Slide 1: Preliminary PK and PD Analysis of the CD123 NK Cell Engager SAR443579
Preliminary Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the CD123 NK Cell Engager (NKCE) SAR443579 in Patients (pts) with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-cell Acute Lymphoblastic Leukemia (B-ALL) or High Risk-Myelodysplasia (HR-MDS) Mojca Jongen-Lavrencic1,
Slide 2: Disclosures
Disclosures • No conflicts of interest to declare 2
Slide 3: Background
Background • CD123 is widely expressed in hematological malignancies1-4 • T cell engagers targeting CD123 have displayed some preliminary clinical efficacy but show some safety concerns of cytokine release syndrome and neurotoxicity5 • SAR443579 (SAR’579) is a trifunctional anti-CD123 NKp46xCD16 nat
Slide 4: First-in-Human Dose Escalation & Enrollment
First-in-Human Dose Escalation & Enrollment Dose Escalation Part R/R-AML, HR-MDS, B-ALL Determine maximum tolerated or administered dose based on 6 initial dose levels (Bayesian Logistic Regression Model) incidence of dose-limiting toxicity in cycle 1 (28-day cycles) IV Dose in µg/kg DL1 DL2 DL3 DL4
Slide 5: Safety and Efficacy Update
Safety and Efficacy Update* • Most common treatment related adverse events remain consistent with previous report1 • CR/CRi achieved in 3 of 8 (37.5%) participants treated at a maximal target dose of 1000 µg/kg/infusion (DL3-DL4)1,2 • Two responders remain in remission after 8.8 and 12.2 months of t
Slide 6: Pharmacokinetics: Mean Plasma Concentration
Pharmacokinetics: Mean Plasma Concentration Cycle 1: Mean Plasma Concentration (DL1-6) Cycle 1: Mean Plasma Concentration (DL1-6) 100000 120000 SAR'579 plasma concentration (ng/mL) SAR'579 plasma concentration (ng/mL) 10000 100000 1000 80000 100 60000 40000 10 20000 1 0 0.1 D1 D4 D8 D11 D15 D22 D28
Slide 7: Pharmacokinetics: Mean Cmax and Ctrough Concentrations
Pharmacokinetics: Mean Cmax and Ctrough Concentrations Cmax: Cycle 1 (DL1-6) Ctrough: Cycle 1 (DL1-6) 160000 100000 DL1 - 100 µg/kg DL1 - 100 µg/kg 140000 DL2 - 300 µg/kg DL2 - 300 µg/kg DL3 - 1000 µg/kg DL3 - 1000 µg/kg 80000 DL4 - 1000 µg/kg DL4 - 1000 µg/kg 120000 DL5 - 3000 µg/kg DL5 - 3000 µg/k
Slide 8: Pharmacodynamics: AML Blast Assessment
Pharmacodynamics: AML Blast Assessment Whole Blood Bone Marrow CRi CR CR Total Blast Number Best % change (baseline) • High variability in baseline AML blasts (marrow and peripheral blood) • AML blast reductions observed across all SAR’579 dose levels 8 NE, non-evaluable; RD, resistant disease.
Slide 9: Pharmacodynamics: NK and AML Blasts in Peripheral Blood at Baseline
Pharmacodynamics: NK and AML Blasts in Peripheral Blood at Baseline Targets (Blasts) Effectors (NK cells) Effector-to-Target (E/T) Ratio • High variability in baseline NK cell counts and E:T ratio • Insufficient data to correlate with response 9 Whole blood characterized by Flow Cytometry
Slide 10: Pharmacodynamics: Expression of CD123 and NKp46
Pharmacodynamics: Expression of CD123 and NKp46 CD123 Receptor Density CD123 Blasts NKp46 NK cells • CD123 expression measured in all patients • High variability in density of CD123 expression • Robust expression (>60%) of NKp46 in all patients 10 sABC, specific antibody binding capacity. Whole bloo
Slide 11: NK Cell Modulation in Peripheral Blood
Pharmacodynamics: NK Cell Modulation in Peripheral Blood Dose Levels 1 4 2 5 3 6 NK Cell Concentrations in Peripheral Blood (Cycles 1&2) % Change from NK Cells/µl Screening • Transient decrease in peripheral blood NK cells in all patients (peak between 4-24h) 11 h, hours.
Slide 12: Pharmacodynamics: Plasma Cytokine Levels (Cycle 1)
Pharmacodynamics: Plasma Cytokine Levels (Cycle 1) Dose Levels IL-6 TNFα 1 TNF-α 4 IL-8 2 5 6 Median pg/ml 3 (min; max) Median pg/ml (min; max) IFNγ IFN-γ IL-8 IL-6 Median pg/ml Median pg/ml (min; max) (min; max) • Transient increases in pro-inflammatory cytokines (IFNγ, TNFα, IL-8) after 1-3h after
Slide 13: Summary and Conclusions
Summary and Conclusions Safety/Efficacy • SAR’579 was well tolerated up to dose of 3000 µg/kg QW with clinical benefit in patients with R/R AML and additional dose levels are being investigated Pharmacokinetics/ADA • PK linearity was achieved from Cycle 1 at 3000 µg/kg QW (TMDD) • Preliminary incide
Slide 14: Acknowledgments
Acknowledgments WE WOULD LIKE TO THANK: Participating patients France and their families Netherlands Study investigators and staff United States All staff who contributed to data collection Australia and analysis Study funding: Sanofi Thank you for your attention Copies of this presentation obtained