823O - 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)

Background

SAR’579, a trifunctional anti-CD123 NKp46×CD16 NKCE, enabling a cytolytic synapse between natural killer (NK) cells and CD123+ tumor cells leading to NK cell activation and tumor cell killing. We report preliminary PK/PD of SAR’579 from a phase 1/2 trial in pts with R/R AML, B-ALL or HR-MDS (EudraCT 2021-004287-98 Apr 26, 2023/NCT05086315).

Methods

SAR’579 was administered IV twice weekly or once weekly (QW) per dose level (DL) in first 2 weeks of cycle 1 and QW for rest of induction cycles. Peripheral blood (to measure plasma concentrations and immunogenicity assessment) and bone marrow samples were collected for PK/PD analysis during each induction cycle. Analysis of cytokines, as potential safety and PD markers, including IL-6, TNFα and IFNγ, was performed using Meso Scale Discovery®.

Results

From Dec 14, 2021, to Oct 17, 2022, 19 pts were treated across 5 DLs (3 in DL1 and 4 each in DL2 to DL5) between 10-3000 μg/kg/dose. No dose limiting toxicities were observed. At 1000 μg/kg QW, 3/8 pts achieved complete remission (CR) (2 CR/1 incomplete hematologic recovery). Early immunogenicity was 26% with no impact on safety/efficacy. Post first administration of SAR’579, circulating maximum (max) concentration increased with dose increase with a supra-dose proportionality between DL1 and DL5. PK linearity was achieved at 3000 μg/kg QW (DL5) at the end of cycle 1. Table: 823O

Median (max) peak cytokine concentrations (pg/mL) observed during DL1-5

Cytokine release syndrome levels of IL-6 (>500/1000 pg/mL) were measured in a single DL1 pt.

Conclusions

SAR’579 was well tolerated till 3000 μg/kg QW with clinical benefit in pts with R/R AML. Observed peak cytokine levels did not show significant dose-related increase and no association between elevated peak cytokine levels and clinical responses. The results are consistent with the improved safety profile compared to CD123-targeted T-cell engagers.

Clinical trial identification

EudraCT 2021-004287-98, 26 April 2023; NCT05086315.

Editorial acknowledgement

Deepshikha Khurana, Sanofi Global Hub.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

A. Bajel: Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Other, Honoraria: Amgen, AbbVie, Pfizer, Astellas, Novartis. A. Maiti: Financial Interests, Personal and Institutional, Research Funding: Celgene, Lin BioScience. S. Fleming: Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other, Honoraria: Novartis, Bristol Myers Squibb, Pfizer; Financial Interests, Personal, Advisory Role, Honoraria: Amgen; Financial Interests, Personal, Advisory Role: Novartis, Bristol Myers Squibb, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Amgen, Pfizer; Financial Interests, Personal and Institutional, Research Funding: Amgen. S. De Button: Financial Interests, Personal and Institutional, Research Funding: Agios, Forma Therapeutics; Financial Interests, Personal, Other, Honoraria: AbbVie, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer, Astellas Pharma a/s Nordic Operations. K. Jensen, S. Ziti-Ljajic, D. Draganov, F. Rotolo, C. Palu, J. Courta, W. Passe-Coutrin, K. Traudtner, T. Wagenaar, G. Abbadessa: Financial Interests, Personal, Stocks/Shares, Employed by Sanofi and may hold stock and/or stock options: Sanofi. A. Selwyn Stein: Financial Interests, Personal, Speaker’s Bureau: Amgen. All other authors have declared no conflicts of interest.