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

Abstract

Abstract Background: LYT-200 is a fully human IgG4 monoclonal antibody targeting galectin-9 (Gal-9), a key mediator of oncogenesis and immunosuppression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). This study evaluates the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of LYT-200 as monotherapy and in combination with venetoclax (VEN) plus hypomethylating agents (HMA) in patients with relapsed/refractory (R/R) AML or high-risk MDS and aims to identify the recommended Phase 2 dose (RP2D). Methods: A Phase 1 dose-escalation trial is conducted using a 4+2 design with backfill cohorts in both single-agent (SA, n = 39) and combination cohorts (CC; n = 59; LYT-200 + VEN/HMA). LYT-200 is administered weekly i.v. (QW) across dose levels of 2–16 mg/kg. An expansion cohort (n = 30) at the RP2D has been fully accrued. Results: As of July 8, 2025, 94 patients received ≥1 dose of LYT-200 (SA: n=39; CC: n=55). Median age was 69 (range 46–83) in SA and 74 (49–88) in CC. Patients included primary and secondary AML and MDS with complex cytogenetics and mutations (e.g., TP53, FLT3, IDH1/2, KRAS, NRAS, BRAF, JAK2). Median prior therapies were 3 (range 1–7 SA; 1–5 CC). No dose-limiting toxicities (DLTs), treatment-related serious adverse events (SAEs), or LYT-200-related discontinuations/deaths were observed. Treatment-related Grade 1/2 AEs (nausea, diarrhea, fatigue, rash, pruritus) occurred in <30% (SA) and <10% (CC). In SA cohorts (≥7.5 mg/kg), 1 marrow complete response (mCR) and 3 partial responses (PRs) were observed, with additional 48% achieving disease stabilization (hematologic improvement, blast reduction). One PR patient at 7.5mg/kg is in a 6th-line R/R, post-transplant AML patient, who remains on therapy at 24 months with near-doubling of donor chimerism. In CC, responses are seen from the dose level of 7.5mg/kg LYT-200 + VEN/HMA, where we observed 2 CRs of which one proceeded to transplant, as well 50% of patients with stable disease (out of n = 10 evaluable patients). At the dose level of LYT-200 of 12mg/kg in combination with Ven/HMA, in n = 26 evaluable patients as of July 9th 2025, the combined CR rate is 38% (n = 10) of which 2 have moved to transplant, overall response rate (ORR) 46% which includes an additional PR and an MLFS response, clinical stabilization is 42%, and disease control rate 88%. Median event-free survival (EFS) is 7 months and overall survival (OS) 9 months in patients treated for ≥3 months. Notably, responders had previously failed VEN/HMA. Some patients who achieve CR also have KRAS, NRAS, HRAS and JAK2 mutations and were previously fully refractory to VEN/HMA. Dose of 12mg/kg of LYT-200 is being considered as an RP2D. Conclusions: LYT-200 demonstrates favorable safety and promising activity in R/R AML/high-risk MDS, including in VEN/HMA-refractory patients. Responses occurred across diverse molecular subtypes. These findings support further evaluation of LYT-200 in a Phase 2 program. Detailed response data including topline efficacy across dose levels, updated survival and PK / pharmacodynamic (PD) data will be presented.