2015 Investor/Analyst Breakfast

Transcription

1 2015 Investor/Analyst Breakfast December 3, 2015

2 Company Update

3 Forward Looking Statements 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

4 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

5 Main Pipeline Assets * * 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 5

6 Major Development Milestones 2015 and 2016 BL-8040 (SC Mobilization) phase 1 completion BL-8040 (SC Mobilization) phase 1 apheresis data BL-8040 (AML) phase 2 partial results BL-8040 (Consolidation) phase 2b initiation BL-5010 (Skin Lesions) CE Mark submission BL-8040 (hmds & AA) phase 1/2 initiation 2015 BL-8040 (SC Mobilization) Meeting with FDA BL-7010 regulatory pathway determination BL-8040 (AML) phase 2 completion BL-8040 (FLT-3) phase 1/2 initiation BL-8040 (SC Mobilization) phase 2 initiation BL-7010 (Celiac) CE pivotal study initiation BL-5010 (Skin Lesions) CE Mark approval 2016 BL-8040 (AML) discussions with agencies BL-5010 (Skin Lesions) product launch BL-8040 (hmds & AA) phase 1/2 interim results BL-8040 (SC Mobilization) phase 2 interim results 6

7 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 DiPersio Lab DiPersioLab.org

8 Stem Cell Mobilization?? - AMD3100 Small molecule CXCR4 antagonist

9 Failure Rate G-CSF G-CSF Failure Rates (<2M CD34/kg) for MM, NHL and HD First Mobilizers after 5 Apheresis Days % 80.0% 60.0% 40.0% 20.0% 0.0% 6.7% 26.5% 26.20% MM (n=387) NHL (n=471) HD (n=130) G-CSF Mobilization G/Chemo Failure Rates (<2M CD34/kg) for MM, NHL and HD First Mobilizers after 5 Apheresis Days. Failure Rate 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% 5.9% G/Chemo 22.9% 18.20% MM (n=17) NHL (n=35) HD (n=11) G/Chemo Mobilization Failure Rates of Mobilization Pusic et al BBMT, 2010

10 Effect of G-CSF and Diabetes on the HSC Niche Ferrraro et al Sci Transl. Med, 2011 Fadini et al Diabetes Care 2012 DiPersio, NEJM, 2012 Fandini et al, Diabetes, 2015

11 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

12 NHL Patients (%) a Achieving CD34+ Cells/kg by Apheresis Day ITT Population Kaplan-Meier Estimate of Proportion of Patients Reaching CD34+ cells/kg % HR = 3.64, 95% CI (2.39, 5.45), P < % 4.2% 14.2% 57.7% 21.6% 65.6% 24.2% Apheresis Day Mozobil Placebo DiPersio et al, JCO, 2009

13 Secondary Efficacy: Patients Achieving 2 million CD34+ cells/kg in 4 Days of Apheresis Intent-to-Treat Population Outcome Plerixafor (n=150) Placebo (n=148) Estimate of Treatment Effect [95% CI] Success 130 (86.7%) 70 (47.3%) 39.4% A [29.7%, 49.1%] p-value* < A Treatment effect estimated using difference in chance of success * p-value of difference in proportions using Pearson s Chi-Squared test DiPersio et al JCO, 2009

14 Impact of Mobilization Strategies on Normal Allogeneic Donor Stem Cell Yields (n=603) % o f P a t i e n t s AMD G+GM G-CSF GM-CSF N= 42 N= 176 N= 419 N= 40 0 <2 x 10^6 2-5 x 10^6 >5 x 10^6 # CD34+ cells collected (cells/kg) first apheresis *Unpublished data

15 Incidence of GvHD in Recipients of IV and SC Plerixafor Grafts p = 0.34 p = 0.24 p = 0.30 BMT CTN Randomized Phase III Trial Results* 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

16 CD34 + Cell Subsets: Relative Percent IV Plerixafor SC Plerixafor G-CSF CD123 CD123 CD45RA CD45RA + CD123 hi CD45RA - CD123 +/-

17 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 preemptive treatment 6% (4/69) 5% (4/80) 0.8% (-24-25) *Verkrujse et al. BMT :51-56

18 Continuous Infusion via Alzet Pump Alzet pump 7 1 day AMD310 0 or ALT1188 C57BL/6 days 1 day Alzet pump Model ul/hr 7 days 1 mg/day

19 Expansion and washout Infusion start / Sham-OP Infusion stop ctr. Day Day 1 Day 7 Day 14 Day 0 Infusion: CXCR4i CVI, 100 mg/kg,day, 2 wks. Day 3

20 Expansion and washout Analysis of Spleen and Blood Blood x10*4 x10*4 *** ** ** ctr cfu CFU-C per ml LSK per ml *** *** *** Spleen cfu lsk per spleen ctr days after CXCR4i CVI days after CXCR4i CVI

21 Expansion and washout Cell Cycle Analysis of BM 100% 80% 60% 40% 20% g2 s m g1 g0 ** ** *** *** LSK 100% 80% 60% 40% 20% g2 s m g1 g0 ** ** *** *** LSK SLAM 0% ctr d0 d1 d3 d7 d14 0% ctr d0 d1 d3 d7 d14 days after CVI CXCRi days after CVI CXCRi n=4-12, ±SD

22 Normal Bone Marrow Microenvironment E-selectin inhibitors VLA-4i G-CSF

23 N-Acylphenylalanine Derivatives VLA-4 Antagonists LDV mimics Lipophilic moiety LDV motif Firategrast LLP2A In general, N-acylphenylalanine derivatives exhibit dual inhibitory activity for integrin α 4 β 1 & α 4 β 7 whereas LDV mimetics are highly specific for α 4 β 1. Ramirez et al Blood, 2010 R 1 = H R 2 = C(O)CH 2 (CH 2 ) 4 NH 2 Bio-5192

24 Kinetics of murine progenitors mobilization in response to BIO5192 and Plerixaflor CFU/mL blood (x10 3 ) 2.5 ns Time after injection (h) BIO mg/kg IV n=10 plerixaflor 5 mg/kg sc n=10 Ramirez et al Blood, 2010

25 Additive mobilization of murine progenitors after combination of Plerixaflor sc and BIO5192 iv CFU/mL blood (x10 3 ) 8 6 *** Time after injection (h) plerixafor 5 mg/kg sc n=10 17-fold BIO mg/kg IV n=10 15-fold plerixaflor + BIO5192 n=10 57-fold

26 Additive Effect on Murine Progenitor CFU/mL blood (x10 3 ) * *** Ramirez et al Blood, Time after plerixaflor + BIO5192 (h) G-CSF n=4 17-fold G-CSF + plerixafor n=4 80-fold G-CSF + BIO5192 n=4 90-fold G-CSF + plerixaflor + BIO5192 n=4 190-fold

27 SDF-1/CXCR4? VCAM-1/VLA-4? E-Selectin/ E-Selectin ligand? Extracelluar Matrix Generic ligand/receptor Stroma-leukemia contact HSC/LSC Raf Mek RAS P P PIP2 P P PI3K PTEN Rapamycin P70S6K PIP3 AKT mtor Hypothesis: Interruption of Stroma-leukemia cell contact and/or inhibition of stromainduced signaling in leukemia cells will result in proliferation apoptosis, differentiation and sensitization to genotoxic stresses such as chemotherapy ER K S6 4EBP1 Stroma-leukemia signaling Anti-apoptosis Anti-proliferation Anti-differentiation

28 AMD3100 enhances effect of chemotherapy Nervi B, et al. Blood 2009;113:

29 Phase I/II Study of G-CSF + AMD MEC in Relapsed or Refractory AML 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/mm 3 4.No previous MEC salvage AMD3100: mcg/kg IV qd/bid on d3-8 G-CSF 10 mcg/kg SQ on d1-8 Mitoxantrone 8 mg/m 2 IV on d4-8 Etoposide 100 mg/m 2 IV on d4-8 Cytarabine 1000 mg/m 2 IV on d4-8 Day 1 Day 2 Day3 Day 4 Day 5 Day 6 Day 7 Day 8 G G A G A G A M E C A G A M E C A G A M E C A G A M E C A G A M E C Uy et al, Blood 2012

30 CXCR4 Expression Side scatter AML blasts CD45 Fold Change in MFI % of max isotype pre 6h post 24h post Hours Post-Plerixafor 0 CXCR4 (1D9)

31 Transwell Migration Assays % Migration 50 Baseline 6hrs Post-Plerixafor *P= % Migration R= P= No SDF-1 PBMC + SDF CXCR4 (1D9) MFI

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

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35 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

36 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 CA NIH/NCI Leukemia SPORE P50 CA NIH/NCI R01 CA152329; NIH/NCI R21 CA NIH/NCI SCC CCSG P30 CA NIH/NCI AML P01 CA Siteman Cancer Center Team Science Award Brian Campbell foundation DiPersio Lab DiPersioLab.org

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

38 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 Hematological and solid tumor indications (Orphan designation for AML and SC mobilization) CXCR4 antagonism Phase II ongoing (under IND) Product Highlights 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 Slide 38

39 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 Induces terminal differentiation of tumor cells BL-8040 directly induces apoptosis BL-8040 sensitizes tumor cells to other drugs BL-8040 induces tumor cells mobilization BL-8040 BL SOC Slide 39

40 Clinical program December 2015

41 Clinical Program PROTOCOL INDICATION Pre-Clinical Phase I Phase II Phase III ACUTE MYELOID LEUKEMIA (AML) BL BL BL R/R AML AML Consolidation (BLAST) AML FLT3-ITD Ph2a - Ongoing Ph2b - Ongoing Ph2a Planned to initiate Q1/2016 OTHER HEMATOLOGICAL INDICATIONS BL hmds and Aplastic Anemia Ph1/2 Ongoing STEM CELL MOBILIZATION BL BKTSC001 BL SCM as Single Agent (Allogeneic) SCM with G-CSF (Myeloma) SCM as Single Agent Ph2a Planned to initiate Q1/2016 Ph1/2 - Completed Ph1 Completed Slide 41

42 r/r AML BL study Ongoing Ph2a study

43 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: Treatment: Endpoints: Dose escalation phase 3+3 design, up to 5 escalating doses ( mg/kg) Expansion phase: expand safe, efficacious dose group 2 consecutive days of BL-8040 monotherapy 5 days of BL Chemotherapy To assess the safety and tolerability of escalating repeated doses of BL-8040 as monotherapy and when combined with highdose 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 Slide 43

44 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 Leukemic blast mobilization Effect on BM disease Apoptosis induction Differentiation induction Slide 44

45 Clinical Outcome 38% ORR (CR+CRi) Cohort (mg/kg) # of Patients CR+CRi Day 30 BM biopsy Clinical response * Persistent PR Discontinued disease *Additional 3 patients treated with BL-8040 on compassionate basis - 2 achieved CR 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 Among the responders were patients with high risk disease many of which were primary refractory to chemotherapy Slide 45

46 Summary 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 Slide 46

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

48 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 ( 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 Part 1 Screening Mobilization Safety follow up BL-8040 Part 2 BL-8040 Screening Mobilization + Collection Safety follow up Day Slide 48

49 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 BL-8040: Time post BL-8040 (hr) CD34+ PB levels in subjects treated with BL-8040 (1 mg/kg) BL-8040: Time (hr) CD34+/µL blood < >30 Slide 49

50 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) ,091,848 5,091, ,964,615 11,998, ,667,866 14,917, ,154,834 11,794,114 CD34+/µL ; WBC x 10 3 / µl ,366,255 15,230, ,068,548 14,711, ,076,197 9,652, ,623,736 9,994,937 Median 16.5 ± 2.3 L 0.77 ± 0.13 % 11.2 x 10 6 (± 2.8 x 10 6 ) 11.9 x 10 6 (±3.5 x 10 6 ) Time post BL-8040 CD34+ PB levels 24 hr post BL-8040 are still high even after leukapheresis 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 10 6 per kg Stem cell levels in the PB 24 hr post BL-8040 facilitate additional apheresis on day 2, if needed Slide 50

51 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 Slide 51

52 Stem Cells Mobilization for Allogeneic Transplantations Assess the efficacy of BL-8040 to mobilize 2 x 10 6 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 10 6 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 Donor BL-8040 Screening Mobilization and collection Safety follow up Day Recipient Screening Myeloablative treatment Transplant Safety follow up Chemotherapy Day Slide 52

53 BL-8040 Development for Cancer Immunotherapy

54 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. Slide 54

55 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 CXCR4 inhibition Ovarian epithelial carcinoma cells express functional SDF-1 High CXCR4 expression in cancer isolated MDSCs MDSCs migration is inhibited by CXCR4 blockade Slide 55 Righi E. et al., Cancer Res 2011; Zou W et al., Nature Medicine, 2001; Obermajer et al., Cancer Res, 2011

56 Summary - BL-8040 Development for Cancer Immunotherapy 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 Slide 56 CONFIDENTIAL

57 Closing Remarks

58 Major BL-8040 Development Milestones - 3 years BL-8040 (r/r AML) - phase 2 results BL-8040 (FLT-3) - FPI BL-8040 (BMF Diseases) - interim results 2016 BL-8040 (SC Mobilization) - phase 2 initiation BL-8040 (r/r AML) - regulatory discussion BL-8040 (SC Mobilization) partial results BL-8040 (FLT-3) - interim results BL-8040 (BMF Diseases) - study completion BL-8040 (FLT-3) - study completion BL-8040 (Consolidation) - LPI BL-8040 (SC Mobilization) - phase 2 completion BL-8040 (Consolidation) - study completion - Today we announced our New Oncology SAB 58

59 Additional programs BL-7010: 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 BL-5010: Omega Pharma/Perrigo submitted for CE Mark registration Expected launch in EU in 2016 OTC solution for non surgical removal of skin lesions

60 THANK YOU!