A Phase I Dose Escalation and Expansion Trial of Lyt-200 (a First-In-Class Anti-Galectin-9 Antibody) Alone and in Combination with Venetoclax/HMA in Relapsed/Refractory AML/MDS

INTRODUCTION: LYT-200 is a fully human, IgG4 monoclonal antibody (mAb) targeting galectin-9 (Gal-9). Gal-9 is a potent oncogenic and immunosuppression protein in hematological malignancies and solid tumors. In vitro and in vivo, in AML models, LYT-200 exerts direct anti-leukemic effects via apoptosis and DNA damage and with venetoclax (VEN) and standard of care (SOC) chemotherapy further enhances survival and protect from long term AML relapse in animal models. LYT-200 is being evaluated clinically as monotherapy and in combination with VEN/hypomethylating agents (HMA) in a US Phase I trial of patients (pts) with relapsed/refractory (R/R) AML/high-risk MDS (NCT05829226 on www.clinicaltrials.gov).

AIMS: To assess the safety, tolerability, and pharmacokinetics (PK) of LYT-200 and LYT-200 + VEN/HMA, in R/R AML/high-risk MDS, and to support selection of a recommended phase 2 dose(s) and expansion studies.

METHODS: This trial enrolls pts in single agent (SA) and combination cohorts (CC) using the 4+2 study design. Dose escalation of SA cohorts has completed enrollment into all 5 dose levels of LYT-200: 2 mg/kg; 4 mg/kg; 7.5 mg/kg; 12 mg/kg and 16 mg/kg weekly (QW). CC of LYT-200 + VEN/HMA has thus far completed enrollment of 3 cohorts with VEN/HMA administered as SOC and LYT-200 at dose levels of 4 mg/kg, 7.5 mg/kg and 12 mg/kg. Bone marrow (BM) assessment is done at cycle 2 day 1 (C2D1), C3D1 and Q3 month thereafter. Treatment emergent adverse events (TEAEs) and initial clinical responses are evaluated using CTCAE 5.0 and ELN 2017 criteria, respectively. Pharmacodynamic markers (PD) are evaluated using Nanostring in peripheral blood mononucleocytes (PBMCs).

RESULTS: As of 23July2024, 37 pts in total have been treated with at least one dose of LYT-200 in SA and CC. 2 pts with R/R AML, and 4 pts with R/R high risk MDS received LYT-200 as SA; and 9 pts with R/R AML and 2 pts with R/R high risk MDS received LYT-200 with VEN+HMA. Median age was 69 (46-83) in SA and 74 (49-88) in CC. 8 pts (26%) had secondary AML, 12 pts (32%) had TP53 mutations, 1 pt (3%) had an IDH2 mutation. Median prior lines of treatment was 3 across SA and CC (range 1-7 for SA and 1-5 for CC). In LYT-200 SA cohorts DLT evaluable set (pts who completed at least 4 doses of LYT-200) (n=20), 2 pts achieved partial response (PR) and 10 pts stable disease. Median time on LYT-200 is 8 weeks (4-44). In cohort 3 SA (LYT-200 at 7.5 mg/kg), clinical benefit (SD, PR, CR, CRi, MLFS) was 100%, of which 25% PR. One PR patient is still active on study for 11 months, with recovery of donor chimerism from HSCT in 2021, from 35% at C1D1 to 67% at C9D1 of LYT-200.

In the CC DLT evaluable set to date (n=8), clinical benefit was observed in 7 pts (88%), 6 SD and 1 CRi, both in previously VEN refractory pts. Median time on LYT-200 in first two CC is 13.5 wks (4-29). Accrual in CC is ongoing.

LYT-200 has been well tolerated, with no DLTs observed at doses ranging from 2mg/kg to 16mg/kg QW in SA and 4mg-12mg/kg in CC, to date. In SA and CC, no serious, related TEAs occurred. 1 pt had a grade 3 infusion related reaction at 12 mg/kg SA.

Based on an initial population PK analysis, exposure was linear over the range of doses tested 2mg/kg-16 mg/kg QW. Estimated PK parameters were consistent with other IgG4 mAbs, with a geometric mean (geometric %CV) elimination t½ of 6.2 (24.1%) days.

PD analyses of the initial SA pts dataset, using Nanostring, show that pts with BM blast reductions of <50% from baseline and peripheral blasts clearance, exhibit activation of pathways related to NK cells, T cells, and PD1/PDL1, and downregulation of LGALS9 (Gal9) gene, compared to pts with progressive disease or transfusion independence without blast reduction.

CONCLUSIONS: LYT-200 represents a novel therapeutic approach in AML/MDS that targets a pivotal onco-immunosuppressor galectin-9. LYT-200, as single agent and in combination with VEN/HMA is safe, well-tolerated, and shows initial clinical activity. Responses were seen at SA and CC at dose levels from 7.5mg/kg, among diverse AML genotypes, including pts with prior VEN/HMA primary refractory disease, and TP53 mutations. Initial PD data, indicate the mode of action of LYT-200 by downregulating Gal-9, and activating NK and T cells. Mature clinical data, full PK and PD analyses will be presented at ASH. Our study supports LYT-200 as a novel, safe and promising therapeutic agent in AML/MDS and provides rationale for dose level selection for further expansion and a Phase 2 program.