Slide 1: Teach In CTCL
TEACH IN CTCL PR MARTINE BAGOT HOP. ST LOUIS, PARIS PARIS, 2 DECEMBRE 2015 Page 1
Slide 2: Forward Looking Statement
FORWARD LOOKING STATEMENT This document has been prepared by Innate warranty or undertaking, express or implied, is Pharma S.A. (the “Company”) solely for the made as to, and no reliance should be placed on, purposes of a presentation to investors the fairness, accuracy, completeness or concerning t
Slide 3: Management Team
MANAGEMENT TEAM Hervé Nicolai Pierre Brailly Wagtmann Dodion PhD, PhD, MD, MBA, CEO & Co-founder Chief Scientific Chief Medical Officer Officer Immunotech SA, Beckman-Coulter Novo Nordisk A/S ARIAD, Pfizer, Novartis, Aventis Jérôme Marcel Tiollier Rozencweig, PhD, MD, Chief Development President, In
Slide 4: Innate Pharma at a Glance
INNATE PHARMA AT A GLANCE Leading scientific edge Primary focus in innate immunity pharmacology in immuno-oncology Portfolio of first-in-class Partnerships with leaders in IO checkpoint inhibitors BMS and AZN Page 4
Slide 5: A Long Term Strategy
A LONG TERM STRATEGY CREATE AND RETAIN MAXIMAL VALUE IPH2201 (PII) NK Cell R&D collaboration • Global co-development and commercialization (2015) 2003 - 2009 • Initial payment: $250 million • Further milestone payments: up to $925 million • Double digit royalties on sales • Right to co-promote in Eu
Slide 6: IPH4102, a Candidate for an In-House Development
IPH4102, A CANDIDATE FOR AN IN-HOUSE DEVELOPMENT • IgG1 - cytotoxic antibody - aiming at depleting KIR3DL2+ cells • Defined, targeted patient population • Potential associated biomarker • Patients treated in a small number of specialized hospitals Straightforward path to market Effort commensura
Slide 7: Martine Bagot, MD, Professor, Head of Dermatology Department
MARTINE BAGOT, MD, PROFESSOR, HEAD OF THE DERMATOLOGY DEPARTMENT AT THE SAINT-LOUIS HOSPITAL, PARIS Mrs Martine Bagot is Professor and Chairperson in the Dermatology Department at Saint Louis Hospital in Paris, Paris 7 University and INSERM Unit U976 “Dermatology, Immunology and Oncology”. Pr M. Bag
Slide 8: First-in-Human Trial of Anti-KIR3DL2 IPH4102 in CTCL
FIRST-IN-HUMAN TRIAL OF ANTI- KIR3DL2 IPH4102 IN CTCL DECEMBER 2015 Page 8
Slide 9: Conflicts of Interests
CONFLICTS OF INTERESTS • Trial participation: Millenium, Kyowa, Innate • No financial compensation or honorarium from Innate Page 9
Slide 10: CTCL: A Rare Disease with High Unmet Medical Need
CTCL A RARE DISEASE WITH HIGH UNMET MEDICAL NEED Page 10
Slide 11: Cutaneous T-Cell Lymphoma
CUTANEOUS T-CELL LYMPHOMA • CTCL is a heterogeneous group of non Hodgkin lymphomas which arise primarily in the skin and are characterized by the presence of malignant clonal mature T cells • CTCL exhibit diverse clinical, histological and molecular presentations Patch Plaque Tumor • In advanced dis
Slide 12: Advanced Mycosis Fungoides
ADVANCED MYCOSIS FUNGOIDES Page 12
Slide 13: Sézary Syndrome
SÉZARY SYNDROME Page 13
Slide 14: Cutaneous T-Cell Lymphoma Epidemiology
CUTANEOUS T-CELL LYMPHOMA EPIDEMIOLOGY • CTCL account for ~4% of all NHL cases • Age-adjusted annual incidence of CTCL is estimated around 4.1 to 6.4 cases per million • Median age at diagnosis is 55-65 yrs > Two-thirds present with early stage disease (IB-IIA) • Factors predictive of disease progre
Slide 15: CTCL Landscape: Survival per WHO-EORTC Subtype
CTCL LANDSCAPE SURVIVAL PER WHO-EORTC SUBTYPE * Depending on TNMB stage Mycosis fungoides (MF) and Sézary syndrome (SS), its leukemic variant, are the most common CTCL subtypes. Overall survival depends in part on disease subtype. Agar et al, JCO 2010; Kempf et al, Blood 2011; Willemze, Blood 1997;
Slide 16: Survival Decreased with Advancing T Class and Clinical Stage
SURVIVAL DECREASED WITH ADVANCING T CLASS AND CLINICAL STAGE DSS UTILIZING REVISED STAGING SYSTEM Plaque worse than patch disease Agar et al. J Clin Oncol 2010;28:4730 Page 16
Slide 17: Current Clinical Management of CTCL, 2015
CURRENT CLINICAL MANAGEMENT OF CTCL, 2015 WWW.NCCN.ORG => NHL => MF/SS IA IB/IIA IIB III IV Limited Generalized Tumors Erythroderma Extracutan patch/plaque patch/plaque disease Topical steroid, retinoid (bex), NM ECP + IFN, bexarotene phototherapy, local RT, imiquimod Phototherapy + bexarotene or IF
Slide 18: Efficacy of Systemic Agents in CTCL
EFFICACY OF SYSTEMIC AGENTS IN CTCL ONLY 4 AGENTS WITH FDA APPROVAL, 1 WITH EU APPROVAL Efficacy data for FDA approval Agent (Class) Indication Year Study N ORR DOR Romidepsin CTCL with prior Pivotal 96 34% 15 mo (HDAC inhibitor, systemic 2009 not approved in EU) therapy Supportive 71 35% 11 mo Vori
Slide 19: Targets for Immunotherapy with Monoclonal Antibodies in CTCL
TARGETS FOR IMMUNOTHERAPY WITH MONOCLONAL ANTIBODIES IN CTCL Monoclonal antibodies Tumour-cell-specific Microenvironment Tumour-surface Immune modulation molecules CTLA-4, PD1, CD4, CD25, CD30, PD-L1, Treg CD52, CD158k, CCR4 CCR4, C-C chemokine receptor type 4; CTCL, cutaneous T-cell lymphoma; CTLA-
Slide 20: Landscape of Monoclonal Antibodies in CTCL
LANDSCAPE OF MONOCLONAL ANTIBODIES IN CTCL • Anti-CD52 mAb (alemtuzumab) • Anti-CD30 mAb (brentuximab vedotin) • Anti-CCR4 mAb (mogamulizumab/KW-0761) • Anti-PD1 mAb (nivolumab) • Anti-CD158k mAb (IPH4102) mAb, monoclonal antibody. Page 20
Slide 21: Alemtuzumab (Anti-CD52)
ALEMTUZUMAB (ANTI-CD52) • CD52 antigen, expressed by most T and B lymphocytes • In retrospective studies: > RR range: 38 to 86% > Median time to progression: 3 – 12 months • Good efficacy in Sézary syndrome at high dose • Lead to severe immune depletion and opportunistic infections • Lack of long du
Slide 22: Drugs in Development in CTCL: Brentuximab Vedotin
DRUGS IN DEVELOPMENT IN CTCL BRENTUXIMAB VEDOTIN (ANTI-CD30 DRUG CONJUGATE) • CD30: is expressed on activated B, T and NK cells, and activated monocytes in hematopoietic tissues. • Brentuximab vedotin (SGN-35) is a chimeric anti-CD30 mAb conjugated to monomethyl auristatin E (MMAE), a cytotoxic anti
Slide 23: Drugs in Development in CTCL: Brentuximab Vedotin
DRUGS IN DEVELOPMENT IN CTCL BRENTUXIMAB VEDOTIN (ANTI-CD30 DRUG CONJUGATE) • Preliminary results: > 2 Phase II studies (48 pts with CD30+ MF/SS and LPD; 30 pts with MF/SS with various degree of CD30 expression) > ORR ~ 70%; CR rate 35 and 3% respectively > Median duration of response ~ 32+ weeks >
Slide 24: Drugs in Development in CTCL: Mogamulizumab
DRUGS IN DEVELOPMENT IN CTCL MOGAMULIZUMAB (ANTI-CCR4) CCR4: trafficking receptor for systemic memory Th2 and regulatory T cells to skin and lung Wilcox RA, 2015 Page 24
Slide 25: Drugs in Development in CTCL: Mogamulizumab
DRUGS IN DEVELOPMENT IN CTCL MOGAMULIZUMAB (ANTI-CCR4) • Preliminary results: > Phase I/II study in MF + SS patients (38 evaluable pts): • ORR = 36.8% (28.6% in 21 MF patients and 47.1% in 17 SS patients) • Median PFS = 11.4 months • Median DOR = 10.4 months • Mogamulizumab well tolerated • Approved
Slide 26: Drugs in Development in CTCL: PD-1 Inhibitor Nivolumab
DRUGS IN DEVELOPMENT IN CTCL PD-1 INHIBITOR NIVOLUMAB • PD-1 expression was evidenced in CTCL • Preliminary results: > Phase I study of nivolumab in pts with relapsed or refractory lymphoid malignancies: 105 patients including 13 with mycosis fongoides > ORR in MF: 2/13 (15%), no complete response L
Slide 27: From KIR3DL2 to IPH4102, a New Targeted Therapy for CTCL
FROM KIR3DL2 TO IPH4102, A NEW TARGETED THERAPY FOR CTCL Page 27
Slide 28: KIR3DL2: A Specific Marker of CTCL Cells
KIR3DL2 A SPECIFIC MARKER OF CTCL CELLS Page 28
Slide 29: How Can We Find New Efficient Treatments for CTCL Patients?
HOW CAN WE FIND NEW EFFICIENT TREATMENTS FOR CTCL PATIENTS ? • Genomic studies to identify mutations and relevant targets within various signaling pathways • Non specific immunotherapy: unleashing the immune system by releasing its negative regulatory checkpoints • Specific immunotherapy: identifyin
Slide 30: T Cell Clones Isolated from CTCL
T CELL CLONES ISOLATED FROM CTCL MAY ARISE FROM TUMOR T LYMPHOCYTES BUT ALSO FROM REACTIVE T LYMPHOCYTES Page 30
Slide 31: KIR3DL2 Is a Phenotypic Marker for Sézary Cells
KIR3DL2 IS A PHENOTYPIC MARKER FOR SEZARY CELLS Patient #19 Patient #20 Patient #17 Clonal leukemic Sézary cells, defined by a single Vβ chain expression, are KIR3DL2+ in patient blood. 100 80 Spearman r = 0.6609 %CD4 +KIR3DL2+ p < 0.0001 Patient #12 Patient #21 Patient #22 60 40 20 0 0 20 40 60 80
Slide 32: Sézary Syndrome: KIR3DL2 Staining
SÉZARY SYNDROME KIR3DL2 STAINING Page 32
Slide 33: Transformed Mycosis Fungoides: KIR3DL2 Staining
TRANSFORMED MYCOSIS FUNGOIDES KIR3DL2 STAINING Page 33
Slide 34: Primary Cutaneous Anaplastic Large Cell Lymphoma: KIR3DL2 Staining
PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA KIR3DL2 STAINING Page 34
Slide 35: Cutaneous γ/δ T-Cell Lymphoma: KIR3DL2 Staining
CUTANEOUS γ/δ T-CELL LYMPHOMA KIR3DL2 STAINING Page 35
Slide 36: Extranodal NK/T Lymphoma, Nasal Type: KIR3DL2 Staining
EXTRANODAL NK/T LYMPHOMA, NASAL TYPE KIR3DL2 STAINING Page 36
Slide 37: Primary Cutaneous Aggressive Epidermotropic CD8+ T-Cell Lymphoma: KIR3DL2 Staining
PRIMARY CUTANEOUS AGGRESSIVE EPIDERMOTROPIC CD8+ T-CELL LYMPHOMA KIR3DL2 STAINING Page 37
Slide 38: CTCL Landscape: KIR3DL2 Expression by WHO-EORTC Subtype
CTCL LANDSCAPE KIR3DL2 EXPRESSION BY WHO-EORTC SUBTYPE KIR3DL2 is expressed in ~65% of all CTCL, irrespectively of disease subtype. Expression is more prominent in Sézary syndrome, transformed mycosis fungoides and CD30+ LPD (ALCL subtype). Page 38
Slide 39: Rationale for Developing an Anti-KIR3DL2 Immunotherapy
CTCL RATIONALE FOR DEVELOPING AN ANTI-KIR3DL2 IMMUNOTHERAPY Page 39
Slide 40: NK Cells of Sézary Patients Are Functional
NK CELLS OF SEZARY PATIENTS ARE FUNCTIONAL Bouaziz et al, J Invest Dermatol, 2005 Page 40
Slide 41: NK Lysis of Tumor Cells Is Enhanced via an ADCC Mechanism
NK LYSIS OF TUMOR CELLS IS ENHANCED VIA AN ADCC MECHANISM Bouaziz et al, J Invest Dermatol, 2005 Page 41
Slide 42: Is It Possible to Develop a Specific Anti-KIR3DL2 Immunotherapy?
IS IT POSSIBLE TO DEVELOP A SPECIFIC ANTI-KIR3DL2 IMMUNOTHERAPY ? • Inhibitory receptor, member of the Killer Immunoglobulin-like Receptor (KIR) family • Specific expression of KIR3DL2 on the malignant CTCL clone, in skin or circulating in blood > In healthy individuals, there is limited expression
Slide 43: Strategy for Generation and Testing of Anti-KIR3DL2 Therapeutic Antibodies
STRATEGY FOR THE GENERATION AND TESTING OF ANTI-KIR3DL2 THERAPEUTIC ANTIBODIES Marie-Cardine A, et al. Cancer Res. 2014;74:6060-70. Page 43
Slide 44: IPH4102 Key Features
IPH4102 KEY FEATURES • Selective binding to human KIR3DL2 with high affinity > No cross-reaction to other human KIRs • Humanized IgG1 designed to deplete KIR3DL2-positive tumor cells • Compelling efficacy in non clinical studies (large set of in vitro, in vivo and ex vivo models) > Main MOA include
Slide 45: IPH4102 Efficacy in Mouse IV Models
IPH4102 EFFICACY IN MOUSE IV MODELS IPH4102 improves survival in a dose-dependent manner 100 10 µg IC 0.01 µg IPH4102 80 Percent survival 0.1 µg IPH4102 1 µg IPH4102 60 10 µg IPH4102 40 20 0 0 20 30 40 50 60 Days (post cell injection) End of Study Mice: SCID (n = 8) RAJI-KIR3DL2: 5 M IV at D0 IPH410
Slide 46: IPH4102 Efficacy Ex Vivo: Autologous ADCC
IPH4102 EFFICACY EX VIVO: AUTOLOGOUS ADCC EXPERIMENTAL CONDITIONS • Fresh blood taken from Sézary Syndrome patients Lympho. Gate • CD4 and NK cells separately sorted from 103 4.05 0.09 PBMC of the same patient (by negative 102 NK cells selection) CD56 • NK and CD4 mixed at various E/T ratios + 101 S
Slide 47: IPH4102 Efficacy Ex Vivo: Autologous ADCC Results
IPH4102 EFFICACY EX VIVO: AUTOLOGOUS ADCC EFFICACY RESULTS Patient #10 Patient #11 Patient #17 Patient #7 100 100 30 50 80 80 40 %7AAD+ CD4+ IPH4102 Sézary cells 20 % killing rituximab 60 60 30 alemtuzumab 40 40 20 10 20 20 10 0 0 0 0 E/T ratio IPH4102 as potent as alemtuzumab in ex vivo autologous
Slide 48: IPH4102-101 FIH Clinical Study Overview
IPH4102-101 FIH CLINICAL STUDY OVERVIEW Page 48
Slide 49: IPH4102-101 First-in-Human Study Design: Overview
IPH4102-101 FIRST-IN-HUMAN STUDY DESIGN OVERVIEW • First-in-Human Phase I study of IPH4102 • Dose-escalation + cohort expansion study • Dose-escalation part: > 10 dose levels of repeated administrations of IPH4102 > Modified 3+3 design with accelerated titration > First patient expected to be treate
Slide 50: IPH4102-101 First-in-Human Study Design: Overview
IPH4102-101 FIRST-IN-HUMAN STUDY DESIGN OVERVIEW • Patient population: > Relapsed/refractory (≥ 2 previous lines of systemic therapy) CTCL patients • All subtypes eligible > For MF/SS patients: clinical stage ≥ IB > KIR3DL2-positivity on skin biopsies is required for eligibility • Centrally assessed
Slide 51: IPH4102-101 First-in-Human Study Design: Objectives
IPH4102-101 FIRST-IN-HUMAN STUDY DESIGN OBJECTIVES • Primary objective: to assess safety & tolerability of increasing IV doses of single agent IPH4102 by: > Characterizing the dose-limiting toxicities (DLT) and (S)AEs > Identifying the MTD or Recommended Ph 2 Dose (RP2D) • Secondary objectives: > To
Slide 52: IPH4102-101 First-in-Human Study Design
IPH4102-101 FIRST-IN-HUMAN STUDY DESIGN STUDY DESIGN • Dose-escalation Part: • Cohort expansion Part: accelerated 3+3 design same dose for all: RP2D pts with KIR3DL2+ tumors pts with KIR3DL2+ tumors all CTCL subtypes eligible pre-selected CTCL subtypes Dose- level 10 3 (+3) pts Dose- level 4 Recomme
Slide 53: IPH4102-101 Participating Sites
IPH4102-101 FIRST-IN-HUMAN STUDY DESIGN PARTICIPATING SITES • Two-continent Phase I study • Clinical sites (dose-escalation part): > St Louis Hospital, Paris France (M Bagot) > UMC Leiden, the Netherlands (M Vermeer) > Guy’s and St Thomas’ Hospital, London UK (S Whittaker) > Stanford U, Stanford CA,
Slide 54: Acknowledgements
Unit 976 (Paris, France) Innate Pharma (Marseille, France) A. Bensussan H. Sicard R. Joly N. Thonnart N. Viaud S. Chanteux A. Marie-Cardine M. Bléry B. Rossi L. Michel C. Bonnafous L. Gauthier C. Paturel Dept of Dermatology St Louis Hospital, Paris, France M. Bagot C. Ram-Wolff Dept of Pathology Dep