Patient-specific immunotherapy T-cell product ATIR

Transcription

1 Patient-specific immunotherapy T-cell product ATIR Unlock full potential of haploidentical hematopoietic stem cell transplantations (HSCT) Company presentation, July 20, 2018 Amsterdam, The Netherlands Euronext (KDS) 1

2 Disclaimer These slides and the accompanying oral presentation contain forward-looking statements and information. Forward-looking statements are subject to known and unknown risks, uncertainties, and other factors that may cause our or our industry s actual results, levels or activity, performance or achievements to be materially different from those anticipated by such statements. The use of words such as may, might, will, should, could, expect, plan, anticipate, believe, estimate, project, intend, future, potential or continue, and other similar expressions are intended to identify forward looking statements. For example, all statements we make regarding (i) the initiation, timing, cost, progress and results of our preclinical and clinical studies and our research and development programs, (ii) our ability to advance product candidates into, and successfully complete, clinical studies, (iii) the timing or likelihood of regulatory filings and approvals, (iv) our ability to develop, manufacture and commercialize our product candidates and to improve the manufacturing process, (v) the rate and degree of market acceptance of our product candidates, (vi) the size and growth potential of the markets for our product candidates and our ability to serve those markets, and (vii) our expectations regarding our ability to obtain and maintain intellectual property protection for our product candidates, are forward looking. All forward-looking statements are based on current estimates, assumptions and expectations by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that we expected. Any forward-looking statement speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. This presentation is not, and nothing in it should be construed as, an offer, invitation or recommendation in respect of our securities, or an offer, invitation or recommendation to sell, or a solicitation of an offer to buy, any of our securities in any jurisdiction. Neither this presentation nor anything in it shall form the basis of any contract or commitment. This presentation is not intended to be relied upon as advice to investors or potential investors and does not take into account the investment objectives, financial situation or needs of any investor. 2

3 Kiadis: Patient specific immunotherapy T-cell product ATIR UNIQUE HAPLO- IDENTICAL HSCT STRONG PHASE 2 DATA CLOSE TO MARKET WORLDWIDE RIGHTS, PREPARING EU LAUNCH LARGE TARGET POPULATION CELL THERAPY & HSCT PLATFORM T-cell product ATIR: haploidentical donor T-cells, depleted of hostreactive T-cells, given after T-cell depleted haploidentical HSCT Clinically meaningful OS benefits over historical control, potential for clinically meaningful benefits over PTCy/Baltimore protocol EMA opinion expected 4Q18; Potential first EU country launch 2H19; FDA RMAT breakthrough designation; Phase 3 vs PTCy enrolling Building own commercialization infrastructure in EU (small number of transplantation sites, worldwide rights retained) 50,000 currently eligible HSCT patients per year; Potential to expand to inherited blood disorders and autoimmune disease Leverage patient specific cell therapy and HSCT platform to expand suite of products HSCT: Hematopoietic Stem Cell Transplantation; GVHD: Graft Versus Host Disease; Haplo: Haploidentical; OS: Overall Survival; 3

4 Kiadis ATIR product: regulatory status (adult blood cancers) Region Phase 1 Phase 2 Phase 3 Filing Potential catalysts Commercial Rights Regulatory Status EU Orphan Drug Designation CHMP opinion (Q4 2018) EU approval (Q1 2019) EU launch (H2 2019) EMA Day 180 List of Issues received (5/2018) USA Orphan Drug & RMAT Designations Phase 3 interim read out (2020; 2/3 of events) RMAT breakthrough designation (9/2017; FDA access, priority review, support) 4

5 Allogeneic Hematopoietic Stem Cell Transplantations (HSCT) Potentially curative: destroy patient s blood/immune system (chemotherapy/radiation), replace with healthy system from donor Inherent risk of Graft versus Host disease (GVHD): donor immune system attacks patient Lack of donors: many patients cannot find matched donor (US 2012: 13,500) Mostly blood cancers (~85%) and adults (84%): potentially also for inherited disorders and autoimmune disease Expensive procedure: around $500,000 (1 year cost; US) Maarten van der Weijden, swimmer: After acute leukemia and HSCT in 2001: Olympic Gold 10 km open water (2008) UK-France-UK double Channel crossing >70km (19 hours; 2017) World distance record 103km (24 hours; 2018) Sources: Broder 2017; Passweg 2018; CIBMTR 2017 summary slides; Besse

6 Graft Versus Host Disease (GVHD): terrible disease Subpopulation of T-cells from donor (i.e. graft) recognize patient tissue (i.e. host) as foreign and attack, mostly due to genetic differences in MHC Class II proteins (major mismatches) Disease Treatment Skin, eye, mouth or GI tract disease Immunodeficiency (infections) Muscle constriction, bone loss, pulmonary disease, thyroid disfunction, solid tumors Sleep deprivation, depression Immunosuppression (steroids, MMF, MTX) The holy grail of HSCT: Give donor T-cells that protect Remove donor T-cells that attack Avoid immunosuppressants Quality of life QoL loss: 27% for severe GVHD (up to 68%) and 20% for moderate GVHD Quality of life with severe GVHD worse than vision impairment, MS, loss of arm/leg, diabetes Impact on patients, donors, families, physicians MMF: mycophenolate mofetil Sources: Jones 2016; Koreth 2013; Lewalle 2003 MTX: methotrexate 6

7 Severe Graft Versus Host Disease (GVHD): high mortality Chronic GVHD severe Acute GVHD grade III/IV 5 year survival: 22% 1 year survival: 24-51% Acute Grade Survival at year 1 Grade III 51% Grade IV 24% Sources: Pidala et al Haematologica (2011); 96(11)

8 HSCT: continued growth due to PTCy/Baltimore protocol (US) Matched Related Donors (MRD) Matched Unrelated Donor (MUD; registries) 13,500 patients could not find matched donor Haploidentical donors Cord blood Matched Donors: Between 25% (White European) and 80% (African American) cannot find a matched donor Haploidentical (half matched) Donors: Motivated donors almost always available (e.g., parent/child); Haploidentical enabled by Post Transplant Cyclophosphamide (PTCy or Baltimore) protocol: Trigger immediate GVHD attack by infusing all T-cells of a haploidentical (half matched) donor, then deplete host-reactive donor T-cells with chemo (cyclophosphamide, day 3 and 5) and immunosuppression Source: CIBMTR 2017 Summary slides; Fuchs 2017; Gragert 2014; Besse

9 PTCy: benefits over MUD, yet still unmet need relapse & GVHD PTCy vs MUD 53% PTCy (up to 3 yr) 51% PTCy (1 year) Average 49% 45% MUD Overall Survival 60% 38% 38% Relapse 29% 26% 27% Relapse Related Mortality (RRM) 18% Acute GVHD II-IV Chronic GVHD Relapse Survival Weighted average of 5 PTCy/MUD comparison publications in the review paper by Fuchs E 2017 that reported AML/MDS/NHL/HL (Ciurea 2015; Rashidi 2016; Burroughs 2008; Kanate 2016; Garciaz 2015); n=463 PTCy and n=2647 MUD patients Non Relapse Mortality (NRM) 22% Acute GVHD grade III/IV 5% Chronic GVHD 24% Chronic GVHD - severe 8% Weigthed average in PTCy publications that reported >50% AML/ALL (Ciurea 2015; Piemontese 2017, Solomon 2012, Ciurea 2012; Devillier 2016; Di Stasi 2014; Esquirol 2016; Sugita 2015); n=571; Chronic GVHD confirmed with other publications PTCy has many advantages over MUD: donor faster available, lower GVHD Still significant unmet medical need: relapse and chronic GVHD, secondary malignancies, toxicity, immunosuppression 9

10 PTCy vs MUD: GVHD-free and Relapse-Free survival (GRFS) McCurdy 2017 (Johns Hopkins, Baltimore) Solh 2016 (Northside, Atlanta) * Haplo and HIDT: both PTCy haploidentical HSCT GVHD-free and Relapse Free Survival (GRFS): Survival without: Acute GVHD grade III/IV Chronic GVHD requiring systemic therapy Relapse 10

11 Haploidentical HSCT: PTCy/Baltimore protocol versus ATIR PTCy/ Baltimore protocol (All T-cells) Conditioning of patient Apheresis of donor, graft infusion Engraftment of donor stem cells Cyclophosphamide and immunosuppression Treat GVHD: kill attacking T-cells in the patient (with chemo and immunosuppression) Haplo HSCT with T-cells (T-cell replete) Haplo HSCT plus ATIR: (Subset of T- cells, depleted of host-reactive T-cells) Apheresis of patient and donor Central ATIR production Produce ATIR 5 days (total 14 days till interim release) Conditioning of patient Apheresis of donor, graft infusion Haplo HSCT without T-cells (T-cell depleted, CD34+) Engraftment of donor stem cells ATIR Infuse ATIR ~30 days after graft infusion Prevent GVHD: kill attacking T-cells outside the patient (without immunosuppression) 11

12 Healthy donor donor ATIR: safe subset of T-cells, aiming to protect, not to attack ATIR TM MANUFACTURING Mix haplo donor T- PROCESS Add TH9402*, which cells with patient accumulates only in cells: host-reactive Step 1 (Day 1 4) activated donor T- Healthy T-cells become cells (MDR pump is donor ATIR ATIR TM MANUFACTURING TM Immune cells are collected and mixed MANUFACTURING activated PROCESS (1-way PROCESS switched off in Mixed Lymphocyte activated T-cells) Step 1 (Day 1 4) Step 2 (Day 5) Step 1 (Day 1 4) Step 2 (Day ` 5) Reaction) ` donor Healthy ATIRPatient TM MANUFACTURING cells PROCESS Healthy Patient cells donor Patient cells inactivated Patient inactivated by radiation by radiation inactivated Immune cells are collected and mixed Immune cells are collected and mixed by radiation Step 1 (Day 1 4) Immune cells are collected and mixed Step 2 (Day 5) Step 2 (Day 5) Expose to green light: TH9402* induces apoptosis: activated and thus host-reactive donor T-cells are killed Step Step 3 (Day 3 (Day 5) ` 5) FEBRUARY Step 3 (Day 5) Step 3 (Day 5) ATIR: remaining potent non-hostreactive donor T- cells (2 million T- cells/kg) FEBR Final ATIR TM FEBR Final Final Step Step - Infusion - Infusion of ATIR101 of ATIR101 Healthy donor Fina Patient Patient patient Patient Patient cells inactivated by radiation Certain T-cells from the donor are activated by the TH9402 is introduced. Mixture is exposed to light. presence of the foreign patient Protect: cells. If not eliminated, Retain protective TH9402 is retained T-cells ONLY in the GvHD-causing to fight T-cells relapse and TH9402 infections is activated by light, causing the these cells would cause GvHD in the patient stained GvHD-causing T-cells to self-destruct Certain T-cells from the donor are activated by the TH9402 introduced. Mixture is exposed to light. The remaining product is infused back Certain T-cells from the donor are activated by the presence of the foreign patient & Not Mixture is exposed to light. cells. If not attack: eliminated, Reduce TH9402 is retained risk TH9402 ONLY in of is introduced. the GvHD-causing GVHD T-cells by depleting TH9402 is activated host-reactive by light, causing the T-cells ex The vivo remaining product is infused back presence of the foreign patient cells. If not eliminated, TH9402 is retained ONLY in the GvHD-causing T-cells TH9402 is activated by light, causing the and helps rebuild their immune system these cells would cause GvHD in the patient stained GvHD-causing T-cells to self-destruct and helps rebuild their immune system these cells would cause GvHD in the patient stained GvHD-causing T-cells to self-destruct to f ght infections and eliminate to f ght infections and eliminate remaining tumor cells remaining tumor cells Patient Pati inac by r The r and h *TH9402 proprietary selective rhodamine derivative, modified to become cytotoxic under green light MANUFACTURING 12

13 ATIR: simplified patient specific supply chain Attractive production process (as compared to CAR-T) 5 day process (total 14 days to interim product release) No genetic engineering (no viral vector production, no BL2) Cleanrooms with LAF cabinets (no bioreactors) Supply chain fits with routine HSCT procedures Ingoing (patient/donor materials): Routine apheresis and fresh shipment (formulated in hypothermosol; 42 hour hold time) Outgoing (final product): Routine frozen shipment and infusion Control over (own) manufacturing Contract manufacturing in Germany, adding CMO capacity Own commercial manufacturing in Netherlands (starting up) 13

14 Kiadis trials: haploidentical HSCT in adult blood cancers Phase 1/2 Phase 2 Phase 3 CR-GVH-001: Single dose ATIR Dose escalation (completed) 19 patients Advanced malignancies AML/ALL 5 year follow up Single site in Canada (CA) Historical controls CR-AIR-004: No ATIR Open label single arm (completed) 44 patients (29 matched to CR-AIR-007*) AML/ALL/MDS Sites in BE, CA, GE, NL, UK, US CR-AIR-006: No ATIR Observational cohort, EBMT registry (completed) 35 patients (all matched to CR-AIR-007*) AML/ALL/MDS 1 year follow up CR-AIR-007: Single dose ATIR Open label single arm (completed) 23/26 patients (MITT/ITT**) AML/ALL/MDS, median age 41 2 year follow up Sites in BE, CA, GE, UK CR-AIR-008: Single dose ATIR and two doses ATIR*** Open label single arm (enrolled, ongoing) 9/11 single dose; 6/6 patients two doses (MITT/ITT**) AML/ALL/MDS 1 year follow up Sites in CA, BE, GE, UK CR-AIR-009: Single dose ATIR Randomized/controlled (ATIR versus PTCy) 2017 (enrolling) 250 patients AML/ALL/MDS Event driven primary endpoint (GRFS) ~50 sites planned CA, Europe, US, Israel All trials: Patients: adult AML/ALL/MDS Conditioning: Myeloablative Graft source: haplo PBMCs HSCT: T-cell depleted (CD34+) ATIR: ~30 days after HSCT * Same in/exclusion criteria and HSCT and overlapping sites; control in accordance with regulatory feedback ** MITT: Modified Intent to Treat (transplanted and ATIR); ITT: Intent to Treat (transplanted) *** CR-AIR-008 was designed to test safety of second dose, but due to higher then expected GVHD it was decided to stop infusing second dose (in accordance with protocol) 14

15 ATIR: improved Overall Survival (OS; ITT, single dose; 1yr) T-cell depleted (CD34+) with ATIR (n=37)* T-cell depleted (CD34+) without ATIR (n=64)* OS 1 yr: 58% [44-77**] *ITT (intention to treat): all patients undergoing T-cell depleted CD34+ HSCT; SD: single dose; All clinical studies have similar patient characteristics and treatment sites; CR-AIR-008 status 1 June 2018 (3 patients at risk) ** 95% confidence interval [ ] OS 1 yr: 23% [14-37**] P=0.005 ( vs ) 15

16 ATIR: improved OS & NRM, low GVHD & relapse (ITT, single dose) T-cell depleted (CD34+) with ATIR (n=37)* T-cell depleted (CD34+) without ATIR (n=64)* CR-AIR-007 CR-AIR CR-AIR-006 CR-AIR single dose single dose single dose control control control 1 year post HSCT (ITT n=26) (ITT n=11) (ITT n=37) (n=35) (n=29) (n=64) Overall survival 58% [42-80] 64% [41-100] 58% [44-77] 20% [10-39] 27% [13-54] 23% [14-37] Non-relapse mortality 35% 27% 33% 66% 59% 63% Relapse-related mortality 8% 9% 8% 15% 14% 14% Relapse 8% 9% 8% NA NA NA ATIR after T-cell depleted HSCT: Improve OS and NRM, Retain low chronic GVHD & relapse Acute GVHD grade II-IV 19% 27% 21% 20% 18% 19% Acute GVHD grade III-IV 0% 18% 5% 6% 7% 6% Chronic GVHD 4% 0% 3% 11% 5% 8% Chronic GVHD severe 0% 0% 0% 9% 5% 7% 6 months post HSCT (MITT n=23) (MITT n=9) (MITT n=32) (n=35) (n=29) (n=64) P-values for vs : OS (0-12 month) p=0.005 NRM (0-6 month) p= 0.02 Non-relapse mortality 13% [0-27] 11% [0-29] 13% [0-24] 37% [19-51] 35% [15-51] 36% [23-47] Notes: NRM at 6 months primary endpoint of CR-AIR-007; Kaplan-Meier estimates for OS and NRM at 6 months; all other estimates cumulative incidence analyses; ITT: patients receiving HSCT; MITT: patients receiving HSCT and ATIR; OS: overall survival; CR-AIR-008 status 1 June 2018 (3 patients at risk) 16

17 Phase 3 (CR-AIR-009) study design: ATIR and PTCy GRFS GRFS in PTCy literature: 30-40% Solh 2016 (n=126) McCurdy 2017 (n=372) Santoro 2017 (n=208) GRFS with ATIR (ITT): 53% [39-72] Sites included Atlanta (single site) Johns Hopkins (single site) 69 EBMT sites Patients AML/ALL/MDS/ NHL/HL, CML AML/ALL/MDS/ NHL/HL, MM ALL GRFS 1-yr [95% CI] Disease risk index (DRI)* 33% [25,41] 20% low 40% intermediate 40% high/v. high 45% [40,50] 14% low 67% intermediate 19% high/v. high 33% (average) Not available 1-year estimates [95% CI]: % [38-77] 008 SD 55% [32-94] SD 53% [39-72] Normalized GRFS 1-yr* 30% 40% Not available 250 patients in CR-AIR-009: 80% power to detect 16% GRFS difference * Normalized by adjusting based on the average DRI of the CR-AIR-007/008 patient population (57% intermediate risk; 43% high/very high risk); using the hazard rates per DRI as reported in the Solh/McCurdy publications (2 patients in Solh for which DRI not known excluded); DRI is an important prognostic factor for OS,: e.g., NHL patient in CR1 is low risk, AML in CR2 is very high risk (Armand 2014); CR-AIR-008 status 1 June 2018 (3 patients at risk) 17

18 Phase 3 (CR-AIR-009): ATIR vs. PTCy/Baltimore protocol Objectives: demonstrate superior clinical benefit and collect pharmacoeconomic data Randomized Controlled (1:1) R HSCT plus ATIR: T-cell deplete CD34+ HSCT plus single dose ATIR 2 mln cells/kg at ~30 days 250 adult patients with AML, ALL or MDS PTCy/Baltimore protocol: T-cell replete HSCT with 50 mg/kg cyclophosphamide at days 3 and 5 post HSCT & prophylactic immunosuppressants Primary endpoint: GVHD-Free and Relapse- Free Survival (GRFS); Interim analysis: at 2/3 of events (17,6% GRFS treatment effect, hazard ratio 0.61) Primary analysis: at 156 events (11,4% GRFS treatment effect, hazard ratio 0.73) Secondary endpoints: Overall Survival (OS), Progression Free Survival (PFS), Relapse, Non Relapse Mortality (NRM) Other: Randomization at enrollment; Balanced conditioning regimens in ATIR/PTCy arms; Stratification for Disease Risk Index, underlying disease and treatment site 50 sites in US, Canada, EU & Israel; multiple open in Canada and EU; Enrolling patients (since December 2017) 18

19 Allogeneic Potential future Hematopoietic studies with Stem ATIR Cell Transplantations (HSCT) Pediatric blood cancers (EMA Pediatric Investigation Plan deferral obtained) ATIR as adjunctive after other haploidentical HSCT protocols, e.g. PTCy/Baltimore protocol α/β T-cell depleted protocol Other (RIC/MA) conditioning regimens Other HSCT indications, e.g. Inherited blood disorders (e.g. thalassemia or sickle cell anemia) Inherited immune disorders (e.g. severe combined immunodeficiency) Autoimmune disease (e.g. multiple sclerosis or lupus) 19

20 Potential: 50,000 annual patients US/EU (based on 2016) Continuation of current growth of haploidentical (3-fold in US in ) 33,500 50,500 20,000 30,800 EU US 13,200* 13, , Haploidentical now (2016) Cannibalize Matched Unrelated & cord blood donors (2016) Haplo donor available to almost all eligible patients** Total potential (based on current number of eligible patients) * 20% of MUDs are partially matched or Mismatched MUDs (MMUD) with worse outcomes & thus first candidates for cannibalization by Haplo ** US: 13,500 patients that could not find matched donor in 2012 (Besse 2015); EU rough estimation by extrapolation from US based on EU population Source: CIBMTR summary slides 2017, Passweg 2017, Besse

21 Potential: > 50% adoption based on GRFS benefit (survey) Market survey among 100 US/EU clinicians (2013): In what percent of your haplo s would you use ATIR given strong Phase 3 data and formal approval? EU US 58% 55% Potential adoption of >50% in US based on GRFS benefit confirmed by 2018 market survey: 9 clinicians representing 27% of US HSCTs ATIR product profile presented: 18% GRFS benefit over PTCy (with or without 5% OS benefit) Source: ATIR Assessment, September 2013 by Defined Health, based on Phase 1 data: 100 transplant physicians/kols (50/50 US/EU; eg Harvard, Johns Hopkins, MD Anderson, Stanford, Dresden, Saint Antoine); July 2018 by Simon Kucher 21

22 Potential: independent commercialization Europe: 63 sites in EU4 US: Top 25 sites perform 65% of HSCTs GE IT FR UK Shortened dossier to G-BA via AMNOG (until sales > 50M) L-648 (named patient basis); P&R Dossier to AIFA/CTS at MAA ATU (named patient basis); HAS/CEPS filing at MAA NICE evaluation; Interim funding potentially via Cancer Drug Fund Source: Simon Kucher survey Building medical affairs, market access, commercial, supply chain and manufacturing infrastructure (EU first) 22

23 Protection: patents, orphan drug designation, know how Patents (owned/ licensed) Orphan drug designation Proprietary know how and infrastructure Methods for reducing GVHD (expiring October 2021) More rhodamine derivatives (expiring January 2024) Improved photodynamic process (expiring February 2036 if granted) US (7 years from launch): for prevention of GVHD or TRM EU (10 years from launch): for treatment in HSCT regardless of disease, for treatment of AML, for prevention of GVHD Manufacturing critical process parameters Release assays based on critical quality attributes Cell handling, storage, formulation and shipment Patient specific supply chain with HSCT clinics (IT, relationships, service) Multiple barriers to entry for competition, many similarities with biologics/biosimilars 23

24 Kiadis: company at a glance ORGANIZATION SHAREHOLDERS FINANCIALS (July 13, 2018) Management team: track record in building biotech and in haemonc and cell therapy late stage development and commercialization from Crucell, Medivation, Dendreon, J&J, AstraZeneca, McKinsey Supervisory board: Novartis ExCom; Actelion COO; Prosensa/Jerini CFO; Dana Farber chief of HSCT & haemonc and board member of NMDP/BeTheMatch Euronext Amsterdam/Brussels, IPO in 2015 Major shareholders (>5%): Life Sciences Partners, Lenildis Holding, Esprit Market cap: ~$240M / 200M 20,1 million shares outstanding Raised > 60M in equity & debt since June 2017 Cash 47.7M end March 18; Cash runway into Q

25 Kiadis: track record late stage development and commercial Arthur Lahr (April 2017) Chief Executive Officer Chief Strategy Officer Crucell (BD, M&A, M&S); Supervisory Board Sanquin; McKinsey; Unilever Andrew Sandler (Oct 2017) Chief Medical Officer SVP Medical Affairs Medivation; CMO Dendreon and Spectrum Pharma; Bayer; Berlex; Seattle Genetics; Board certified medical oncologist Robbert van Heekeren Chief Financial Officer Head Global Finance & Control Akzo/Organon Jan Feijen (April 2017) Chief Operations Officer EVP Operations J&J Vaccines and VP Manufacturing and Ops J&J Vaccines & Advanced Therapies; VP Crucell Asia; Managing Director Operations Avebe; Gist-Brocades Karl Hård (Sept 2017) Head IR & communications Head investor relations AstraZeneca; 10 years investor relations; 10 years pharma R&D; Assistant Professor chemistry James Joy (July 2018) General Counsel Group General Counsel TomTom; VP Legal and Compliance Royal Ahold; General Counsel Navigator Asset Management; Norton Rose; Latham & Watkins; Member New York State Bar 25

26 Kiadis key milestones and upcoming catalysts EMA submission of ATIR for marketing authorization approval First patient enrolled for ATIR Phase 3 FDA Regenerative Medicine Advanced Therapy (RMAT) designation Secured own commercial manufacturing facility Completion of enrollment of second Phase 2 (CR-AIR-008) Submission of answers to EMA Day 120 questions (End Q1) Submission of answers to EMA Day 180 List of Issues (Q3) Potential EMA CHMP opinion (Q4) Updates Phase 2 data and Phase 3 enrollment Potential approval of ATIR by the European Commission (Q1) Potential initial commercial launch of ATIR in first EU countries (H2) Initiate trial with ATIR as adjunctive to PTCy (H2) Potential reimbursement and commercial roll out across EU countries (H1) Potential interim read out Phase 3 (at 2/3 of GRFS events) (H2) 26

27 Practice two things in your dealings with disease: either help or do not harm the patient Epidemics, Book I, of the Hippocratic school I will prevent disease whenever I can but I will always look for a path to a cure for all diseases Hippocratic oath, Louis Lasagna, Academic Dean of the School of Medicine at Tufts University (1964) 27

28 Attachments 28

29 Haploidentical HSCT approaches Haplo HSCT Haplo T-cell Product (after HSCT) GVHD Treatment/ Prophylaxis Approach ATIR (Kiadis) T-cell depleted (CD34+) Subset of T-cells, depleted of hostreactive T-cells No immunosuppressant Prevent GVHD Zalmoxis (MolMed) BPX-501 (Bellicum) T-cell depleted (CD34+ and αβt-cell depleted) All T-cells (including host-reactive T-cells), engineered with suicide gene Eliminate host-reactive T-cells by infusing suicide agent, if GVHD occurs Treat GVHD PTCy or Baltimore protocol T-cell replete (All T-cells, including alloreactive T-cells) Post Transplant Cyclophosphamide & immunosuppressants Treat GVHD Table provided for illustrative purposes, not for direct comparison 29

30 Molmed/Bellicum: January 2018 (1 year) Patients Survival* Relapse NRM Status EMA Zalmoxis** (MolMed) Adult Approval Q BPX-501 (Bellicum) Pediatric Submission 2019 Product (Matched) Historical Control Zalmoxis pricing/dose*** (1-4 doses per patient): Germany: 163,900 Italy: 149,000 Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials * Leukemia Free Survival for BPX-501 (BPX-501 Overall Survival is 89%, Overall Survival not reported for controls); ** CD34+ HSCT; 74% AML; 10% ALL; 16%MDS/NHL/HD; patients receiving Zalmoxis (MITT= 36 patients) *** Prices as at 16 January 2018 and 13 December 2017, respectively; subject to negotiation with GBA in Germany Source: CHMP Assessment report (Zalmoxis); Merli EHA 2017 (BPX-501); Locatelli 2017 (BPX-501) 30

31 CR-GVH-001: Overall Survival (5 years) Patients: 19 with advanced hematological malignancies (14 not in remission at transplant) ATIR101 doses: 10k cells/kg to 5 mln cells/kg; median of 31 days after HSCT Results: 67% Overall Survival at middle dose level after 5 years No acute GVHD grade III/IV related to ATIR101 at any dose 100% 80% 60% 40% 20% 0% Overall Survival (OS) 9 patients, 320k- 2M cells/kg Dose L4-L6 3 patients; 2,6-5M cells/kg) Dose L7 7 patients, 10- Dose 130k cells/kg L1-L Time after HSCT (months) Note: an unmanipulated donor lymphocyte infusion from a haploidentical donor Source: Lewalle 2003 that still contains all T-cells may cause GVHD at significantly lower doses of 10,000 cells/kg 31

32 CR-AIR-007: Outcomes (2 years, MITT) primary and secondary efficacy endpoints in CR-AIR-007, MITT Kaplan Meijer estimates 6 months 12 months 24 months... Non Relapse Mortality 13% 32% 48%... Relapse Related Mortality 5% 10% 25%... Progression Free Survival 78% 61% 39%... Overall Survival 83% 61% 39% Outcome No. of pts Cause of death < 6 months 6-12 months months RRM 1 TRM Infections 2 Adenovirus and JC virus infections TRM Other 1 Pulmonary embolism RRM 1 TRM Infections 3 Respiratory/pulmonary infections/distress TRM Other 1 Multi-organ failure RRM 2 TRM-Infections 3 * Pneumonia/sepsis/septic shock * All 3 patients immunosuppressed, subsequently contracted infections, leading to death: 2 patients who received un-manipulated DLI s in 2 nd year after HSCT and subsequently developed severe acute GVHD; 1 patient with chronic GVHD 32

33 Proliferation Index (PI) ATIR: alloreactive T-cells depleted, potency retained 12 6 Donor ATIR * Autologous Recipient 3 rd Party CD3/28 Functional release assay based on Quality Target Product Profile & Critical Quality Attributes Control: no donor reactivity Safety: depleted allo-reactivity Potency: other reactivity retained Source: Bonig ISCT

34 Healthcare costs of allogeneic HSCTs and complications (US) Total HSCT costs* $402,000 (MA) $301,000 (RIC) $549,000 (MA) $432,000 (RIC) Period / Source 100 days; Broder year; Broder 2017 $893, days; Milliman 2017** HSCT complications Cancer death $165,000 Relapse $69,000*** Hemorrhagic cystitis Acute GVHD $324,000 Chronic GVHD moderate/mild Chronic GVHD severe Costs to healthcare system $242,000***/**** $124,000 ($14,400 per year*****) $322,000 ($37,400 per year*****) * Includes Inpatient/Outpatient/pharmacy costs: MA: myeloablative conditioning; RIC: reduced intensity conditioning ** Includes different physician charges, graft procurement costs *** Cost based on Broder total cost and cost multiplier Khera **** Side effect of PTCy protocol **** 10 years, discounted Sources: Mariotto 2011; Yu 2017; Broder 2017; Khera 2014; Milliman 2017; Svan 2006; literature PTCy analysis 34

35 so that many more patients with otherwise incurable diseases will have a reasonable chance of long survival and cure Dr. E. Donnall Thomas established bone marrow transplantation as a treatment for leukemia Nobel Lecture