Oryzon Genomics Sa · BME:ORY

Oryzon Genomics Sa — ASH Annual Meeting 2016 (ancillary meeting)

43 slides from Oryzon Genomics Sa's conference presentation, Dec 5, 2016

  1. Slide 1: Información relevante: Oryzon presents ORY-1001 results at ASH

    ORYZON GENOMICS, S.A. De conformidad con lo establecido en el artículo 228 del Real Decreto Legislativo 4/2015, de 23 de octubre, por el que se aprueba el texto refundido de la Ley del Mercado de Valores, ORYZON GENOMICS, S.A. (“ORYZON” o la “Sociedad”) comunica lo siguiente INFORMACIÓN RELEVANTE OR

  2. Slide 2: Development of ORY-1001, an LSD1 Inhibitor, in Acute Myeloid Leukaemia

    DEVELOPMENT OF ORY-1001, AN LSD1 INHIBITOR, A NOVEL THERAPEUTIC APPROACH IN ACUTE MYELOID LEUKAEMIA by Dr. Tim Somervaille, PhD FRCP FRCPath Ancillary meeting to the ASH Annual Meeting 2016 S a n D i e g o , D e c e m b e r 5 th, 2 0 1 6

  3. Slide 3: Disclaimer

    DISCLAMER This document has been prepared by Oryzon Genomics, S.A. exclusively for use during the presentation. Oryzon Genomics, S.A. does not assume liability for this document if it is used with a purpose other than the above. The information and any opinions or statements made in this document ha

  4. Slide 4: Development of ORY-1001, an LSD1 Inhibitor, in AML

    DEVELOPMENT OF ORY-1001, AN LSD1 INHIBITOR, A NOVEL THERAPEUTIC APPROACH IN ACUTE MYELOID LEUKAEMIA by Dr. Tim Somervaille, PhD FRCP FRCPath 3 3

  5. Slide 5: Tim Somervaille

    Tim Somervaille Consultant for Novartis , Imago Biosciences & Roche 4

  6. Slide 6: Normal polyclonal haematopoiesis vs leukaemic haematopoiesis

    Normal polyclonal haematopoiesis Leukaemic haematopoiesis 5 5

  7. Slide 7: We need better treatments

    ….we need better treatments. 6 6

  8. Slide 8: LSD1 expression in leukaemic stem cells

    SELF- LSC RENEWAL DIFFERENTIATION LSD1 expression (Somervaille et al., 2009, Cell Stem Cell) 7 7

  9. Slide 9: LSD1 histone demethylase biology

    o An essential gene in embryogenesis and adult haematopoiesis o Protein is found in repressive chromatin complexes: CoREST, NuRD o A histone tail demethylase, the first to be discovered o Demethylates mono- and dimethyl-H3K4 o High expression in many human malignancies  Interest as a potential ther

  10. Slide 10: Loss of clonogenic activity and increased differentiation

    Spleen or BM explant AML Semi-solid culture Type 1 Type 2 Type 3 Loss of clonogenic activity Increased differentiation Blasts Mixed Macrophages 9 9

  11. Slide 11: LSD1 contributes to differentiation block in murine MLL leukaemia

    LSD1 contributes to the differentiation block in murine MLL leukaemia William Harris 10 10

  12. Slide 12: Tranylcypromine as LSD1 inhibitor

    [PCPA= tranylcypromine] Yang et al., 2007; Biochemistry A monoamine oxidase inhibitor licensed for the treatment of depression IC50 for LSD1 is ~5-20 uM 11 11

  13. Slide 13: OG-86 effects on clonogenic activity and differentiation

    OG-86: trans-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropan-1-amine ( WO2010/084160 James Hitchin OG-86 Loss of clonogenic activity Increased differentiation OG-86 12 12

  14. Slide 14: OG-86 similar results in cell lines and in vivo

    OG-86: trans-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropan-1-amine ( WO2010/084160 James Hitchin OG-86 Loss of clonogenic activity Increased differentiation Similar results in: Human AML cell lines Primary patient cells MLL-AF9 cells In vivo mouse model OG-86 13 13

  15. Slide 15: LSD1 inhibitor programs and indications

     LSD1 is an enzyme that demethylates histones: specifically mono and dimethylated H3K4 and H3K9  LSD1 belongs to the family of FAD – dependent amine oxidases, which include known CNS drug targets, such as MAO-A and MAO-B  The MAO inhibitor tranylcypromine (TCP) is a chemical starting point to des

  16. Slide 16: ORY-1001 is a potent and selective LSD1 inhibitor

    OG-L002 LSD1: 25uM MAO-B: 0.5uM MAO-A: 1.8uM = OG-98 OG-86 (Compound B) 4SC-202 HDAC1,2,3/LSD1 LSD1: 0.018 mM MAO-B>100 uM MAO-A> 100 uM LSD1: 1.183 mM MAO-B >100uM MAO-A> 100 uM 15

  17. Slide 17: Most potent LSD1 inhibitor in cells reported

    ORY-1001 is a potent and selective LSD1 inhibitor, first and best in class  Small compound, highly druggable  Inhibits LSD1 by covalent binding to the FAD cofactor  Potency ≈1000 x tranylcypromine, ≈100x GSK2879552 Biochemical IC50 LSD1 18nM  Very high selectivity vs related FAD dependent enzym

  18. Slide 18: Gene expression across leukaemia cell lines

    EC50 < 1nM ORY-1001 VEHICLE 5nM ORY-1001 60 + Cells 11b cells 40 Cd11b+ % CD 20 enantiomer % 0 0.1 1 10 100 Concentration (nM) Concentration (nM) The most potent LSD1 inhibitor in cells reported THP-1 cells LSD1 Fold selectivity Fold selectivity CODE Kinact/ki (sec-1.M-1) differentiation assay (IC50

  19. Slide 19: Most potent LSD1 inhibitor in cells: % CFC of vehicle

    Myeloid Lymphoid M2* M0M0 M1M1 M3M3 M4M4 M5M5 M5M5 M5M5 M7M7 M2* B-ALL T-ALL T-ALL T-ALL T-ALL T-ALL T-ALL T-ALL T-ALL B-cell ATLL cBCL AML AML AML AML AML AML AML AML AML CMLCML CMLCML PCLPCL B-ALL T-ALL T-ALL CCRF-HSB-2 T-ALL VvsT T-ALL T-ALL T T T-ALL T-ALL T-ALL B-cell vs THP1 ATLL cBCL AML AML

  20. Slide 20: ORY-1001 highly potent selective LSD1 inhibitor; orphan drug status

    80 70 % CFC of vehicle 60 50 40 30 20 nM 20 250 nM 10 0 The most potent LSD1 inhibitor in cells reported 19

  21. Slide 21: Principal Investigators Coordinators

    ORY-1001 a highly potent and selective LSD1 inhibitor Orphan drug status granted by the European Medicines Agency (EMA) for AML Pharmacological Properties • High druggability • Optimal ADMET and PK profiles • Orally bioavailable once daily • Easy to scale up • Good pharmaceutical properties Phase I/

  22. Slide 22: Refractory & relapsed acute leukaemia trial design

    Principal Investigators Coordinators: Dr. Tim Somervaille Dr. Francesc Bosch Honorary Consultant in Haematology & Chief Haematology Department Professor of Haematological Oncology Hospital Universitari Vall d’Hebron The Christie NHS Foundation Trust Barcelona, Spain Manchester, UK 21

  23. Slide 23: Phase I patient population and sites

    Refractory & Relapsed Multi-Center (10), Multiple Ascending Dose (8 Acute Leukaemia multinational, Open label Cohorts) Evaluate Safety (haematological and non-haematological toxicities) and Tolerability Assess Responses Evaluate surrogate PD Characterize PK (CR/Cri/PR), particularly for markers for

  24. Slide 24: Dose escalation cohorts and schedule

    Patient population: relapsed or refractory acute leukemia >16 years Unselected AML+ AL First patient in: 10 February 2014 Last patient out: 15 July 2015 Total patients: 27 5 Hospitals in 2 Countries UK • Christie Hospital, Manchester SPAIN • Valle de Hebron, Barcelona • La Fe, Valencia • Virgen del

  25. Slide 25: Extension arm (Phase IIa)

    Cohort Dose Patient population: relapsed or refractory AL >16 years  unselected AML + 1 ALL Cohort 1 5 ug/m2/d Cohort 2 15 ug/m2/d Oral administration Cohort 3 30 ug/m2/d Patients treated five days per week for four weeks in a 28-day Cohort 4 45 ug/m2/d cycle Cohort 5 60 ug/m2/d 28-day rest (or les

  26. Slide 26: Patient cohorts overview

    The extension arm (Phase IIa) with selected profiles , including MLL gene translocation (n=6), other MLL gene rearrangement or mutation (n=4) and AML M6 (n=4) Dose: RD = 140 ug/m2/d First patient in: 2 September 2015 Last patient out: 25 August 2016 Total patients: 14 10 Hospitals in 3 Countries UK

  27. Slide 27: Primary outcomes

    Dose escalation phase: (8 COHORTS) Cohort 7, 140 ug/m2 : (n=3) Unselected AML Cohort 8, 220 ug/m2 (n=5) Unselected AML Extension arm : (n=14) MLL gene translocation (n=6) Other MLL gene rearrangement or mutation (n=4) AML M6 (n=4) 26

  28. Slide 28: Safety summary

    PRIMARY OUTCOMES 27 ORYZON

  29. Slide 29: Serious adverse events during the study

    Summary  ORY-1001 was well tolerated  Predicted toxicities were thrombocytopaenia & anaemia and, in patients not transfusion dependent at the start of treatment, development of a low platelet count after 12-15 days was invariable and evidence of in vivo activity  The great majority of AEs and SAE

  30. Slide 30: Expected adverse drug reactions reported

    SAEs during the study: Total 71 Pneumonia / lung infection 9 Febrile neutropenia 9 Febrile neutropenia 7 Progressive disease 5 Sepsis 5 Leukocytosis 3 Intracranial haemorrhage 3 Pulmonary infection 3 Respiratory failure 2 Supraventricular tachycardia 2 Rising white cell count/ differentiation Line i

  31. Slide 31: Secondary outcomes

    Preliminary Expected ADR Reported Very common Thrombocytopenia 5 (16.7) 0 (0.0) 5 (16.7) 0 (0.0) Common Febrile neutropenia 2 (6.7) 1 (3.3) 0 (0.0) 1 (3.3) Neutropenia 2 (6.7) 0 (0.0) 2 (6.7) 0 (0.0) Common Dysgeusia 2 (6.7) 0 (0.0) 0 (0.0) 0 (0.0) Lethargy 2 (6.7) 0 (0.0) 0 (0.0) 0 (0.0) Common Pet

  32. Slide 32: Trial outcomes: pharmacokinetics all cohorts

    SECONDARY OUTCOMES 31 ORYZON

  33. Slide 33: Pharmacokinetic parameters table

    Trial outcomes (2) - pharmacokinetics all cohorts 80— Rr 6—4 Mean vs Time —| j ~~ Cohort 1 & ~-&- Cohort 2 a Fi © Cohort 3 5 Ht \ a A ~ Cohort 4 4 ro. / \ fi ™ J V\\ Cohort 5 5 Pa Ni J ‘i y, 1 \ \ —+ Cohort 6 = d + y \ J \ / ¢ \ ~» Cohort 7 324 } i \ 7 0 i \ q o~ Cohort 8 3 oe fhe a \ --«- Extension

  34. Slide 34: MLL fusion gene patients: blast differentiation

    98.76 ± 85.46 664.636 ± 722.734 937.69 ± 542.04 (3.38–321.31) (71.18–2995.80) (335.40–1763.80) 7.49 ± 6.46 35.01 ± 40.08 54.93 ± 32.44 (1.17–22.10) (5.49–166.00) (16.00–107.00) 5.00 (4.00-6.50) 5.00 (4.00-8.00) 6.00 (4.00-8.00) 5523.265 ± 5060.258 - - (1126.97-13.660.00) - - 55.70 (39.39-117.69) * M

  35. Slide 35: AML M6 and other MLL patients: BM blasts

    Patient 0701 MLL fusion gene patients (n=6) 100 o In vivo blast differentiation (including differentiation syndrome) 90 observed in 4/6 patients (67%) % BM blasts 80 o Falling BM blasts following each cycle in 1/6 patient (0701) 70 o Blast cells cleared from blood & stable disease in BM in 1/6 patie

  36. Slide 36: Differentiation genes monitored by qRT-PCR

    AML M6 patients 100% P=NS (one way ANOVA) 90% 80% AML M6 patients (n=4) 70% % BM blasts 60% Stable disease in all 4 patients 50% 40% 30% 20% 10% 0% Other MLL patients (n=4) Pre Post #1 Post #2 Differentiation (n=1) Skin disease only (n=1) Withdrew D8 – unevaluable (n=1) Progressive disease (n=1) 35

  37. Slide 37: Variability in biomarker induction profile

    12 genes associated with monocyte/macrophage differentiation were monitored by qRT-PCR in the peripheral blood cells of treated patients Gene Protein Gene Protein VCAN Versican core protein ANXA2 Annexin A2 LYZ Lysozyme C CRISP9/PI16 Peptidase inhibitor 16 GPR65B Psychosine receptor VIM Vimentin S10

  38. Slide 38: Variability in gene expression response

    *(P): pre-dose (P) (P) (P) (P) (P) Induction Days 1-8 → (P) q.d. dose OFF Inhibition D1 D2 D3 D4 D5 D6 D7 D8 (P) Induction Days 26-33 → Inhibition OFF D26 As expected from preclinical data, variability in the biomarker induction profile is seen: Examples of the time course of PI16/CRISP9 induction i

  39. Slide 39: ORY-1001 highly active LSD1 inhibitor with differentiation activity

    Variability in gene expression response due to differences in disease etiology: M4/M5 (monocytic) => induction of nearly all differentiation marker genes (except CTSG and CAMSAP2) when both blast morphological differentiation and decrease in the blast % was observed. No morphological differentiation

  40. Slide 40: Promising clinical responses mandate further research

    ORY-1001 is a highly active LSD1 inhibitor with strong differentiation-inducing activity in patients with MLL leukaemia An excellent safety profile in AL patients Well tolerated and has been administered to 41 patients in total up to a maximum of three cycles Excellent oral bioavailability in humans

  41. Slide 41: Thank you

    Promising clinical responses were observed mandating further clinical research and investigation Taking the four M6 patients together, there was no significant rise in blast cell count after two cycles of therapy – suggesting the possibility of disease stabilization. 4/6 patients with MLL leukaemia

  42. Slide 42: Oryzon contact details

    Thank you Serena Lunardi Clinical Investigators Filippo Ciceri Paola Dessanti Tim Somervaille PhD FRCP FRCPath Julio Castro Palomino Francesc Bosch, MD, PhD Drug Discovery Matthew Fyfe Olga Salamero, MD, PhD Donald Ogilvie Marc Martinell Pau Montesinos MD, PhD, Carlos Buesa Alan Jordan Iñigo Tirapu

  43. Slide 43: Oryzon contact details

    Sant Ferran 74 08940 Cornella de Llobregat. Barcelona (Spain) : SQ T: + 34 93 5151313 F: + 34 93 3774028 = ’ www.oryzon.com Emili Torrell, BDO [email protected]

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