Cell-based immunotherapy products for the treatment of blood cancers and inherited blood disorders Company Presentation June 2016
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Company highlights and introduction to ATIR 1 Lead product ATIR is an innovative immunotherapy which addresses the risks and limitations of current bone marrow and stem cell treatments (HSCT) 2 Strong clinical Phase I and Phase II data package No patient (0/42) experienced grade III/IV GVHD Significantly improved Overall Survival Excellent safety and efficacy profile demonstrated to date 3 Clear upcoming route to market and strong news flow catalysts Initiation of Phase III trial in 2H 2016 (ATIR101) Expected submission to EMA for conditional approval (ATIR101) Initiation of clinical trial in Thalassemia (ATIR201) 4 Experienced management team and international, diverse shareholder base 3
HSCT as curative treatment for blood cancer and inherited blood disorders Basic principle of HSCT 1. Destroy the diseased bone marrow 2. Create bone marrow space in the recipient for the donor cells to engraft 3. Replace it with healthy donor cells 4. Suppress the immune system or eliminate the recipient T-cells to minimize risks of rejection 4
Significant risks & limitations in HSCT Causes of death after MUD HSCT 1% 6% Risks Opportunistic infections Immunosuppressed patients are highly susceptible to pathogens 19% 17% 20% 37% Graft-versus-Host Disease (GVHD) GVHD occurs when donor T-cells recognize a patient s tissue as foreign. Incidence of grade III/IV GVHD is as high as 30% and often fatal Relapse GvHD Infections Other Organ Failure New Malignancy 20% CIBMTR-data includes centers located globally and is measured over 2011-2012 Limitations Cancer relapse Ablated immune system has poor ability to fight residual leukemic cells Donor availability Approx. 75% of patients do not have a matched family donor and approx. 35% of patients eligible for HSCT will not find a matched donor in time 5
Haplo-HSCT with ATIR101: addressing risks and limitations of HSCT within standard hospital procedures ATIR101 allows for an immunosuppressant-free transplant regimen for haploidentical donor transplantation (i.e. from a family member) Adjunctive to (partially) T-cell depleted stem cell graft donor Donor CD34+ PBMC graft Selective photodepletion to eliminate GVHD-causing T-cells Conditioning Haplo HSCT Isolation ATIR101 infusion Myeloablative conditioning including ATG T-cell depleted stem cell graft from family member No prophylactic immunosuppression Donor lymphocyte infusion 28 32 days post- HSCT 6
ATIR101 manufacturing removes GVHD-causing T-cells while retaining key immune cells 1. Immune cells collected and mixed ex vivo 2. Activation of donor T- cells 3. TH9402 addition 4. Exposure to light 5. ATIR101 infusion ATIR101 characteristics Selective removal of GVHD-causing T-cells Patient Key immune cells are retained to protect against infections T-cells directed against leukemic cells are Donor GVHD-causing donor T- cells are activated by patient cells TH9402 is added TH9402 is retained only in activated donor T-cells Light induced killing Cells formulated for infusion Infusion 28-42 days after haplo HSCT retained Day 1-4 Day 5 Non-activated GVHDcausing donor T-cells Irradiated patient cells Activated GVHD-causing donor T-cells Graft-versus-Leukemia T-cells Activated GVHD-causing donor T-cells with TH9402 retained Other immune cells (e.g. virus specific memory and effector cells, naïve cells, NK cells) 7
ATIR101: alloreactive T-cells eliminated while T-cell response to allo viruses/bacteria/fungi Example from Phase II CR-AIR-007 release testing Typical example in CR-AIR-007 Donor ATIR Proliferation Index (PI) 10 8 6 4 1.6 1.4 1.2 Donor ATIR : Cells from the donor/starting material : Final product manufactured from donor Donor Recipient 1.0 Donor Recipient 3rd party CD3/28 Selective depletion Retained functional cells 3rd party SAFETY POTENCY 8
ATIR101 contains virus-specific T-cells Virus-specific T-cells before and after manufacturing of ATIR101 Control EBV CMV Influenza Donor ATIR 9
Graft-versus-Leukemia T-cells have been detected in ATIR101 Figure 2: ATIR101 cells were thawed, recovered for two days in medium supplemented withil-2, IL-7 and IL-15 followed by stimulation with Myb628/HLA-B44 aapcs. Myb628 specific T cell expansion was assessed after one (upper panel) or two (lower panel) rounds of stimulation with a Myb628/HLA-B44 multimer. As control, cells were stained with an irrelevant HLA-B44 multimer. Collaboration with Prof. Angela Krackhardt, Medizinische Klinik III, Klinikum Rechts der Isar, TU Munich, Munich, Germany 10
Overview of ATIR101/201 clinical studies Trial ID # Patients Aim Phase Design Status CR-GVH- 001 CR-AIR- 006 19 Dose finding Phase I/II Open-label, dose- escalation 158 Control group Observational cohort trial Completed 5 year follow-up completed Completed Data analysis CR-AIR- 007 23 Safety and efficacy Phase II Open-label, multi-center trial using optimal ATIR101 dose On-going All patients enrolled CR-AIR- 008 15 Dose Optimization Phase II Open-label, exploratory trial using repeat dose administration On-going First patient enrolled and treated Planned Clinical Studies 2016 CR-AIR- 009 Approx. 200 Safety and efficacy Phase III Randomized clinical trial: Haplo + ATIR101 (KIADIS) vs. Haplo + Cyclophosphamide (Baltimore) CR-BD- 001 Approx. 10 Safety and efficacy Phase II Exploratory Phase II trial in pediatric patients suffering from β-thalassemia major 11
Trial characteristics & endpoints Phase II CR-AIR-007 Trial characteristics (EudraCT 2012 004461 41: US-IND#14255) Design: open-label, single arm, multi-center study Patient population: AML or ALL in first remission with high-risk features or in second or higher remission No suitable matched donor Haploidentical family Locations: CA, BE, DE, UK (8 sites in total) Primary endpoint: Transplant Related Mortality (TRM) at 6 months Secondary endpoints: Acute and chronic GVHD Immune reconstitution TRM, relapse, Overall Survival (OS), up to 24 months Patient follow-up (per 24 March 2016): Median 414 days (range 110 742) Last patient reached primary endpoint on 24 March 2016 12
Patient & donor characteristics Patient and donors N=23 patients (HSCT + ATIR101) Median patient age (range): 41 years (21 64) Gender: 13 female, 10 male Median donor age (range): 33 years (21-61 ) Diagnosis AML: n=16 (70%): 11 in CR1 5 in CR2 ALL: n =7 (30%): 4 in CR1 3 in CR2 Risk classification Cytogenetic risk profile 1 : Favorable 0 Intermediate 9 (39 %) Adverse 14 (61 %) Disease-risk index 2 : Low risk index 0 Intermediate risk index 10 (43 %) High risk index 13 (57 %) 1 Mrozek K, et al. JCO 2012, 30 (36): 4515-4523 2 Armand P, et al. Blood 2014, 123 (23): 3664-3671 13
HSCT characteristics Myeloablative conditioning TBI (1200 cgy; n=11) or melphalan (120mg/m 2 ; n=12) Thiotepa (10 mg/kg), fludarabine (30 mg/m 2 x 5d) and ATG (2.5mg/kg x 4d) HSCT CliniMACS CD34 isolation system (Miltenyi Biotec) Target: 8-11x10 6 CD34+ cells/kg, with max. of 3x10 4 CD3+ cells/kg Prophylaxis No GVHD prophylaxis CMV/EBV monitoring Prophylactic use of ganciclovir/foscarnet (CMV + recipient/donor) ATIR101 infusion Day 28 post HSCT (median) 14
Top-line results: acute and chronic GVHD Acute GVHD No (0%) grade III/IV GVHD after ATIR101 infusion Only 3 cases of grade II GVHD Chronic GVHD Only 1 case of chronic GVHD (severe) has been reported (median of >400 days follow-up) Conclusions top-line results GVHD ATIR101 is safe Haplo HSCT without any grade III/IV GVHD Overall exposure to ATIR101 Phase I/II + Phase II combined: N=42 Grade III/IV acute GVHD: 0% 15
Top-line results: Transplant Related Mortality, relapse and Overall Survival Results at 100 days, 6 months and 12 months 1 Time after HSCT N = 23 100 days 6 months 12 months Transplant Related 0 3 (13%) 29% Mortality Death due to relapse/disease progression 0 1 (4%) 10.5% Overall Survival 23 (100%) 19 (83%) 64% Primary endpoint: TRM 6-months = 3 / 23 (13%); all infection-related No mortality within first 100 days post-hsct Only two patients relapsed within 12 months post-hsct Relapse at day 61 and 90 post-hsct 1 based on Kaplan-Meier estimates 16
Comparison with control data from an observational cohort study 1 Transplant Related Mortality Overall Survival P=0.005 P=0.0026 HSCT + ATIR101 HSCT + ATIR101 ATIR101 significantly reduces TRM and improves OS compared to CD34+ haplo-transplants 1 Data from cohort study, CR-AIR-006: poster S. Mielke, P442 EBMT2016 17
GRFS 1 Comparing transplant regimens on GRFS GVHD-free/relapse-free survival (GRFS) is survival without: Acute GVHD (grade III/IV) Chronic GVHD Cancer relapse Key advantage HSCT + ATIR101 1 2, 3 No acute GVHD, limited chronic GVHD Low relapse rate Comparison to alternative donor source Improved GRFS compared to one-locus Mismatched Unrelated Donor transplants (MMUD) and to Umbilical Cord Blood (UCB) transplants 1. Haplo + ATIR101 vs MUD* (10/10) p=0.134 2. Haplo + ATIR101 vs MMUD (9/10) p=0.0057 3. Haplo + ATIR101 vs UCB p=0.0014 1 Holtan et al. 2015, Blood 125: 1333-1338 * Matched Unrelated Donor 18
Comparison with literature on post-transplant cyclophosphamide (PTCy) PTCy (Baltimore protocol) Post-HSCT use of high doses of cyclophosphamide (PTCy) is an emerging standard for haploidentical stem cell transplantations Unmanipulated graft used Post-HSCT use of high dose cyclophosphamide to control GVHD Additional use of immunosuppressants (calcineurin inhibitors/mmf) for 6 months Outcome 1 PTCy 2 ATIR101 Grade II/IV agvhd 3 16% 4% Grade III/IV agvhd 3 7% 0 cgvhd 28% 4% NRM 12% 29% Relapse 41% 10.5% OS 65% 64% Patient characteristics: Disease-risk index (DRI) Low risk index 5% 0 Intermediate risk index 63% 43% High risk index 32% 57% 1 Data at 12-months post-hsct (Kaplan-Meier estimates) 2 AML patients, myeloablative conditioning (Ciurea 2015) 3 GVHD at day 90 2 Ciurea et al. 2015, Blood 126: 1033-1040 19
Conclusions Phase II (CR-AIR-007) ATIR101 significantly reduces TRM and improves OS ATIR101 is safe and does not cause grade III/IV GVHD Relapse rates on ATIR101 protocol are very low Improved clinical benefit over 9/10 MMUD or umbilical cord transplants on event-free survival (GRFS) ATIR101 provides a safe and effective, immunosuppressant-free regimen for haploidentical transplantation Substantially less relapse and GVHD on ATIR101 compared to posttransplant cyclophosphamide (PTCy) Second dose of ATIR101 might improve survival even further Kiadis is preparing a randomized Phase III trial comparing haploidentical HSCT with PTCy against a T-depleted HSCT + ATIR101 20
EMA FDA Regulatory strategy update Process of Marketing Authorization Application (MAA) submission started, Rapporteurs appointed Meetings held with Rapporteur and co-rapporteur Decision taken to prepare for MAA filing in 1Q 2017 (awaiting 1 year results CR- AIR-007, dossier writing, completion process validation) New ODD submitted: treatment in hematopoeitic stem cell transplantation (covers all indications) End-of-Phase II meeting held in June 2016 Health Canada Possibility to submit MAA to be discussed 2H 2016 21
Phase III: CR-AIR-009 Phase III design (CR-AIR-009) Randomized, controlled trial Comparing outcome of two haplo-hsct protocols: 1) Kiadis Protocol: T-cell depletion (CD34+ selection) + ATIR101 2) Baltimore Protocol: post HSCT Cyclophosphamide (PTCy) Primary endpoint: GFRS Event-free-survival (EFS) defined as GVHD-free AND Relapse-Free Survival (GRFS) Secondary endpoints: GVHD, NRM, RRM, DFS, OS Estimated sample size: 200 patients total Assumption of EFS of 60% for HSCT+ATIR and 40-45% for control group (PTCy) Trial conduct Global trial: North-America: USA & Canada Europe: Belgium, NL, UK, Germany, France, Italy Estimated number of trial sites: 40-50 End-of-Phase II meeting held with FDA (June 2016) Protocol will be finalized based on feedback Timelines Trial initiation 3Q 2016 First patient in 4Q 2016 Enrollment appr. 1.5 years 2Q 2018 Expected analysis 2Q 2019 22
Route to market in EU & US for ATIR101 FDA Launch Data submission Analysis Phase Trial ID # Patients 2015 2016 2017 2018 2019 2020 Observational cohort trial CR-AIR- 006 157 Establish control group for EMA II (Efficacy trial) CR-AIR- 007 23 Confirm and extend safety and effectiveness II (Repeat administration trial) CR-AIR- 008 10-15 Dosing study III (Pivotal trial) CR-AIR- 009 appr. 200 Pivotal trial randomized, controlled Past Ongoing/planned 23
Route to market in EU & US for ATIR101 Submission EMA and HC 1 Endpoint reported FDA Launch Data submission Analysis Phase Trial ID # Patients 2015 2016 2017 2018 2019 2020 Observational cohort trial CR-AIR- 006 157 Establish control group for EMA II (Efficacy trial) CR-AIR- 007 23 Confirm and extend safety and effectiveness II (Repeat administration trial) CR-AIR- 008 10-15 Dosing study III (Pivotal trial) CR-AIR- 009 appr. 200 Pivotal trial randomized, controlled Past Ongoing/planne d 24
ATIR may be used in additional indications Growth options and market size ATIR Market size (in new patients p.a.) ~ 19,000 ~ 6,000 19,000 TBD Growth options Total potential market Haplo HSCT in blood cancers Thalassemia ATIR201 Cannibalization of cord blood and MUD based HSCT in blood cancers Expansion into: Additional cancer indications Inherited blood disorders Creating chimerism in solid organ transplantation Time 25
ATIR201 in β-thalassemia major: current therapeutic environment Current approaches in β-thalassemia major: Symptomatic approaches (lifelong): Standard of care is symptomatic: blood transfusions and iron chelators Drug support to improve hematopoiesis Curative approaches (by intent): Allogeneic bone marrow transplantation to replace the diseased system: Limited availability of matching donors or healthy sibling donors Significant/high risk of infectious complications and GVHD Gene-therapy based autologous approaches (e.g. Bluebird Bio): Unknown duration of gene expression Unknown level of gene expression Risk of proto-oncogenic insertion of gene into genome 26
Clinical program ATIR201 Collaboration with TIF Awareness on HSCT option (specifically haploidentical) Access to families and to HSCT CR-BD-001 Exploratory Phase I/II trial in pediatric patients with β-thalassemia major ATIR201 as adjuvant to a T-cell depleted haploidentical HSCT Optimize manufacturing for pediatric setting Expected centers: Regensburg (Germany), London, Manchester, Birmingham (UK) Protocol drafted, submissions planned Trial to be initiated in 2H 2016 First results to be expected in 2017, full read-out in 2018 27
Anticipated Company milestones 2016 1H 2016 Topline results announced CR-AIR-007 trial (ATIR101) Set-up US-based ATIR101 manufacturer for Phase III Opening US clinical sites and strengthening US footprint and presence 2H 2016 Read-out (safety) of CR-AIR-008 trial First patient to be enrolled in ATIR101 Phase III trial (CR-AIR-009) Initiation ATIR201 Phase I/II Thalassemia trial (CR-BD-001) Expected submission to EMA for (conditional) approval ATIR101 (Q1, 2017) 28
Financial information Financial highlights Shares listed via an initial public offering (IPO) on Euronext Amsterdam and Euronext Brussels on 2 July 2015 raising gross proceeds of EUR 34.7 million. The equity position of the Company improved significantly and increased to EUR 25.7 million at year-end 2015 compared to EUR 2.7 million at the end of 2014. With net proceeds of EUR 31.2 million raised in the IPO, the Company s cash position improved to EUR 28.7 million at year-end 2015, which is an increase of EUR 23 million compared to cash of EUR 5.7 million at the end of 2014. Operating loss increased to EUR 16 million in 2015 from a loss of EUR 6.2 million in 2014. Operating expenses for 2015 included non-cash share-based payments of EUR 7.8 million. Net loss increased from EUR 7.8 million in 2014 to EUR 16.5 million in 2015. 29
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