+GMG-CSFGM-CSF

N= 42 N= 176 N= 419 N= 40

*Unpublished data

Presenter

Presentation Notes

A retrospective analysis at our own center looking at various mobilizing agents in the matched sibling donor setting shows that G-CSF failed to mobilize in one apheresis in less than 5% of donors compared to plerixafor and GM-CSF that failed to mobilize in 30-40% of donors.

Incidence of GvHD in Recipients of IV and SC Plerixafor Grafts

Acute GvHD II-IV Acute GvHD III-IV Any cGvHD Incidence 47% (40% - 53%) 16% (12% - 21%) 53% (45% - 60%)

*Anasetti et al. ASH Annual Meeting 2011, Abstract #1

BMT CTN Randomized Phase III Trial Results*

p = 0.34 p = 0.24 p = 0.30

Presenter

Presentation Notes

There is no apparent difference in acute GvHD incidence between IV and SC plerixafor mobilized grafts Both forms of mobilization result in lower rates of acute GvHD Our institutional experience with G-CSF mob are 50-60% (Devine study) At this meeting presented at the plenary session the BMT CTN reports the results of a randomized phase III trial evaluating filgrastim mobilized PBSC grafts with BM grafts and found that the incidence of cGVHD for filgrastim mobilied PBSC grafts was 53% (45% - 60%) compared to our incidence of 35% and acute grade II-IV GvHD was 47% compared to our incidence of 21%

CD45RA+CD123hi

SC Plerixafor

CD45RA

IV Plerixafor

CD

123

CD34+ Cell Subsets: Relative Percent G-CSF

CD

123

CD45RA-CD123+/-

Presenter

Presentation Notes

Peripheral blood apheresis products mobilized by plerixafor compared with G-CSF have a unique composition of cells and are enriched for plasmacytoid DCs and lymphocytes. (Rettig et al. Blood 2009 114: a32) In the representative dot plots at the top of the slide are peripheral blood samples after IV plerixafor followed by a 4 day washout then remobilization with SC plerixafor and analysis of apheresis product. The right represents apheresis product of G-CSF. The bottom left are early HSC (CMP), bottom right are precursors (GMP and CLP) and upper right are pDCs progenitors The phenotyping was done on CD34+ cells mobilized by P IV vs P SC vs G. All were CD34 selected first. There are distinct populations of CD123++CD45A++. This phenotype is consistent with pDC precursors. The bottom panels summarize these results showing an increase in pDC precursors in plerixafor grafts and increase CMP in G-CSF products. Both absolute numbers (not shown here) and percentages of pDCs are increased after IV and SC plerixafor compared to G.

Incidence of CMV Viremia and Disease

G-CSF* plerixafor Risk Difference (95% CI)

CMV viremia ≥10,000

copies/mL

62% (43/69)

15% (12/80)

47% (23 - 69)

CMV disease with pre-emptive

treatment

6% (4/69)

5% (4/80)

0.8% (-24 - 25)

*Verkrujse et al. BMT 2006. 37:51-56

Presenter

Presentation Notes

Historical* CMV viremia >10,000 copies/mL in a cohort of 98 recipients was 62% (43/69) in those at risk. 6% (4/69) developed disease despite pre-emptive treatment with GCV. The incidence of CMV viermia >10,000 copies/mL in at risk recipients (defined as serology positive in donor or recipient) was 3/20 (15%). The incidence of CMV disease in at risk individuals was 1/20 (5%). The relative risk of CMV viremia in recipients of IV plerixafor is 4.15. There was no significant difference in CMV disease. The risk difference between GCSF – plerixafor is 47% with exact 95% confidence interval (23%, 69%). So the smallest plausible difference is that the risk with GCSF is 23% greater than with plerixafor.

Continuous Infusion via Alzet Pump

C57BL/6

1 day

AMD3100 or

ALT1188

Alzet pump

7 days

1 day

• Model 2001 • 1 uL/hr • 7 days • 1 mg/day

Alzet pump

Expansion and washout

ctr.

Day 0

Infusion start / Sham-OP Infusion stop

Day 0

1 3 7 14

Infusion: CXCR4i CVI, 100 mg/kg,day, 2 wks.

Day 3

Day 14 Day 7 Day 1

05

101520253035

ctr 0 1 3 7 14

Spleen

cfu

lsk perspleen

0

2

4

6

8

10

ctr 0 1 3 7 14

Blood

cfu

Analysis of Spleen and Blood

days after CXCR4i CVI days after CXCR4i CVI

x10*4

x10*4

CFU-C per ml LSK per ml

***

** **

***

*** ***


0%

20%

40%

60%

80%

100%

ctr d0 d1 d3 d7 d14

LSK g2 s m g1 g0

0%

20%

40%

60%

80%

100%

ctr d0 d1 d3 d7 d14

LSK SLAM

g2 s m g1 g0

Cell Cycle Analysis of BM

n=4-12, ±SD

days after CVI CXCRi

*** ***

**

**

*** ***

**

**


days after CVI CXCRi

Normal Bone Marrow Microenvironment

VLA-4i E-selectin inhibitors G-CSF

Presenter

Presentation Notes

The surface chemokine receptor CXCR4, expressed on CD34+ hematopoietic stem cells (HSCs), interacts with SDF-1α, which is expressed in bone marrow1 The SDF-1α/CXCR4 interaction anchors HSCs to the bone marrow matrix1 Mozobil™ inhibits the CXCR4/SDF-1α bond, thereby releasing these cells from the bone marrow1 References: Pusic I, DiPersio JF. The use of growth factors in hematopoietic stem cell transplantation. Curr Pharm Des. 2008;14:1950-1961. Cashen AF, Nervi B, DiPersio JF. AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent. Future Oncol. 2007;3:19-27.

VLA-4 Antagonists N-Acylphenylalanine

Derivatives

Firategrast

In general, N-acylphenylalanine derivatives exhibit dual inhibitory activity for integrin α4β1 & α4β7 whereas LDV mimetics are highly specific for α4β1.

LDV mimics LDV motif

Lipophilic moiety

LLP2A

Bio-5192

R1 = H R2 = C(O)CH2(CH2)4NH2

Ramirez et al Blood, 2010

Presenter

Presentation Notes

Dual inhibitory activity for integrin α4β1 & α4β7

Kinetics of murine progenitors mobilization in response to BIO5192 and Plerixaflor

0 1 2 3 4 5 6 70.0

0.5

1.0

1.5

2.0

2.5

BIO5192 1 mg/kg IV n=10plerixaflor 5 mg/kg sc n=10

Time after injection (h)

CFU/

mL

bloo

d (x

103 ) ns


Presenter

Presentation Notes

Mice were injected with BIO5192, Plerixaflor and G-CSF and assayed for the mobilization over time. The optimal dose of iv BIO5192 was 1 mg/kg that induced a rapid and transient maximum progenitor mobilization 45-60 min after 1 dose. In contrast, the optimal dose of Plerixaflor was 5mg/kg sc that induced progenitor mobilization 3-6 hrs after injection. This also was significantly more active than the highest tolerable iv dose of 3mg/kg G-CSF at 250ug/kg day for 5 days, induced peak mobilization at the end of the 5 days Overall, these data show that BIO5192 has an in vivo activity with a rapid and robust effect measured in minutes, compared to hours with Plerixaflor and days with G-CSF

Additive mobilization of murine progenitors after combination of Plerixaflor sc and BIO5192 iv

0 1 2 3 4 5 6 70

2

4

6

8

plerixafor 5 mg/kg sc n=10 17-foldBIO5192 1 mg/kg IV n=10 15-foldplerixaflor + BIO5192 n=10 57-fold

***

Time after injection (h)

CFU/

mL

bloo

d (x

103 )

Presenter

Presentation Notes

The combination of Plerixaflor and BIO5192 induced a robust and synergistic 57-fold mobilization over basal that peaked at 3hrs and lasted for 6h. Plerixaflor alone induced a 17-fold increase over basal progenitor mobilization 3 hrs after single sc injection, In contrast BIO5192 induced a 15-fold increase 45-60 min after a single iv dose.

-120 0 2 4 6 8 10 240

10

20

30

40

50

G-CSF n=4 17-foldG-CSF + plerixafor n=4 80-foldG-CSF + BIO5192 n=4 90-foldG-CSF + plerixaflor + BIO5192 n=4 190-fold

***

*

Time after plerixaflor + BIO5192 (h)

CFU/

mL

bloo

d (x

103 )

Additive Effect on Murine Progenitor


Presenter

Presentation Notes

additive mobilization was observed when BIO5192 and Plerixaflor were combined with G-CSF. A massive 200-fold mobilization over basal with the triple combination was seen. Taken together, these results show that BIO5192 alone has a kinetics of progenitors mobilization in minutes, compared to hours and days with plerixaflor and G-CSF. The combination of Plerixaflor and BIO5192 with and without GCSF, induced a massive, rapid and synergistic progenitor mobilization 3 hours after the injection The combination of GCSF+BIO5192 and Plerixaflor also is synergistic and more potent than the combination of Plerixaflor and BIO5192 without GCSF

P

P

P

P

Raf

RAS

PI3K

Mek

ERK

PTEN

PIP2 PIP3

AKT

mTOR P70S6K

4EBP1 S6

Anti-apoptosis Anti-proliferation

Anti-differentiation

Rapamycin

HSC/LSC

Generic ligand/receptor

Extracelluar Matrix SDF-1/CXCR4? VCAM-1/VLA-4? E-Selectin/ E-Selectin ligand?

Stroma-leukemia contact

Stroma-leukemia signaling

Hypothesis: Interruption of Stroma-leukemia cell contact and/or inhibition of stroma- induced signaling in leukemia cells will result in proliferation apoptosis, differentiation and sensitization to genotoxic stresses such as chemotherapy

AMD3100 enhances effect of chemotherapy

Nervi B, et al. Blood 2009;113:6206-6214.

Phase I/II Study of G-CSF + AMD3100 + MEC in Relapsed or Refractory AML

G

Day3

Eligibility Criteria 1.Dx of AML and either

1° refractory or relapsed disease 2.Age 18-65, ECOG PS < 2 3.Blast ct < 30,000/mm3

4.No previous MEC salvage

AMD3100: 240-480mcg/kg IV qd/bid on d3-8 G-CSF 10 mcg/kg SQ on d1-8

Mitoxantrone 8 mg/m2 IV on d4-8 Etoposide 100 mg/m2 IV on d4-8 Cytarabine 1000 mg/m2 IV on d4-8

Day 4 Day 5 Day 6 Day 7 Day 8

A G

AMEC

A G

AMEC

A G

AMEC

A G

AMEC

A G

AMEC

Day 2 Day 1

A G

G

Uy et al, Blood 2012

100 101 102 103 1040

20

40

60

80

100

CXCR4 (1D9)

% o

f max

.

24h post 6h post pre isotype

CXCR4 Expression

100 101 102 103 1040

200

400

600

800

1000

50.5

CD45

Side

sc

atte

r

AML blasts

Hours Post-Plerixafor

Fold

Cha

nge

in M

FI

No SDF-1 + SDF-10

10

20

30

40

50 Baseline6hrs Post-Plerixafor

PBMC

% M

igra

tion

Transwell Migration Assays

0 2 4 6 80

10

20

30

40

CXCR4 (1D9) MFI

% M

igra

tion

R=0.8828 P=0.0016 *P=0.0112

Notch induced mouse T-ALL model Human T-ALL xenograft model

Conclusions • CXCR4-SDF-1 represents a key pathway for normal and leukemic stem cell

trafficking

• Transient blockade results in modest mobilization of HSC and sensitization of AML and T-ALL to chemotherapy and to pancreatic cancer cells to checkpoint inhibitor therapy in preclinical mouse models

• Prolonged blockade of CXCR4 results in dramatic HSC mobilization, HSC expansion and inhibition of HSC re-homing in mice

• CXCR4 inhibitors can act synergistically with G-CSF or VLA-4i to mobilize HSCs

• CXCR4 mobilized HSCs are heterogenous and phenotypically and epigenetically distinct from G-CSF mobilized HSC

• Optimizing blockade of CXCR4 and VLA-4 axes may represent the “holy grail” for rapid and robust stem cell mobilization for both autologous and allogeneic stem cell transplantation

DiPersio Lab DiPersioLab.org

Acknowledgements DiPersio Lab

– Julie Ritchey – Linda Eissenberg – Mike Rettig – Darja Karpova – JaeBok Choi – Mark Schroeder – Matthew Holt – Armin Ghobadi – Pablo Ramirez – Geoff Uy

The Genome Institute – Rick Wilson – Elaine Mardis – Li Ding

WU/ SCC Proteomics Core Reid Townsend Department of Cell Biology William Frazier Chris Ho

Funding provided by: NIH P50 Molecular imaging grant CA094056-09 NIH/NCI Leukemia SPORE P50 CA171063-01 NIH/NCI R01 CA152329; NIH/NCI R21 CA 141523-01 NIH/NCI SCC CCSG P30 CA91842-01 NIH/NCI AML P01 CA101937 Siteman Cancer Center Team Science Award Brian Campbell foundation

BL-8040 NOVEL CXCR4 ANTAGONIST FOR TREATMENT OF ONCOLOGICAL MALIGNANCIES DECEMBER 2015

BL-8040 Overview

Feasibility & CMC

Pre-Clinical Development

Development to Clinical POC

Out-License For Advanced Clinical

Development Approved Drugs

Indication Mode of Action Status Product Highlights

Hematological and solid tumor indications (Orphan designation for AML and SC mobilization) CXCR4 antagonism Phase II ongoing (under IND) •Induces apoptosis of cancer cells •Mobilizes cancer cells and immune cells from bone marrow and lymph nodes to peripheral blood •Sensitizes cancer cells to chemo- and bio-based anti-cancer therapy •Induces terminal differentiation of immature cancer cells •Increases infiltration of immune cells into tumors and distracts their immuno-suppressive barriers

BL-8040’s Unique Mechanism Presents an Opportunity Across Many Hematological Indications

Results And MOA • Binds CXCR4 with high affinity (1-2 nM) and works as inverse agonist • Maintains extended inhibition through long receptor occupancy (>24 hours) • Induces apoptosis of tumor cells dependent on CXCR4 for survival • Increases sensitivity to anti-cancer agents by mobilizing tumor cells from protective microenvironment • Induces terminal differentiation of immature cancer cells

BL-8040 directly induces apoptosis

BL-8040 sensitizes tumor cells

to other drugs

BL-8040 Induces terminal differentiation of

tumor cells

BL-8040 BL-8040 + SOC

BL-8040 induces tumor cells

mobilization

Clinical program December 2015

Pre-Clinical Phase I Phase II Phase III INDICATION PROTOCOL

Ph2a - Ongoing

Ph1/2 - Completed

Ph2a – Planned to initiate Q1/2016

R/R AML BL-8040.01

BL-8040.07

BKTSC001 SCM with G-CSF (Myeloma)

SCM as Single Agent (Allogeneic)

AML Consolidation (BLAST) BL-8040.04 Ph2b - Ongoing

ACUTE MYELOID LEUKEMIA (AML)

Ph2a – Planned to initiate Q1/2016 AML FLT3-ITD BL-8040.05

Clinical Program

OTHER HEMATOLOGICAL INDICATIONS

Ph1 – Completed BL-8040.02 SCM as Single Agent

Ph1/2 – Ongoing hMDS and Aplastic Anemia BL-8040.06

STEM CELL MOBILIZATION

r/r AML BL-8040.01 study Ongoing Ph2a study

Phase IIa - Treatment of r/r AML Patients

A Phase IIa, Multicenter, Open-label Study Designed to Evaluate Safety and Efficacy Profile of Repeated Escalating Doses of BL-8040 in Adult Subjects with Relapsed or Refractory Acute Myeloid Leukemia Study design:

– Dose escalation phase – 3+3 design, up to 5 escalating doses (0.5-1.5 mg/kg) – Expansion phase: expand safe, efficacious dose group

Treatment: – 2 consecutive days of BL-8040 monotherapy – 5 days of BL-8040 + Chemotherapy

Endpoints: – To assess the safety and tolerability of escalating repeated doses of BL-8040 as monotherapy and when combined with high-

dose Ara-C in AML adult subjects with relapsed or refractory disease – To assess the clinical efficacy (response rates) of escalating repeated doses of BL-8040 – To assess the apoptotic effect of BL-8040 on leukemic blasts – To assess the effect of BL-8040 on mobilization of AML blasts to peripheral blood (PB) – To assess the single and multiple dose pharmacokinetic profile of BL-8040

Biological Activity POC

• Robust leukemic blast mobilization was observed (median of 40-fold increase) • BL-8040 monotherapy decreased amount of leukemic cells in BM by median of ~55% • BL-8040 monotherapy achieved 3.5-fold increase in AML cell apoptosis • BL-8040 monotherapy triggered terminal differentiation of immature AML cells

Apoptosis induction Effect on BM disease Leukemic blast mobilization

Differentiation induction

Clinical Outcome

Cohort (mg/kg)

# of Patients

Day 30 BM biopsy – Clinical response *

CR+CRi PR Persistent disease Discontinued

0.5 3 0 0 3

0.75 3 0 1 1 1

1 6 2 0 3 1

1.25 4 1 0 3

1.5 6 3 0 3

*Additional 3 patients treated with BL-8040 on compassionate basis - 2 achieved CR

38% ORR

(CR+CRi)

Among the responders were patients with high risk disease many of which were primary refractory to chemotherapy

• Most of the patients enrolled in the dose escalation phase had high risk disease • More than 1/3 of the patients were refractory to chemotherapy • Expansion phase open for enrollment

Presenter

Presentation Notes

Single chemo agent Single cycle High risk patients

• The dose escalation phase was completed

• All tested doses were found to be safe and well tolerated

• Robust leukemic blast mobilization was observed

• Two days of BL-8040 monotherapy decreased the amount of leukemic cells in the BM

• Two days of BL-8040 monotherapy induced cancer cell death (apoptosis)

• Topline results are expected in early 2016

Summary

SC Mobilization BL-8040 – A novel single agent treatment for SC mobilization

Phase I Healthy Volunteers Study Design

A Phase I, Two Part Study Exploring the Safety, Tolerability, Pharmacodynamic and Pharmacokinetic Effect of Ascending Doses of BL-8040 in Healthy Subjects

Study design: • Part 1 – Dose escalation, randomized, placebo controlled - 3 escalating doses (0.5-1.0 mg/kg) • Part 2 – Dose expansion (1.0 mg/kg)

Treatment:

• 1 or 2 administrations of BL-8040 monotherapy

Endpoints: • Safety and tolerability • Effect of BL-8040 on mobilization of HSC • Yields of cells collected by leukapheresis (4hr post BL-8040) • Viability, biological activity and repopulating capacity of the collected cells

Mobilization Safety follow up

Safety follow up

Screening

Screening

Part 1

Part 2 BL-8040

1 Day 2 7 3

BL-8040

Mobilization + Collection

BL-8040 is a Powerful Mobilizer of Stem Cells

• Substantial mobilization of HSC from BM to PB was observed • Consistent pattern of mobilization across all subjects treated with BL-8040

CD34+/µL blood <15

15-20 20-30 >30

Time post BL-8040 (hr)

BL-8040:

Time (hr) 0 2 4 8 23 2 4 8 24 48 3001 3002 3004 3105 3006 3008

CD34+ PB levels in subjects

treated with BL-8040

(1 mg/kg)

BL-8040:

Single BL-8040 Administration Results in Robust Collection of Stem Cells Using a Single Apheresis

Subject # Whole blood processed (L) % CD34+ cells CD34+/KG

(Donor weight)

CD34+/KG (70kg recipient

weight)

5001 9.8 0.75 4,091,848 5,091,429

5002 16.0 1.01 11,964,615 11,998,800

5003 16.6 0.85 13,667,866 14,917,500

5004 16.2 0.76 10,154,834 11,794,114

5005 16.6 0.78 11,366,255 15,230,781

5006 16.5 0.87 13,068,548 14,711,451

5007 17.5 0.64 11,076,197 9,652,114

5008 16.7 0.61 9,623,736 9,994,937

Median 16.5 ± 2.3 L 0.77 ± 0.13 % 11.2 x 106

(± 2.8 x 106) 11.9 x 106

(±3.5 x 106)

• Leukapheresis started 4 hr post BL-8040 injection using the Spectra Optia® Apheresis System

• The amount of collected stem cells was higher than 11 x 106 per kg • Stem cell levels in the PB 24 hr post BL-8040 facilitate additional apheresis on

day 2, if needed

CD34

+/µL

; W

BC x

103 /

µL

Time post BL-8040

CD34+ PB levels 24 hr post BL-8040 are still high even

after leukapheresis

Summary and Future Plans

• Robust and rapid stem cell mobilization was evident in all treated participants supporting a novel approach to stem cell collection

• The results support a novel method for SC mobilization and collection using BL-8040 single administration followed by a single apheresis all in one day procedure

• BioLine met with the FDA in order to discuss the next steps in the clinical development program for this indication

• The Agency agrees with the overall development of BL-8040 as a new agent for stem cell mobilization for allogeneic hematopoietic stem cell transplantation

• A phase 2a study is being prepared in collaboration with Washington University

Stem Cells Mobilization for Allogeneic Transplantations

Assess the efficacy of BL-8040 to mobilize ≥ 2 x 106 CD34+ cells/kg after up to two leukapheresis collections and the SCT recipient outcome Study design: • Donors will be treated with BL-8040 at a dose of 1 mg/kg and will undergo standard leukapheresis • Recipients with advanced hematological malignancies will undergo myeloablative chemotherapy and transplant with the

BL-8040 derived allograft Treatment: • 1 day of BL-8040 monotherapy and up to two apheresis Endpoints: • Efficacy of BL-8040 to mobilize ≥ 2 x 106 CD34+ cells/kg after no more than two leukapheresis collections • Safety and tolerability • Kinetics of neutrophil and platelet recovery post-transplant • Incidence of primary and secondary graft failure after transplantation with BL-8040 derived graft • Incidence of grade 2-4 acute graft versus host disease (GvHD) and incidence of chronic GVHD at 1 year • Characterization of the graft cellular composition including T-cell subpopulations

Transplant

Mobilization and collection Safety follow up

Safety follow up Myeloablative treatment

Screening

Screening

Donor

Recipient

BL-8040

1 Day 2 365

Chemotherapy

Day ≥3 365 1

BL-8040 Development for Cancer Immunotherapy

BL-8040 Development for Cancer Immunotherapy

• The tumor microenvironment actively suppresses trafficking of immune cells by secretion of SDF-1/CXCL12, the CXCR4 ligand, which retain the immune cells at the edge of the tumor.

• CXCR4 inhibition induces T cell infiltration into PDA tumors - exhibiting a synergistic effect with anti PD1/PD-L1 antibodies.

• BL-8040 induces the mobilization of T-cells, B-cells, NK cells and immature DC from the BM and lymph nodes into the periphery.

• BL-8040 induces the expression of CCL20/MIP-3α which stimulates immunity against cancer cells and may increase the trafficking of immune cells towards tumors.

The immuno-suppressive role of CXCR4 in the tumor microenviroment

• CXCL12 expression is an independent predictor of poor survival in cancer patients

• CXCR4-CXCL12 axis is the key pathway mediating the attraction of immuno-suppressive cells (MDSCs, T-regs, pDCs) to the tumor microenvironment preventing local T-cell activation

• CXCR4 inhibition selectively reduces intratumoral Tregs-cell infiltration

• CXCR4 inhibition selectively significantly inhibits the migration of MDSCs to the tumor

Ovarian epithelial carcinoma cells express functional SDF-1

High CXCR4 expression in cancer–isolated MDSCs

MDSCs migration is inhibited by CXCR4 blockade

CXCR4 inhibition

Righi E. et al., Cancer Res 2011; Zou W et al., Nature Medicine, 2001; Obermajer et al., Cancer Res, 2011

• Immunostimulant - BL-8040 is a powerful mobilizer of immune cells (T-cells, B-cells, immature Dendritic-cells and NK cells) from the bone marrow and lymph nodes.

• Potentiator - BL-8040 increases the infiltration of immune cells into tumors and distracts their immunological barriers.

• Chemo-attractant - BL-8040 induces the expression of CCL20/MIP-3a which stimulates immunity against cancer cells in animal models and may increase the trafficking of immune cells toward tumors.

• Microenviroment modifier - BL-8040 may affect the suppressive tumor microenviroment by decreasing the CXCR4 mediated migration of immune suppressor cells

Summary - BL-8040 Development for Cancer Immunotherapy

CONFIDENTIAL

Closing Remarks

2016

Major BL-8040 Development Milestones - 3 years

58

BL-8040 (BMF Diseases) - study completion

BL-8040 (r/r AML) - phase 2 results

BL-8040 (SC Mobilization) - phase 2 initiation

BL-8040 (FLT-3) - study completion

BL-8040 (FLT-3) - FPI

2017 2018 BL-8040 (Consolidation) - study completion

BL-8040 (SC Mobilization) - phase 2 completion

BL-8040 (Consolidation) - LPI

BL-8040 (SC Mobilization) – partial results

BL-8040 (r/r AML) - regulatory discussion

BL-8040 (FLT-3) - interim results

BL-8040 (BMF Diseases) - interim results

- Today we announced our New Oncology SAB

Additional programs :7010-BL

• EU pivotal study expected to start in H1 for celiac disease

• Depends on device designation in EU • Drug route in US

• Evaluation of food route for gluten sensitivity & gluten free lifestyle

• Faster time to market • Larger population • Risk reduction

:5010-BL • Omega Pharma/Perrigo submitted for CE Mark registration • Expected launch in EU in 2016 • OTC solution for non surgical removal of skin lesions

THANK YOU!

2015 investor/analyst breakfast - biolinerx - a drug ... investor breakfast (all...fandini et al,...

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