Patient-specific immunotherapy designed to reduce the risk of GVHD and relapse in stem cell transplantations

Transcription

1 Patient-specific immunotherapy designed to reduce the risk of GVHD and relapse in stem cell transplantations Unlock full potential of haploidentical hematopoietic stem cell transplantations (HSCT), with allo-depleted T-cell product ATIR Company presentation, May 14, 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 ATIR product: HSCT with reduced risk of GVHD & relapse STRONG CLINICAL DATA CLOSE TO MARKET RETAINED WORLDWIDE RIGHTS BROAD POTENTIAL APPLICABILITY OF ATIR INFRASTRUCTURE FOR CELL-BASED PRODUCTS ATIR allo-depleted T-Cell product, given after HSCT, designed to reduce risk of relapse and GVHD EMA opinion expected 4Q18; Potential initial EU launch 2H19; FDA RMAT breakthrough designation; Phase 3 enrolling Allows for independent commercialization in EU and US, due to small number of transplantation sites Potential >50,000 target patients per year; Could be used for haploidentical HSCT more broadly Creating a patient-specific cell therapy supply chain and commercial organization 3

4 Kiadis ATIR product: regulatory status in adult blood cancers Product Phase I Phase II Phase III Filing Catalysts Commercial Rights Comments ATIR101 (Europe) Orphan Drug Designation CHMP Opinion 4Q18 EU Launch 2H19 Phase II & historical control accepted for filing & review* Day 120 response submitted end of 1Q18 ATIR101 (USA) Orphan Drug & RMAT Designations Phase III (interim) read out RMAT benefits: access to FDA, priority/rolling review, support * Various hemato-oncology products (conditionally) approved by the EMA based on Phase II, e.g., Zalmoxis (MolMed, 36 patients, versus matched historical control), Blincyto, Venclexta, Bosulif 4

5 Allogeneic HSCT: The first cell therapy, yet huge unmet need Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Curative intent: destroy diseased blood/immune system (chemo/radiation), replace with healthy system from donor Inherent risk of Graft versus Host disease (GVHD): Donor immune system attacks patient due to genetic mismatches* Lack of donors: Consistent growth in US/EU, yet many patients cannot find matched donor (US 2012: 13,500) Mostly blood cancers (~85%) and adults (84%): potentially also curative for inherited disorders and autoimmune disease Modest outcomes: 20-30% long term severe GVHD-Free and Relapse-Free survival (GRFS**) Expensive procedure: around $500,000 (1 year cost; US) * Mature T-cells that need to be transplanted along with stem cells (T-cells take 6-12 months to re-emerge from stem cells; survival without T-cells 10-20%) ** GRFS: Survival without relapse, Grade III/IV acute GVHD or chronic GVHD requiring immunosuppression Source: Solh 2017; McCurdy 2017; Broder 2017; Passweg 2018; CIBMTR 2017 summary slides; Besse

6 Graft Versus Host Disease (GVHD): a terrible disease Subpopulation of mature T-cells from donor (i.e., graft) recognize patient tissue (i.e., host) as foreign and attack, due to genetic differences in MHC Class II proteins Types Disease Acute: life threatening (grade III/IV; 75% mortality) Chronic: often severely debilitating; 50% five year mortality if severe Skin, eye, mouth or GI tract disease Immunodeficiency (infections) Muscle constriction, bone loss, pulmonary disease, thyroid disfunction, solid tumors Sleep deprivation, depression Treatment 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 Loss of income 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 75% of patients lose 3 years of earnings 25% of patients permanently lose earnings MMF: mycophenolate mofetil Source: Jones 2016; Koreth 2013 MTX: methotrexate 6

7 HSCT: Strong growth, still large unmet need (U.S. numbers) Matched Related Donors (MRD) Unmet need 2012: 13,500 per year (lack of matched donors) Matched Unrelated Donor (MUD; registries) Haploidentical donors Historical: Matched Donors Between 25% (White European) and 80% (African American) will not find a matched donor in time Increasing, due to increasing genetic diversity and decreasing family size Emerging: Haploidentical or half matched donors Donor availability >95% (parents/children) Has been enabled by Post Transplant Cyclophosphamide (PTCy) or Baltimore protocol (patient-specific T- cells killed in the patient with chemo*) * 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

8 Haplo PTCy/Baltimore: better than MUD 38% 53% 26% 27% 38% 45% 51% 49% 'Average' Matched Unrelated Donor Acute GVHD II-IV Chronic GVHD Relapse Survival Simple but rough : Trigger GVHD attack with half matched graft; then kill/treat activated T- cells with chemotherapy (cyclophosphamide) on days 3 & 5 and immunosuppressants Many advantages over MUD: No need to search for matched donor (many patients drop out during search; donor often not available); Lower GVHD Still room for improvement: Still 1 in 4 with GVHD and higher relapse than MUD 'Average' Haploidentical (PTCy)* * 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 8

9 Kiadis: potential improvement vs. PTCy/Baltimore HAPLOIDENTICAL HSCT PTCy Conditioning of patient Apheresis of donor, graft infusion Engraftment of donor stem cells Chemo & immunosuppressants Treat GVHD: kill attacking T-cells in the patient (with chemo) stem cells + all T-cells (T-cell replete) Day 2 & 5 after HSCT Kiadis ATIR (add on to HSCT) Apheresis of patient and donor Central ATIR production, 5 day process Conditioning of patient Apheresis of donor, graft infusion Engraftment of donor stem cells Infusion of ATIR (no immunosuppression) Prevent GVHD: kill attacking T-cells before infusion (with light) Produce ATIR ( safe T-cells): 14 days before HSCT safe stem cells only (T-cell depleted) Infuse ATIR ( safe T-cells) ~30 days after HSCT 9

10 Healthy donor donor ATIR production: safe subset of T-cells that protect, but not attack ATIR TM MANUFACTURING Mix patient cells & PROCESS Add TH9402*, which haplo donor T-cells: accumulates only in alloreactive Step 1 (Day donor 1 4) activated T-cells Healthy T-cells become (MDR pump is donor ATIR ATIR TM MANUFACTURING TM Immune cells are collected and mixed MANUFACTURING activated PROCESS (Mixed PROCESS switched off in 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 alloreactive T-cells are killed ` Step Step 3 (Day 3 (Day 5) 5) FEBRUARY Step 3 (Day 5) Step 3 (Day 5) ATIR: remaining potent nonalloreactive donor T-cells, infused on day after HSCT 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 Protect: Retain protective T-cells to fight relapse and infections Certain T-cells from the donor are activated by the TH9402 is introduced. Mixture is exposed to light. 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 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 & cells. Not If not eliminated, attack: Reduce Mixture is exposed to light. TH9402 is retained risk TH9402 ONLY in the of is introduced. GvHD-causing GVHD T-cellsby depleting TH9402 is activated alloreactive 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 10

11 ATIR production: fast & simple, own facility secured 5 day process No genetic engineering (No viral vector production/transfection) Clean rooms with LAF cabinets (No BL2; No bioreactors) 42 hour hold time for ingoing material, final product frozen down Lower COGS per batch and capex compared to e.g. CAR-T Contract manufacturing; Own commercial manufacturing facility secured (lease) 11

12 Phase 2 (007): potent T-cell product, yet low GVHD (1 yr) Improved Overall Survival due to ATIR 61%, MITT 58%, ITT 20% CD34+ stem cells with ATIR 3x CD34+ stem cells without ATIR 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+ 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 * ITT (intention to treat; n=26): Patients enrolled; MITT (modified intention to treat; n=23): Patients enrolled and receiving ATIR ** Non allodepleted donor lymphocyte infusion can cause severe GVHD at 10,000 cells/kg 12

13 Phase 2 (007): GRFS vs. literature for PTCy/Baltimore (1 yr) GVHD-Free and Relapse-Free Survival (GRFS) 57% 54% 36% Composite endpoint, capturing survival and future outlook Defined as survival without: Chronic GVHD requiring immunosuppression Acute grade III/IV GVHD Relapse ATIR (MITT*; n=23) ATIR (ITT*; n=26) GRFS PTCy DRI adjusted** (n=500) PTCy: single site results from Johns Hopkins (Baltimore, MD) and Northside (Atlanta, GA) Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials * ITT (intention to treat; n=26): Patients enrolled; MITT (modified intention to treat; n=23): Patients enrolled and receiving ATIR ** Solh 2016 (Atlanta; DRI normalized GRFS 30%; n=128); McCurdy 2017 (Johns Hopkins; DRI normalized GRFS 38%; n=372) 13

14 Phase 2 (007): GVHD, relapse & OS vs. literature for PTCy Initial 12 months ATIR101 (CR-AIR-007 study in acute leukemia) PTCy protocol (reported in scientific literature) Difference (between ATIR101 & PTCy) Chronic GVHD 4% 24% 1 20 p.p. Chronic severe GVHD 0% 8% 3 8 p.p. Acute grade III/IV GVHD 0% 5% 2 5 p.p. Relapse (MITT/ITT) 9% 29% 2 20 p.p. RRM (MITT/ITT) 9% 18% 9 p.p. TRM (MITT/ITT) 30% 22% -8 p.p. OS (MITT, DRI normalized) 61% 57% 4 4 p.p. OS (ITT, DRI normalized) 58% 57% 4 1 p.p. Comparison provided for illustrative purposes based on literature, not based on randomized controlled trials. 1 Weighted average in literature in which at least 50% of patients had AML or ALL (n=571): Ciurea 2015; Piemontese 2017, Solomon 2012, Ciurea 2012; Devillier 2016; Di Stasi 2014; Esquirol 2016; Sugita Of which 11% relapsed and 18% relapsed and died 3 Weighted average in literature in which at least 50% of patients had AML/ALL: Solomon 2012; Ciurea 2012; Esquirol Weighted average in literature adjusted for DRI (n=561): Ciurea 2015; McCurdy 2017, Devillier 2016, Sugita 2015.The DRI normalization was based on Armand 2014 and the DRI of the CR-AIR-007 patient population: 53% high/47% intermediate. 14

15 Reduce risk of (severe) GVHD, relapse and GRFS Approximate risk with PTCy 1 in 4 1 in 12 Overall chronic GVHD Severe chronic GVHD Approximate risk with ATIR 1 in in 3 Relapse 1 in 9 GVHD-Free 1 in 2 and Relapse- 1 in 3 Free Survival Comparison provided for illustrative purposes based on literature, not based on randomized controlled trials. For exact numbers and references, please refer to slide

16 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 Primary endpoint: GVHD-Free and Relapse-Free Survival (GRFS**) Secondary endpoints: OS, Progression Free Survival, Relapse Related Mortality, Transplant Related Mortality PTCy/Baltimore protocol: post-hsct cyclophosphamide & immunosuppressant Aligned with FDA and regulators in EU; Enrolling patients * Sample size to be increased: current assumption based on 80% power to detect 20% GRSF difference; 15% difference will be statistically significant; allowed under protocol to increase sample size; 245 patients would give 80% power to detect 18% difference ** Survival without chronic GVHD requiring immunosuppression, acute grade III/IV GVHD or relapse 16

17 Future options for patients: ATIR after CD34+ or after PTCy Overall Survival (OS) Stem cells (CD34+; Phase 2) 20 % + ATIR 61% PTCy (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 17

18 ATIR potential: target >50,000 annual patients USA/EU 33,500 50,500 20,000 *** 30,800 13,200*,** 13, , * 4700 EU Haplo MUD & Cord Blood Unmet Need Total USA * 2016 numbers ** 20% of MUDs are partially matched or Mismatched MUDs (MMUD) with worse outcomes & thus first candidates for cannibalization by Haplo *** Extrapolated from the USA number 13,500 from 2012 Source: CIBMTR summary slides 2017, Passweg 2017, Besse

19 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) 19

20 EU4 proven pathways, national funding at launch No of transplant centers Priority Approach Examples Germany (22 sites) Shortened dossier to G-BA via AMNOG (national funding); Full dossier once annual sales exceed 50M; Zalmoxis ( 164k/dose); Blincyto ( 170k), Defitelio ( 120k) 17 UK Italy (8 sites) Accelerated process via AIFA, with immediate regional/local formulary access (L- 648) Strimvelis ( 593k); Holoclar ( 95k); Zalmoxis ( 149k/dose) Germany 22 France 16 France (16 sites) ATU (name patient basis); HAS/CEPS filing/negotiation afterwards (national funding) Spinraza, Luthatera, Holoclar Italy 8 UK (17 sites) Single Technology Appraisal to NICE (national funding) Strimvelis ( 593k), Holoclar ( 88k), Imlygic (Amgen 80k) Small number of transplant centers allows for independent commercialization 20

21 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 Competition would require full development program, including potential head to head trial against ATIR101 21

22 Kiadis: company at a glance ORGANIZATION SHAREHOLDERS FINANCIALS (May 7, 2018) Management track record late stage and commercial (Crucell, Medivation, J&J, AstraZeneca, Organon, DSM, McKinsey) Strong supervisory board (ex Cipla CEO/Novartis ExCom; ex Actelion COO; ex Prosensa/Jerini CFO; Prof, Dana Farber) Euronext Amsterdam/Brussels, first listed in 2015 Major shareholders (>5%): Life Sciences Partners, Draper Esprit Analysts: Jefferies, Canaccord, Oppenheimer, Chardan, KBC, Kempen, LifeSci Market cap: ~$240M / 201M 20,1 million shares outstanding Raised > 60M in equity & debt since June 2017; Cash 47.7M end March 18; Cash runway into Q

23 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 23

24 Kiadis key milestones and upcoming catalysts 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 (RMAT) 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) EMA (CHMP) opinion (Q4) Updates Phase 2 data and Phase 3 enrollment Potential initial commercial launch of ATIR in first of EU5 countries (H2) Initiate trial with ATIR as adjunctive to PTCy Potential interim read out Phase 3 24

25 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) 25

26 Attachments 26

27 Additional information Competition Pricing ATIR product characteristics Clinical trial information Disease Risk Index adjustment for literature comparisons 27

28 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 stem cells) Safe subset of T- cells, depleted of alloreactive T-cells No prophylactic immunosuppressant Prevent Zalmoxis (MolMed) BPX-501 (Bellicum) T-cell depleted ( Safe stem cell s) 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 28

29 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) 29

30 Zalmoxis (MolMed) EMA filing data and EU pricing Survival 60% 51% Relapse and NRM 46% 42% GVHD Matched historical control for Zalmoxis Zalmoxis (MolMed) Phase II data in EMA filing, n=36* 34% 21% 29% 22% 20% 24% PTCy/Baltimore Literature, at least 50% AML/ALL** (n=571) Overall Survival Relapse Non Relapse Mortality 7% 5% Acute GVHD III/IV 6% 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 30

31 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. alloreactive T-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) 31

32 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 (Gilead/Kite): list price $373,000 Often 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 e.g. 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 32

33 Novel cell therapies establishing themselves Selected companies Product Status Company valuation Kymriah (list price $475,000) FDA approved Yescarta (list price $373,000) liso-cel darvadstrocel FDA approved Potential FDA filing 2H 2018 EU approved $11.9bn 8/2017 acquisition by Gilead $9.0bn 1/2018 offer by Celgene $596M 12/2017 acquisition by Takeda tabelecleucel Phase 3 $1.8bn* market capitalization 1/2018 $128m capital raise * As of market close May 7,

34 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 34

35 Costs of HSCT complications HSCT complications Costs to healthcare system (US) Cancer death $165,000 Relapse $69,000* Hemorrhagic cystitis $242,000*/** Acute GVHD $324,000 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 35

36 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) 36

37 Proliferation Index (PI) ATIR101: 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

38 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 38

39 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 39

40 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 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 40

41 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; median of 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: 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 41

42 Phase 2 (CR-AIR-007): trial characteristics & endpoints Design: Patient population: Locations: Open-label, single arm, multi-center study 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 (up to 24 months), Relapse Related Mortality (RRM), Progression Free Survival (PFS), Overall Survival (OS) Median 485 days (range ) 42

43 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: 11 female, 12 male Median donor age (range): 33 years (20 60) 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

44 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 TRM Infections 3 Respiratory/pulmonary infections/distress TRM Other 1 Multi-organ failure Relapse 2 TRM-Infections 3 * Pneumonia/sepsis/septic shock Total 14 * 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 44

45 Phase 2 (CR-AIR-008): second dose (April 2018) Objective Design Patients Status Interim results Interim conclusion Explore safety of a second dose, to extend the length of protection and provide flexibility for physicians HSCT followed with ATIR between days; additional dose of ATIR between days 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): 4 deaths, 2 of which were caused by grade III/IV acute GVHD 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; single death due to Relapse, 0% 1 year Non Relapse Mortality Single dose (for 4 patients that have < 1 year follow up): 1 death; 2 suspected grade III acute GVHD Safety/efficacy profile of 007 supported in the 5 patients with a single dose that have >1 year follow up, but not confirmed with remainder of single dose patients. Administration of second dose abandoned; Phase trial based on 007, not based on 008' 45

46 Overall Survival (%) DRI adjustment (Armand 2014) DRI adjusted 1-year survival (OS) comparison ATIR vs all HSCT Conclusion: Disease Risk Index (DRI) is strongest prognostic factor for Overall Survival % 57% ATIR101 Phase (n=23) GRFSAverage HSCT in Armand 2014; DRI adjusted* Comparison provided for illustrative purposes, based on literature comparison, NOT based on randomized controlled trials 20 P< Months from transplantation Armand 2014: 9849 HSCT patients (CIBMTR ): MRD, non-mrd, MUD, mismatched PB, BM, cord Leukemia, lymphoma, MM, etc Myeloablative, RIC * Weighted average in literature adjusted for DRI (n=561): Ciurea 2015; McCurdy 2017, Devillier 2016, Sugita 2015.The DRI normalization was based on Armand 2014 and the DRI of the CR-AIR-007 patient population: 53% high/47% intermediate. 46

47 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