Help patients with immunotherapy designed to reduce risk of GVHD in stem cell transplantations

Transcription

1 Help patients with immunotherapy designed to reduce risk of GVHD in stem cell transplantations Unlock full potential of haploidentical hematopoietic stem cell transplantations (HSCT), with allo-depleted T-cell product ATIR Company presentation, February 25, 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 Novel cell therapies establishing themselves Selected companies Product Status Company valuation Kymriah (list price $475,000) Yescarta (list price $373,000) liso-cel darvadstrocel FDA approved FDA approved Potential FDA filing 2H 2018 EMA positive CHMP opinion $11.9bn 8/2017 acquisition by Gilead $9.0bn 1/2018 offer by Celgene $596M 12/2017 acquisition by Takeda tabelecleucel Phase 3 $1.7bn* market capitalization 1/2018 $128m capital raise * As of market close February 13,

4 The very first cell therapy: allogeneic HSCT Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Curative intent: replace disease blood/immune system with healthy one from donor Risk of Graft versus Host disease (GVHD): Donor immune system attacks the patient Disease indications for allogeneic HSCT in Europe in 2015 IDM, 0.8% PID, 3% AID, 0.1% Thal/sickle, 3% Others, 1% BMF, 5% Solid tumors, 0.2% PCD, 7.1% NHL, 4% HD, 3% AML, 39% (early AML 21%, advanced AML 12%, transformed AML 6%) Mostly blood cancers (85%) and adults (82%) CLL, 2% ALL, 16% CML, 2% MPN, 35% 3% MDS/MPN, 12% Adoption of HSCT limited by high risk Blood cancers: Only 20-30% long term GVHD-Free and Relapse-Free Survival (GRFS) Inherited blood disorders or autoimmune disease: Risk of replacing chronic disease with (chronic) GVHD Source: Solh 2017; McCurdy 2017; Broder 2017; Passweg 2017; CIBMTR 2016 summary slides; Besse

5 Kiadis: aim to enable HSCT with reduced risk of GVHD FUNDAMENTALLY SAFER HSCT STRONG PATIENT BENEFIT CLOSE TO MARKET ATTRACTIVE BUSINESS OPPORTUNITY PLATFORM FOR GROWTH ATIR allo-depleted T-Cell product, given after HSCT, designed to reduce risk of GVHD, can unlock full HSCT potential Improvement in GVHD-Free and Relapse-Free Survival (GRFS) vs. literature for PTCy/Baltimore protocol EMA potential approval 4Q18 (CHMP); Potential initial EU launch 2H19; FDA RMAT breakthrough designation; Phase 3 enrolling Potential >27,900 target patients per year; Sustainable; Attractive economics vs. CAR-T Ability to leverage cell therapy infrastructure: manufacturing, supply chain, medical, commercial 5

6 HSCT challenge: give potent donor T-cells, yet avoid GVHD Donor stem cells (CD34+) Stem cells engraft in patient bone marrow: create blood and immune system But, stem cells alone not enough: T-cells take 6-12 months to re-emerge from stem cells; survival without T-cells 10-20% Immunosuppressants (reduce GVHD, but hamper engraftment and protection) Donor T-cells (CD3+) Protect against viruses and tumor cells Attack patient tissue Source: Walker 2004 The holy grail of HSCT: Give donor T-cells that protect Remove donor T-cells that attack Avoid immunosuppressants 6

7 Graft Versus Host Disease (GVHD): a terrible disease Subpopulation of mature T-cells from donor attack antigenically foreign antigens on patient tissues, due to genetic differences between patient and donor (MHC Class II proteins) Types Organs Manifestations Effects Treatment Acute: can be life threatening (grade III/IV) Chronic: can be severely debilitating Skin, mouth, eyes, liver, GI tract, lungs Scleroderma, rash, ulceration, erythema, cirrhosis, immunodeficiency Skin disease, infections, muscle constriction, bone loss, pulmonary disease, thyroid disfunction, ophthalmology, solid tumors, sleep deprivation, depression Immunosuppression (steroids, MMF, MTX) MMF: mycophenolate mofetil Source: Jones 2016; Koreth 2013 MTX: methotrexate 7

8 HSCT: Strong growth, still large unmet need Unmet need: 13,000 per year (lack of matched donors) Matched Related Donors (MRD) Matched Unrelated Donor (MUD; registries) Haploidentical donors Historical: Matched Related or Unrelated Donors Donor availability 20-80% (due to family size & genetic diversity) Declining, despite unmet need Emerging: Haploidentical or half matched donors Donor availability >95% (parents/children) 32% compound annual growth Made possible due to Post Transplant Cyclophosphamide (PTCy) or Baltimore protocol* * Cyclophosphamide (chemotherapy, days 3 and 5) & immunosuppressants to treat immediate attack from alloreactive haploidentical donor T-cells Source: CIBMTR 2017 Summary slides; Fuchs 2017; Gragert 2014; Besse

9 Haplo PTCy/Baltimore vs MUD: improved GVHD, worse relapse 38% 53% 26% 27% 38% 45% 51% 49% 'Average' Matched Unrelated Donor Acute GVHD II-IV Chronic GVHD Relapse Survival 'Average' Haploidentical (PTCy)* Post Transplant Cyclophosphamide (PTCy or Baltimore protocol): Trigger immediate GVHD attack by activation of half-matched donor T-cells in the patient, treated with chemotherapy on days 3&5 and immunosuppressants Lower GVHD for PTCy than MUD (ie effective depletion of alloreactive T-cells) Higher relapse for PTCy than MUD (ie also depleting protective T-Cells) * Not a true average: Mix of indications (AML, NHL, HL), follow up (1.5, 2 and 3 yr) and patient populations; analysis based on ratio within each of the publications in the review paper shows similar results Source: Fuchs E 2017 MUD: Matched Unrelated Donor 9

10 Kiadis: potential improvement versus PTCy/Baltimore Haplo HSCT 30 days after Haplo HSCT GVHD Treatment/ Prophylaxis Approach Kiadis T-cell depleted ( safe stem cells) ATIR: subset of T- cells, depleted of alloreactive T-cells ( safe T cells) No prophylactic immunosuppressant Prevent GVHD PTCy or Baltimore protocol T-cell replete (stem cells plus all T-cells) Chemo (cyclophosphamide) & immunosuppressants to treat immediate attack from alloreactive donor T-cells Treat GVHD Kiadis: reduce risk of GVHD: give T-cells that protect; not T-cells that attack Table provided for illustrative purposes, not for direct comparison 10

11 ATIR: outpatient infused drug; add on to HSCT HSCT Conditioning of patient Apheresis of donor, graft infusion Engraftment of donor stem cells ATIR (add on to HSCT) Apheresis of patient and donor Central ATIR production, 5 day process Infusion of ATIR 14 days before HSCT ~30 days after HSCT 11

12 ATIR production: subset of T-cells that protect, but not attack donor Healthy donor Mix patient cells & haplo donor T-cells: alloreactive donor T-cells become activated (Mixed Lymphocyte Step 1 (Day 1 4) Reaction) ` Immune cells are collected and mixed Add TH9402*, which accumulates only in activated T-cells (MDR pump is switched off in activated T-cells) Step 2 (Day `5) Expose to green light: TH9402* induces apoptosis: activated and thus alloreactive T-cells are killed ` Step 3 (Day 5) ATIR: remaining potent nonalloreactive donor T-cells, infused on day after HSCT Patient cells inactivated by radiation Patient patient Protect: Retain protective T-cells to fight relapse and infections & Not attack: Reduce risk of GVHD by depleting alloreactive T-cells ex vivo *TH9402 proprietary selective rhodamine derivative, modified to become cytotoxic under green light 12

13 ATIR production: fast & simple, own facility secured ü 5 day process ü No genetic engineering (No viral vector production/transfection) ü Clean rooms with LAF cabinets (No BL2; No bioreactors) ü 42 hour hold time for ingoing material, final product frozen down Lower COGS per batch and capex compared to e.g. CAR-T ü Own commercial manufacturing facility secured (lease) 13

14 ATIR: Past and current clinical trials in blood cancers ATIR as add on to haploidential CD34+ HSCT AML/ALL/MDS Phase 1 Phase 2 Phase 3 CR-GVH-001 Dose finding 19 patients; Complete CR-AIR-006 Historic observational cohort (control) 35 patients; Complete CR-AIR-009 Randomized/controlled 195 patients; Enrolling CR-AIR-007 Open label single arm efficacy 23 patients; Complete CR-AIR patients only 1 st dose; 6 patients also 2 nd dose 15 patients; Enrolment complete 14

15 Phase 2 (007): potent T-cell product, yet low GVHD (1 yr) Improved Overall Survival due to ATIR 61% 20% CD34+ stem cells with ATIR 3x Low GVHD due to ATIR no acute grade III/IV 3 acute grade II (13%) 1 chronic (4%) 007: Haplo CD34+ plus single dose ATIR Open label single arm AML/ALL patients receiving ATIR (MITT) 4 sites Canada/EU Dose 2 million cells/kg* 006: Haplo CD34+ CD34+ stem cells without ATIR Historical observational cohort patients, similar indications/sites Protocol based on EMA scientific advice 2 million cells/kg of potent T-cells: increasing survival 3x, yet low GVHD** No need for prophylactic immunosuppression * Non allodepleted donor lymphocyte infusion can cause severe GVHD at 10,000 cells/kg 15

16 Phase 2 (007): relapse & GVHD vs literature for PTCy (1 yr) Overall Survival 61% 60% 57% Relapse and NRM* 29% 30% 22% GVHD 24% ATIR Phase 2, 007 (MITT, n=23) PTCy/Baltimore Literature, at least 50% AML/ALL*** (n=571) Overall Survival 9% Relapse Non Relapse Mortality 5% 0% 0% Acute GVHD III/IV 8%** Severe Chronic GVHD 4% Chronic GVHD PTCy/Baltimore Literature, adjusted for DRI**** (n=561) PTCy: results from EBMT/CIBMTR databases, Johns Hopkins (Baltimore) and Northside (Atlanta) Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials * PTCy: Relapse: of which 11% relapsed and 18% relapsed and died ** Solomon 2012; Ciurea 2012; Esquirol 2016 *** Ciurea 2015; Piemontese 2017, Solomon 2012, Ciurea 2012; Devillier 2016; Di Stasi 2014; Esquirol 2016; Sugita 2015 **** Ciurea 2015; McCurdy 2017, Devillier 2016, Sugita 2015 (normalization based on Armand 2014); DRI CR-AIR-AIR-007: 53% high/47% intermediate 16

17 Phase 2 (007): GRFS versus literature for PTCy/Baltimore (1 yr) GVHD-Free and Relapse-Free Survival (GRFS) 57% 36% Composite endpoint, capturing survival and future outlook Defined as survival without: Chronic GVHD requiring immunosuppression Acute grade III/IV GVHD Relapse ATIR GRFSPTCy/ Phase 2 Baltimore 007 DRI (MITT; adjusted* n=23) (n=500) PTCy: single site results from Johns Hopkins (Baltimore) and Northside (Atlanta) Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials * Solh 2016 (Atlanta; DRI normalized GRFS 30%; n=128); McCurdy 2017 (Johns Hopkins; DRI normalized GRFS 38%; n=372) 17

18 Future options for patients: ATIR after CD34+ or after PTCy Overall Survival (OS) GVHD Stem cells (CD34+; Phase 2) 20 % + ATIR 61% PTCy/ Baltimore (literature*) 57 % +ATIR? future study Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials * Ciurea 2015; McCurdy 2017, Devillier 2016, Sugita 2015 (normalization based on Armand 2014); DRI CR-AIR-AIR-007: 53% high/47% intermediate 18

19 Filed in EU & received breakthrough in US, based on Phase 2 EMA (EU) Marketing Authorization Application filed, potential (conditional) approval Q ATMP certificate for quality and non-clinical data in 2015 Pediatric Investigation Plan agreed Phase 2 and historical control accepted for filing and review* Day 120 questions received, adequate response end Q FDA (US) Regenerative Medicine Advanced Therapy designation received (same benefits as Breakthrough) Increased access to FDA (not limited to customary timepoints) Possibility for priority/rolling review of BLA Development support (program/endpoints) * Various hemato-oncology products EMA (conditionally) approved based on Phase 2, e.g., Zalmoxis (MolMed, 36 patients, versus matched historical control), Blincyto, Venclexta, Bosulif 19

20 Phase 3 (009): ATIR vs. PTCy/Baltimore protocol Objectives: demonstrate superior clinical benefit and collect pharmacoeconomical data (cost, days in hospital, incidence of severe infections and quality of life) Randomized Controlled (1:1) R HSCT plus ATIR: CD34+ HSCT + single dose ATIR patients* with acute leukemia or MDS sites in US, Canada and EU PTCy/Baltimore protocol: post-hsct cyclophosphamide & immunosuppressant Primary endpoint: GVHD-Free and Relapse-Free Survival (GRFS**) Secondary endpoints: OS, Progression Free Survival, Relapse Related Mortality, Transplant Related Mortality Event driven: Primary analysis at 93 GRFS events, Interim analysis at half GRFS events Aligned with FDA and regulators in EU; Enrolling patients * 80% powered to detect 20% GRSF difference; 15% difference will be statistically significant; allowed under protocol to increase sample size; 245 pts would give 80% power to detect 18% difference ** Survival without chronic GVHD requiring immunosuppression, acute grade III/IV GVHD or relapse 20

21 ATIR potential: target >27,900 annual patients US/EU Growth haploidentical HSCT: Historic 32% compound annual growth with PTCy; potential for acceleration upon increased benefits of ATIR TBD >27,900 12,000 13,000 (US*) 2,900 Haploidentical transplants 2016** Unmet need (lack of matched donors) Matched Unrelated Donor Blood disorders, auto-immune disease Potential haploidentical transplants * EU Not Known; ** EU 2000, US 900 Provided for illustrative purposes Source: CIBMTR summary slides 2017, Passweg 2017, Besse 2015; 21

22 Reduce risk of (severe) GVHD and relapse Risk with PTCy Risk with ATIR Death 50% five year mortality for severe chronic GVHD 1 in 4 1 in 12 Overall chronic GVHD Severe chronic GVHD 1 in 28 0 Quality of life QALY 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 1 in 3 Relapse 1 in 9 Loss of income 75% of patients lose 3 years of earnings 25% of patients permanently lose earnings 22

23 ATIR market survey 100 US/EU KOLs (2013) EU US In what percent of your haplo s would you use ATIR given strong Phase 3 data and formal approval? 58% 55% It s got to show an advantage over PTCy somewhere. I m not saying necessarily superiority of survival but even if there s a superiority in terms of infection rate, it s got to show that it s better in some respect Note: Needs to be updated 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) 23

24 ATIR potential reimbursement: drug, separate from HSCT ATIR (Medicare: Part B, J-code) HSCT (Medicare: MS-DRG-14) Outpatient infused drug (~30 days after HSCT, 1-2 weeks after end of hospitalization); no hospitalization for infusion* Cost of drug billed to payer ( buy & bill, mark up for physician); Apheresis reimbursed via procedure code or bundled into ATIR Examples: Checkpoint inhibitors Covers HSCT procedure, including hospitalizations and follow ups Additional CD34 selection already routinely reimbursed within DRG Cost savings to hospital due to reduced use of cyclophosphamide and AEs (e.g., Hemorrhagic cystitis) Likely differentiated from CAR-T* CAR-T SAEs require hospitalization and thus inpatient/drg Source: interviews 24

25 ATIR protection: patents, orphan drug, know how Patents (owned/ licensed) Orphan drug designation Proprietary know how Methods for reducing GVHD including composition (P015; October 2021) More rhodamine derivatives (P019; January 2024) Improved photodynamic process (P040; 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 and communication Biosimilar unfeasible: head to head comparative trial not possible for patient specific cell therapy product 25

26 Kiadis management: track record commercial/medical/ops Arthur Lahr (April 2017) Chief Executive Officer Chief Strategy Officer Crucell (8 years; head BD, M&A, M&S US/EU); Supervisory Board Sanquin (Dutch blood bank); 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 Organon Karl Hård (Sept 2017) Head IR & communications Head investor relations AstraZeneca; 10 years investor relations; 10 years pharma R&D; Assistant Professor chemistry 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 Margot Hoppe General Counsel 20+ years in corporate legal, including Gist-Brocades, DSM 26

27 Kiadis: company at a glance ORGANIZATION SHAREHOLDERS FINANCIALS (February 21, 2018) Management track record operations, development and commercial (Crucell, Medivation, J&J, AstraZeneca, Organon, DSM, McKinsey) Strong supervisory board (Cipla CEO/Novartis ExCom; Actelion COO, Prosensa/Jerini CFO; Prof Dana Farber) Euronext Amsterdam/Brussels, listed in 2015 Major shareholders (>5%): LSP, Draper Esprit, Alta Analysts: Jefferies, Canaccord, Oppenheimer, Chardan, KBC, Kempen, LifeSci Market cap: ~$248M / 202M 17.5 million shares outstanding Raised 40M in equity & debt since June 2017; 77M in/since IPO 27

28 Kiadis key (potential) milestones EMA submission of ATIR for marketing authorization approval First patient enrolled for ATIR Phase 3 Updates enrollment, regulatory, new clinical sites FDA Regenerative Medicine Advanced Therapy designation Secured own commercial manufacturing facility (lease) New management and supervisory board members Completion of enrolment of second Phase 2 (CR-AIR-008) Submission of answers to EMA Day 120 questions (End Q1) Potential (conditional) EMA approval in EU (CHMP opinion, Q4) Updates Phase 2 data and Phase 3 enrollment Potential initial commercial launch ATIR in first of EU5 countries (H2) Initiate trial with ATIR as adjunctive to PTCy Potential interim read out Phase 3 (extra) (extra) (extra) 28

29 Kiadis: aim to enable HSCT with reduced risk of GVHD FUNDAMENTALLY SAFER HSCT STRONG PATIENT BENEFIT CLOSE TO MARKET ATTRACTIVE BUSINESS OPPORTUNITY PLATFORM FOR GROWTH ATIR allo-depleted T-Cell product, given after HSCT, designed to reduce risk of GVHD, can unlock full HSCT potential Improvement in GVHD-Free and Relapse-Free Survival (GRFS) vs. literature for PTCy/Baltimore protocol EMA potential approval 4Q18 (CHMP); Potential initial EU launch 2H19; FDA RMAT breakthrough designation; Phase 3 enrolling Potential >27,900 target patients per year; Sustainable; Attractive economics vs. CAR-T Ability to leverage cell therapy infrastructure: manufacturing, supply chain, medical, commercial 29

30 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) 30

31 Attachments 31

32 Additional information Competition Pricing ATIR product characteristics Clinical trial information Disease Risk Index adjustment for literature comparisons 32

33 Comparison Kiadis with MolMed/Bellicum Haplo HSCT Haplo donor T-cell Product (after HSCT) GVHD Treatment/ Prophylaxis (in patient) Approach to GVHD ATIR (Kiadis) T-cell depleted Safe subset of T- cells, depleted of alloreactive T-cells No prophylactic immunosuppressant Prevent Zalmoxis (MolMed) BPX-501 (Bellicum) T-cell depleted All T-cells, but engineered with suicide gene Eliminate activated T-cells by infusing suicide agent, if GVHD occurs Treat PTCy or Baltimore protocol T-cell replete (All T-cells) Post Transplant Cyclophosphamide & immunosuppressants Treat Table provided for illustrative purposes, not for direct comparison 33

34 Competitive overview available data January 2018 (1 year) Patients Effect of product* Survival** Relapse NRM Status EMA ATIR (Kiadis) Adult 3.0x Potential CHMP Q Zalmoxis (MolMed) Adult Approval Q BPX-501 (Bellicum) Pediatric 1.1x Submission 2019 Product (Matched) Historical Control MUD or PTCy*** Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials * ATIR 007 MITT data (N=23). Matched historical control for Zalmoxis includes T-cell replete and T-cell deplete, thus effect of product cannot be determined ** Leukemia Free Survival for BPX-501 (BPX-501 Overall Survival is 89%, Overall Survival not reported for controls); *** Adults PTCy, pediatric MUD; except for ATIR not DRI adjusted/matched Low GVHD for all three; 5% Grade III/IV for BPX-501 (resolved after rimiducid) Source: CHMP Assessment report (Zalmoxis); Merli EHA 2017 (BPX-501); Locatelli 2017 (BPX-501) 34

35 Zalmoxis (MolMed) EMA filing data and EU pricing Survival Relapse and NRM GVHD ATIR Phase II (007, MITT, n=23) 61% 51% 60% 42% 29% 30% 22% 20% 24% Zalmoxis (MolMed) Phase II data in EMA filing, n=36* PTCy/Baltimore Literature, at least 50% AML/ALL** (n=571) Overall Survival 9% Relapse Non Relapse Mortality 7% 5% Acute GVHD III/IV 6% 4% Chronic GVHD 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 * CHMP Assessment report (agvhd III/IV: Kempen 2017 report); CD34+ HSCT; 74% AML; 10% ALL; 16%MDS/NHL/HD; patients receiving Zalmoxis ** Ciurea 2015 (CIBMTR); Piemontese 2017 (EBMT), Solomon 2012 (Atlanta), Ciurea 2012; Devillier 2016; Di Stasi 2014; Esquirol 2016; Sugita 2015 *** Prices as at 16 January 2018 and 13 December 2017, respectively 0% 35

36 BPX-501 (Bellicum): AML/ALL pediatric (Zhou 2014) Population Pediatric, aged 3-17, 10 pts CD34+ HSCT 1 Year data Survival 80% Relapse 30% Non Relapse Mortality 0% Observations Low GVHD, at high doses of T cells (incl. alloreactivet-cells) 3 out of 4 patients treated with rimiducid to treat GVHD subsequently died from relapse (day 158, 164, 591) Infused T cells/kg 1x10 6 agvhd cgvhd Administration of AP1903 Grade I/II None Yes Alive, CR (D+1440) Current status (day after SCT * 1x10 6 Grade I None Yes Relapse of ALL (D+552), death D+591 3X10 6 None None None Alive, CR (D+1388) 3X10 6 Grade I None Yes Relapse of ALL (D+57), death D+158 1X10 7 Grade I None Yes Relapse of ALL (D+158), death D+164 1X10 6 None None None Alive, CR (D+1016) 1X10 7 None None None Alive, CR (D+954) 1X10 7 None None None Alive, CR (D+835) 1X10 7 None None None Relapse (D+312), alive, CR (D+475) 1X10 6 second allo-hsct) 1X10 7 None None None Death from respiratory failure secondary 5X10 6 to refractory AIHA (D+615) 36

37 CAR-T therapies First products approved by FDA (B-cell lymphomas), EU approval expected in 2018 Kymriah (Novartis): list price $475,000 (outcome based) Yescarta (Kite/Gilead): list price $373,000 In most cases used as a bridge to a HSCT Most successes from targeting CD19 (i.e., ALL, CLL, B-cell lymphomas; esp. refractory ALL) Also pursued by Juno, Cellectis, Amgen, Pfizer, Celgene, Merck KgaA Reported issues Persistence: Even in ALL with remissions of 90%, many patients relapse (most in ALL) Antigen-negative relapse: CAR-T no longer able to target because cells no longer display the desired antigen, so far only with CD19 Safety: severe cytokine release syndrome and neurotoxicity correlated with efficacy Manufacturing (viral vectors): complexity, time, capacity, yields, batch failures, costs Source: Evaluate Pharma report 2016; Novartis and Gilead/Kite press releases 37

38 Healthcare costs of Allogeneic HSCTs* Total HSCT costs $401,000 (MA) $301,000 (RIC) $549,000 (MA) $432,000 (RIC) Period / Source 100 days; Broder year; Broder 2017 $893, days; Milliman 2017** Excludes lifelong costs of chronic GVHD * Includes Inpatient/Outpatient/pharmacy costs ** Includes different physician charges, graft procurement costs MA: myeloablative conditioning RIC: reduced intensity conditioning 38

39 Costs of HSCT complications HSCT complications Costs to healthcare system (US) Cancer death $165,000 Relapse $69,000* Hemorrhagic cystitis $242,000*/** Acute GVHD $527,000* Chronic GVHD moderate/mild $124,000 ($14,400 per year***) Chronic GVHD severe $322,000 ($37,400 per year***) * Cost based on Broder total cost and cost multiplier Khera ** Side effect of cyclophosphamide *** 10 years, discounted Sources: Mariotto 2011; Yu 2017; Broder 2017; Khera 2014; literature PTCy analysis 39

40 Examples EU conditionally approved ATMPs/leukemia drugs Approved indication Trial Design Trial size List Price Treatment of patients with ADA-SCID who cannot be treated by a bonemarrow transplant because they do not have a suitable, matched, related donor Open-label, prospective, sequential study in children with SCID due to ADA deficiency who lacked a healthy HLA-identical sibling 12 patients GBP 594,000 (UK) Treatment of moderate to severe limbal stem-cell deficiency caused by burns, including chemical burns, to the eyes Adjunctive treatment to CD34+ haploidentical stem cell transplantation Treatment of adults with Philadelphia chromosome negative relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL) Second or third-line treatment in chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients Two retrospective, multicentre, case series based, non-randomised, and uncontrolled observational studies 135 patients over 9 years GBP 80,000 (UK) Open label, single arm phase II study 36 patients 163,900 per dose (DE); 149,000 per dose (Italy) Open-label, multicentre, single-arm Phase 2 study Open-label, single-arm Phase 1 and 2 studies 87,000 (UK, DE; per course) 99,000 (DE) 40

41 ATIR101: alloreactive T-cells depleted, potency retained 12 Proliferation Index (PI) Donor ATIR101 * 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

42 ATIR101: T-cells reactive against infections & tumor retained Donor Myb 628 multimer ATIR Control CD8 T-cells Source: Bonig ISCT 2017 Collaboration with Prof. Angela Krackhardt, Medizinische Klinik III, Klinikum Rechts der Isar, TU Munich, Munich, Germany 42

43 ATIR101: T-cells reactive against EBV retained examples Examples of two patients in clinical study with ATIR: EBV reactivation triggered response of (viral specific) T-cells in several patients Increase in CD3+ T-cells detected in peripheral blood EBV copy numbers reduced after increase in CD3+ T-cells, indicating effective immunological T-cell response 43

44 Phase 1 (CR-GVH-001): Overall Survival (5 year) Patients: 19 with advanced hematological malignancies (14 not in remission at transplant) ATIR101 doses: 10k cells/kg to 5 mln cells/kg; 31 days after HSCT Results: 67% Overall Survival at middle dose level after 5 years No acute grade III/IV GVHD 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: un-manipulated haplo-identical Donor Lymphocyte Infusion escalated Source: Lewalle 2003 above 10k T cells/kg induce GVHD 44

45 Phase 2 (CR-AIR-007): trial characteristics & endpoints Design: Patient population: Locations: Open-label, single arm, multi-centerstudy AML or ALL in first remission with high-risk features or in second or higher remission No suitable matched donor Haploidentical family CA, BE, DE, UK (8 sites in total, patients from 4 sites) Primary endpoint: Secondary endpoints: Patient follow-up (per 27 September 2016): Transplant Related Mortality (TRM) at 6 months Acute and chronic GVHD Immune reconstitution Infections TRM, relapse, Overall Survival (OS) Median 485 days (range ) 45

46 Phase 2 (CR-AIR-007): 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 Armand

47 Phase 2 (CR-AIR-007): causes of death Period post HSCT < 6 months Classification No. of pts Classification of cause of death Relapse 1 TRM Infections 2 Adenovirus and JC virus infections TRM Other 1 Pulmonary embolism Relapse months months Total TRM Infections 3 Respiratory/pulmonary infections/distress TRM Other 1 Multi-organ failure Relapse 2 TRM-Infections 3 * Pneumonia/sepsis/septic shock 14 (61%) * All 3 patients immunosuppressed, subsequently contracted infections, leading to death: 2 patients who received un-manipulated DLI s and subsequently developed severe acute GVHD; 1 patient with chronic GVHD 47

48 Phase 2 (CR-AIR-008): second dose (January 2018) Objective Extend the length of protection (further improve TRM); investigate flexibility for physicians Design HSCT followed with ATIR101 at day 30, and additional dose of ATIR101 at day 72 Patients Status Interim results Interim conclusion AML, ALL and MDS Enrolment completed: 15 patients treated with ATIR101: 9 with one dose (of which 5 with > 1 year follow up) and 6 with two doses (all with > 1 year follow up) Study ongoing, not all data yet monitored and thus subject to change Two doses (for 6 patients): grade III/IV acute GVHD in two patients within 30 days of 2 nd dose Single dose (for 5 patients that have > 1 year follow up): No grade III/IV GVHD 80% Overall Survival; 20% 1 year Relapse, 0% 1 year Non Relapse Mortality Single dose (for 4 patients that have < 1 year follow up): 1 suspected grade III acute GVHD Confirming safety/efficacy findings of 007 in the 5 patients with a single dose that have >1 year follow up; Not confirmed with two doses or with remainder of single dose patients. Phase based on 007, not based on

49 Phase 2 (007 & 007/008) vs. PTCy literature (1 yr) Survival OS 64% 61% 58% 57% 59% 61% GRFS 57% 54% 36% 37% ATIR Phase 2 007/008 (MITT; pts receiving ATIR; n=28*) ATIR Phase (MITT; pts receiving ATIR; n=23) ATIR Phase (ITT; pts receiving HSCT; n=26) PTCy Literature, adjusted for 007 DRI for OS (n=561)** & for GRFS (n=500)** PTCy Literature, adjusted for 007/008 DRI for OS (n=561)* & for GRFS (n=500)** Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials: * 23 AML/ALL patients from 007 (study completed) plus 5 AML/ALL patients from 008 that have completed 1 year follow up with single dose (008 data not all monitored and thus subject to change); for 28 AML/ALL 007/008 patients: Relapse rate 11% and NRM 25%, chronic GVHD 4% ** Ciurea 2015 (CIBMTR); McCurdy 2017 (Baltimore), Devillier 2016, Sugita 2015 (57% high DRI; normalization based on Armand 2014) *** Solh 2016 (Atlanta; DRI normalized GRFS 30%; n=128); McCurdy 2017 (Johns Hopkins; DRI normalized GRFS 38%; n=372) 49

50 ATIR201 Phase 1/2: β-thalassemia Disease Anemia due to defects in haemoglobin and red blood cells Transfusion dependency and iron overload, leading to high mortality HSCT Trial design Status Potential cure of blood forming system, yet high risk ATIR201 to increase safety ATIR201 as adjunctive to αβ T-cell depleted HSCT 10 pediatric patients with β-thalassemia major No patient dosed yet Postponed 50

51 DRI adjustment (Armand 2014) DRI adjusted 1-year survival (OS) comparison ATIR vs all HSCT 61% ATIR101 Phase (n=25) GRFS 55% Average HSCT in Armand 2014; DRI adjusted Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials Conclusion: Disease Risk Index (DRI) is strongest prognostic factor for Overall Survival Overall Survival (%) Low Risk Intermediate Risk High Risk Very High Risk P< Months from transplantation Armand 2014: 9849 HSCT patients (CIBMTR ): MRD, non-mrd, MUD, mismatched PB, BM, cord Leukemia, lymphoma, MM, etc Myeloablative, RIC 51

52 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