Slide 1: IPH4102, an anti-KIR3DL2 monoclonal antibody in refractory Sézary Syndrome
IPH4102, an anti-KIR3DL2 monoclonal antibody in refractory Sézary Syndrome: Results from a multicenter international phase 1 trial M. Bagot1,2, P. Porcu3, B. William4, M. Battistella1,2, M. Vermeer5, S. Whittaker6, C. Ram-Wolff1,2, M. Khodadoust7, H. Sicard8, H. A. Azim Jr8 and Y. H. Kim7 1Hôpital S
Slide 2: Conflicts of Interest
CONFLICTS OF INTEREST Consultant: Innate Pharma Advisory committee: Innate Pharma, Actelion, Takeda, Kyowa Kirin Equity Ownership: Innate Pharma Bagot M et al, ASH 2018 Page 2
Slide 3: IPH4102: first in class mAb directed against KIR3DL2
IPH4102 FIRST IN CLASS mAb DIRECTED AGAINST KIR3DL2 NK cells kill primary Sézary cells in ex vivo autologous model through IPH4102-mediated ADCC VL IPH4102 Patient #10 Patient #11 KIR3DL2 100 100 30 D0 80 80 %7AAD+ CD4+ IPH4102 Sézary cells rituximab 20 60 60 alemtuzumab D1 40 40 10 20 20 VH 0 0 0 D
Slide 4: IPH4102 improves survival in mouse xenograft models
IPH4102 IMPROVES SURVIVAL IN MOUSE XENOGRAFT MODELS 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 Marie-Cardine A et al, Cancer Res 2014 Bagot M et al, ASH 2018 Page 4
Slide 5: KIR3DL2 is expressed in CTCL particularly in Sézary syndrome
KIR3DL2 IS EXPRESSED IN CTCL PARTICULARLY IN SÉZARY SYNDROME KIR3DL2 expression by IHC in a SS patient EID: erythrodermic inflammatory disease, MF: mycosis fungoides, SS: Sézary syndrome, cALCL: cutaneous anaplastic large cell lymphoma, LyP: lymphoid papylosis, HTLV1 Adult T-cell lymphoma, TNKL nasa
Slide 6: Study design: first in human phase 1 clinical trial
STUDY DESIGN FIRST IN HUMAN PHASE 1 CLINICAL TRIAL Dose-escalation Cohort expansion 10 dose levels (up to 10mg/kg) – accelerated 3+3 design Recommended Phase 2 dose (750 mg) All CTCL subtypes SS and tMF only ≥ 2 prior systemic therapies ≥ 2 prior systemic therapies KIR3DL2 ≥5% in skin
Slide 7: Study objectives
STUDY OBJECTIVES • Primary objective: determination of Maximal Tolerated Dose (MTD) and RP2D, overall safety • Secondary objectives: > Overall Response Rate (ORR, Olsen JCO 2011 criteria), duration of response (DOR) and Progression-Free Survival (PFS) > PK and immunogenicity • Quality of Life > Prur
Slide 8: Baseline disease characteristics, Sézary syndrome (N=35)
BASELINE DISEASE CHARACTERISTICS SÉZARY SYNDROME (N=35) Total N = 35 Median age in years (range) 70 (37 – 90) Evidence of LCT*, n (%) 7 (20%) KIR3DL2 expression, n (%) - Skin 27 (77%) - Blood 33 (94%) - Skin and/or blood 33 (94%) Median time from diagnosis in months (range) 23 (6 – 268) Median N. of
Slide 9: Safety profile: IPH4102 displays a favorable safety profile
SAFETY PROFILE IPH4102 DISPLAYS A FAVORABLE SAFETY PROFILE Dose escalation: no DLT / MTD not reached / RP2D = 10mg/kg - 750 mg flat dose All AEs Related AEs* Common AEs All grades Grade 3-4 All grades Grade 3-4 Peripheral edema 10 (29%) 0 0 0 Asthenia 9 (26%) 0 5 (14%) 0 Fatigue 8 (23%) 0 3 (9%) 0 C
Slide 10: Clinical efficacy results: high overall response rate
CLINICAL EFFICACY RESULTS HIGH OVERALL RESPONSE RATE Best global response Best change in mSWAT as compared to baseline Best global response 42.9% (95% CI: 28.0 – 59.1) Data Cut-off: October 15, 2018 Bagot M et al, ASH 2018 Page 10
Slide 11: Clinical efficacy results: durable responses
CLINICAL EFFICACY RESULTS DURABLE RESPONSES Best global response Duration of response, median (95% CI) 13.8 months (7.2 – NR) Data Cut-off: October 15, 2018 NR: Not Reached Bagot M et al, ASH 2018 Page 11
Slide 12: Clinical efficacy results: long progression free survival
CLINICAL EFFICACY RESULTS LONG PROGRESSION FREE SURVIVAL PFS, median (95% CI) 11.7 months (8.1 – NR) Median follow-up: Data Cut-off: October 15, 2018 14.2 months (95% Ci: 11.8 – 20.5) Bagot M et al, ASH 2018 Page 12
Slide 13: Clinical efficacy results: subgroup analysis
CLINICAL EFFICACY RESULTS SUBGROUP ANALYSIS All SS SS without LCT Prior treatment with mogamulizumab N=35 N=28 N=7 Best global response 42.9% (28.0 – 59.1) 53.6% (35.8 – 70.5) 42.9% (15.8 – 75.0) - CR 2 (5.7%) 2 (7.1%) 0 - PR 13 (37.2%) 13 (46.5%) 3 (42.9%) - SD 16 (45.7%) 11 (39.3%) 3 (42.9%) - PD
Slide 14: Quality of life: Skindex29 (N=35)
QUALITY OF LIFE SKINDEX29 (N = 35) Data Cut-off: October 15, 2018 Bagot M et al, ASH 2018 Page 14
Slide 15: Quality of life: pruritus visual analogue scale score
QUALITY OF LIFE PRURITUS VISUAL ANALOGUE SCALE SCORE (N = 35) Data Cut-off: October 15, 2018 Bagot M et al, ASH 2018 Page 15
Slide 16: Exploratory biomarkers: changes in KIR3DL2 expressing cells in skin
EXPLORATORY BIOMARKERS CHANGES IN KIR3DL2 EXPRESSING CELLS IN SKIN Patient 11-005, global partial response since W10 lasting 1 year and 8 months Baseline Week 5 Baseline Week 64 KIR3DL2: 52% KIR3DL2: 4.4% mSWAT: 80.5/1/0 mSWAT = 5.2/0/0 ^ 77 y old woman, received 6 prior lines of systemic therapies
Slide 17: Exploratory biomarkers: changes in tumor cells and KIR3DL2 in blood
EXPLORATORY BIOMARKERS CHANGES IN TUMOR CELLS AND KIR3DL2 IN BLOOD Aberrant cells KIR3DL2+ CD4+ T cells Patient 01-036, ongoing complete response > 1 year Number CD7- or CD26- CD4+ T cells/µL Number KIR3DL2+ CD4+ T cells/µL Screening W5 W14 TCR-Vβ CD26 KIR3DL2 Bagot M et al, ASH 2018 Page 17
Slide 18: Exploratory biomarkers: reduction in KIR3DL2 / MRD and global response
EXPLORATORY BIOMARKERS REDUCTION IN KIR3DL2 / MRD AT WEEK 5 AND GLOBAL RESPONSE ORR with 95% CI ORR in all patients Global ORR Exploratory analysis unadjusted for possible confounders Global ORR Bagot M et al, ASH 2018 Page 18
Slide 19: Conclusions
CONCLUSIONS • IPH4102 is safe and well tolerated in heavily pretreated relapsed/refractory SS. • IPH4102 shows impressive clinical activity, demonstrated by high and durable response rate and long PFS. • IPH4102 substantially improved QOL even in patients with stable disease. • Exploratory biomarker
Slide 20: Phase 2 study TELLOMAK: T-cell lymphoma anti-KIR3DL2 therapy
PHASE 2 STUDY (N≈250) TELLOMAK : T-CELL LYMPHOMA ANTI-KIR3DL2 THERAPY Sézary Syndrome ≥ 2 prior systemic therapies that must include mogamulizumab IPH4102 single agent Mycosis Fungoides ≥ 2 prior systemic therapies IPH4102 Peripheral T Cell Lymphoma + ≥ 1 prior systemic therapy including anthracycli
Slide 21: Acknowledgements
ACKNOWLEDGEMENTS Dpts of Dermatology & Pathology Stanford Cancer Institute (CA, USA) St Louis Hospital (Paris, France) Youn Kim Martine Bagot Michael Khodadoust Caroline Ram-Wolff Steve Mathieu Ohio State University (OH, USA) Maxime Battistella Basem William Pierluigi Porcu INSERM Unit 976 (Paris, F