Making cancer a chronic disease. Troels Jordansen

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1 Making cancer a chronic disease Troels Jordansen

2 Glycostem corporate summary Clinical stage company developing allogeneic cellular products for cancer immunotherapy using NK-cells Founded in 2007 Until 2013 Glycostem collaborated as spin-in company with University Medical Centre Nijmegen (UMCN) resulting in a phase I clinical study in elderly patients with acute myeloid leukaemia (AML) From 2014 Glycostem is located at research facilities in the Netherlands close to Eindhoven Experienced executive team in place; 20+ staff Focus on production optimisation in a fully closed system and establishing GMP facilities in class-c cleanroom 2

3 Executive team Troels Jordansen, CEO 20+ years experience with cellular therapy and 5 product launches Jan Spanholtz, PhD, CSO 15+ years background in stem cell biology, translational clinical research Marty Wulferink, PhD, IP Advisor Long background in cell biology/ immunology and patent attorney Hareth Nahi, MD, CMO Associated professor and haematologist at Karolinska Hospital Didier Haguenauer, MD, Senior Vice President - Clinical 20+ years in setting up and management of clinical trials Ingrid Cuppers, Finance Manager Looking after accounts, cash flow and all aspects of finances Bianca Eve, HR Manager Identifying and retaining unique talent in an international environment Volker Huppert, COO 20+ years of experience with NK-cells and closed system production 3

4 Scientific advisors Prof Wim Jongen, PhD (Chair) Dr Jongen has more than 25 years of experience in R&D and Business Development in life sciences. Dr Jongen has been active in the last 7 years as investment manager in Life Sciences. Prof Bob Pinedo, MD, PhD Dr Pinedo, the 2014 ASCO recipient of the David A. Karnofsky Memorial Award and Lecture, is professor emeritus of AUmc in Amsterdam, Netherlands. Prof Ulrike Köhl, MD, PhD Ulrike Köhl is director of the Institute of Cellular Therapeutics at Medical School Hannover, Germany and Fraunhofer Institute of Cellular Therapeutics and Immunology in Leipzig Prof Henk Verheul, MD Prof Verheul is scientific co-director of the Cancer Center of Amsterdam and Professor of Medical Oncology. He is heading the Department of Medical Oncology in the AUmc, the Netherlands 4

5 Natural Killer cells (NK-cells) Natural Killer cells (NK-cells) are a type of lymphocyte (a white blood cell) and a component of the innate immune system NK-cells commonly recognise and attack viral infected and cancer cells by balancing the immune system Glycostem is focused on developing oncology applications for NK-cells Clinical use of allogeneic NK-cells has been proven CAR-T cells are currently very popular, but Autologous; high cost Off-the-shelf not possible Deemed higher risk than NK-cells 5

6 Lead Candidate onkord for Immuno-oncology Allogeneic Cellular medicine Autologous Universal Donor Principle No Graft-versus-Host disease with NK cells offers allogeneic use while allowing mismatch and off-the-shelf capabilities Matched Mismatched Unlimited Sourcing High availability of donor material NK-cells are derived from UCB CD34+ cells Unrestricted Use NK-cells provide versatility opportunity to target various tumour types and used either as monotherapy or in combination Glycostem s production technology platform allows for a multitude of off-the-shelf products 6

7 Patent protected platform technology Highly pure (99% ± 1%) and activated cell products according to SOPs under GMP and advanced therapy medicinal products (ATMP) regulations including standardised certificate of analysis Patented, flexible cell expansion (>50,000 fold) and differentiation platform Full closed, automated GMP manufacturing process Proprietary composition of expansion and differentiation growth factors 7

8 hcd45 Tissue distribution of onkord cells following adoptive transfer in NSG mice A 111 In-NK cells B +1h +24h Blood Spleen Femur Lung Liver Kidney hcd56 Cany et al., PlosOne

9 Survival (%) onkord mediate in vivo a strong and local anti-leukemic response A PBS rhil-15 BLI Day+15 after K562 cell IF injection B PBS IL-15 NK + IL-15 UCB-NK + rhil Days after tumor cell IF injection Cany et al., PlosOne

10 onkord phase I study Ten elderly AML patients ineligible to receive allogeneic stem-cell transplantation All patients received one transfusion only Treated with onkord following chemotherapy and Flu-Cy conditioning Phase I safety was primary outcome * * * * * Historical survival onkord patients shows better survival than population in general 10

11 11 Patient overview

12 Key clinical outcome onkord is a safe treatment - no dose limiting toxicities or Graft-versus-Host Disease observed in the study 5 out of 10 patients survived Oldest surviving patient is 60 months (5 years) from date of treatment 1-year survival = 80% Median survival = 22 months Median follow-up = 48 months (based on 5 surviving patients) onkord cells show in vivo survival, expansion and further maturation onkord cells home to the bone marrow and target leukaemia cells onkord resulted in strong reduction of residual disease as well as Prolonged Progression Free Survival and Overall Survival as compared to historical data onkord is safe to use and shows clear signs of efficacy 12

13 Product Pipeline Product Indication Product development Pre-clinical Phase I Phase II Partner onkord AML Refrac/Relap Glycostem Multiple Myeloma Glycostem Solid tumours Glycostem Pre-conditioning agent Solid tumours Glycostem CAR-NK-cells Not disclosed MolMed CAR-NK-cells Not disclosed Glycostem Glycostem s production technology platform allows for a multitude of off-the-shelf products 13

14 CAR-NK-cells; feasibility study in a mouse model Tumour CAR-oNKord CAR-oNKord CAR-oNKord Day 0 Day 3 Day 6 Day 9 Day 12 Day 15 Day 18 Day 35 IL-15 IL-15 IL-15 IL-15 IL-15 IL-15 14

15 Liver weight (gm) CAR-NK-cells kills cancer cells in vivo 12 UCB CD34+ cells have been successfully transduced > 70% CAR * Transduction of the CAR construct did NOT affect the expansion and differentiation process of CAR-NK-cells 6 4 Functionality data confirm that the CAR-NK-cells are specifically activated with a higher cytotoxicity towards the tumor cells (not shown) 2 0 Saline NK A NK-CAR A NK B NK-CAR B In vivo data of condition B CAR-NK-cells shows the ability to control tumor growth in a murine model Good recovery of progenitor cells and CAR-NK-cells after reconstitution from cryopreservation 15

16 Overview of clinical development: onkord AML n=33 Phase I Phase I/II Follow-up Conditional approval Phase III AML historical cohort MM n=14 Phase I/II Follow-up Conditional approval Phase III MM Historical cohort Compassionate use Patient registry for all treated patients AML trial: safety of repeat infusion and efficacy MRD/OS 16

17 Pivotal studies in AML and MM 2-stages study to enroll 33 patients Safety of repeat infusion Safety of treatment Justification 3 doses Extension 3 doses NK-cell persistence Relapse and MRD-free survival Overall survival QoL SF36-MDASI Tumour genetic profiling predictive of response 1 dose = 750 million viable cells / infusion +/- 250 million 1 dose 2 doses 3 doses 3 doses Cohort A1 Cohort A2 Cohort A3 Cohort B N=9 in 4 sites/3 countries N=24 in 10 sites/5 countries N= 27 N= 33 follow-up 12 months onkord MRD MRD CyFlu D-14 D-6 D-3 D0 D+4 D+8 M+1 M+3 M Pivotal study aimed at early registration With comparative analysis to historical cohort

18 Other clinical trials Solid tumour Phase I Cooperation with Amsterdam University Medical Center (AUmc) Safety and tolerability evaluation - New pre-conditioning agent - Dose ranging - Sequential infusion 3 weeks apart CAR-NK MolMed and proprietary CAR-NK products in phase I clinical trials in 20 18

19 Competitor landscape Development landscape Natural Killer cell Therapy July 2018 Chimeric Antigen Receptor (CAR) Natural Killer cell Therapy July

20 IP protected technology platform Cell expansion with the absence of feeder layer - GRANTED Key medium factors - GRANTED Different culture steps - GRANTED Closed system and product composition FINAL OFFICE ACTION Culture modification / IL12 OFFICE ACTION Clinical use of NK cells in mismatch setting/solid tumours OFFICE ACTIONS CAR-NK-cell production and products - PCT Further NK-cells production patents - DRAFTING Expansion media - KNOWHOW AML Orphan Drug Designation with FDA and EMA Due to Glycostem s pioneering activities strong patent portfolio has led to strong Freedom to Operate situation 20

21 Market details Acute Myeloid Leukaemia (AML); affects 5 out of 100,000 US, Europe, Japan = 900,000,000 or a total of 45,000 new cases p.a. Multiple Myeloma (MM); 100,000 new cases p.a. 2 indications = 145,000 new patients p.a. onkord market penetration 10% onkord expected price around 180,000 onkord 2.6 billion onkord has blockbuster potential based on two indications only 21

22 Financial details Current funding until 2 nd half 19 Series B funding under way to support pivotal trial, research and corporate burn rate Corporate deals Financially supported by Lupus Ventures; Dutch VC RVO; Innovation Credit (Dutch government supporting new technology) IMAGINe and MODIFY; EuroStars grants. MODIFY is a Glycostem led consortium NK-Mature, Marie Curie grant with 15 institutions and companies Glycostem is planning to invest over the coming 2-3 years the same as over the first 10 years 22

23 Next steps Finalise production optimisation work Increase cell yield Improve to GMP standards Certified GMP manufacturing (Q1 19) Clinical trials (Q2 19) Adding new collaboration agreements for NK-cells in solid tumours New pre-conditioning agents CAR-NK Gene modified NK-cells Advancing discussions on Sales and Marketing rights for onkord Clear road map to enter phase II clinical trial in AML and other blood cancers 23

24 Summary Leader in the highly exciting NK-cell sector with extensive patent protection Phase I trial data showing onkord to be safe and with some effect in the treatment of AML patients Glycostem has a unique, versatile cell expansion and differentiation platform Production platform offers very attractive cost structure and should provide high licensing potential for commercial partners Well documented procedures and GMP protocols Solid IP position with freedom to operate secured Excellent facilities for production, research and development work Received Orphan Drug Designation from the FDA and EMA for the treatment of AML Poised for growth as leader in the highly exciting NK-cell sector 24

25 Thank you!