Odyssey: A first-in-human study of the aldehyde dehydrogenase (ALDH) inhibitor abd-3001 in patients with refractory/relapsed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS)

Abstract Background Despite therapeutic advances in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (HR-MDS), outcomes for patients with relapsed/refractory (R/R) disease remain dismal. Novel therapeutic targets are urgently needed. One such target is aldehyde dehydrogenase 1 (ALDH1), whose overexpression is associated with chemoresistance and poor prognosis. ABD-3001 is a first-in-class, selective ALDH1 inhibitor developed as a single agent in R/R AML (NCT05601726). We report data from the Dose Ranging Study (DRS) of an ongoing Phase 1, multicenter trial evaluating ABD-3001 monotherapy in R/R AML and HR-MDS. The primary objective is to determine the recommended Phase 2 dose (RP2D) and assess safety and tolerability. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity at the RP2D. Methods Patients (pts) in the DRS received ABD-3001 intravenously on a 28-day cycle for up to 3 cycles. Three dosing regimens were evaluated: 270 mg/m² once weekly (QW), 270 mg/m² twice weekly (BIW), and 405 mg/m² BIW. Adverse events (AEs) were graded per NCI CTCAE v5.0. The safety population included all pts receiving ≥1 dose of ABD-3001. Efficacy was assessed per ELN 2017 criteria in pts who completed ≥1 treatment cycle. Target engagement was evaluated via ALDH1 activity in peripheral blood and phosphorylation of JNK (pJNK) as a molecular PD marker. Results As of July 22, 2025, 19 pts (16 AML, 3 HR-MDS) were treated (median age: 71 years [range 29–90]; 47% female; 63% ECOG PS 1). ELN 2022 risk was adverse in 11 pts (58%) and intermediate 4 pts (21%). Median number of prior therapies was 3 cycles (range 2–10); 81% had prior venetoclax + azacitidine exposure and 2 pts (10%) were post-HCT. 4 TP53 (27%), 5 N/KRAS (33%) and 1 FLT-3-ITD (6%) mutation were detected in pts. Treatment-related AEs (TRAEs) of any grade occurred in 15/19 pts (79%). The most common TRAEs were infusion-related reactions (IRRs, 16%), fever (11%), back pain (11%), and nausea (11%). Grade ≥3 TRAEs were reported in 5 pts (26%), including IRR (5%), diffuse interstitial pneumonitis (5%), dyspnea (5%), and febrile neutropenia (5%). ABD-3001-related dose interruptions occurred in 3 pts (16%), one in each dosing level. Among 13 evaluable pts, 1 achieved complete remission (CR). Six pts (46%) showed a reduction in bone marrow blasts, including 2 with ≥50% decrease. After a median follow-up of 13 weeks, overall survival median of all treated pts is not reached yet. PK analysis confirmed systemic exposure across all doses, with non-dose-proportional increases and no drug accumulation over 3 cycles. PD assessments demonstrated ALDH1 inhibition and pJNK activation, with the 270 mg/m² dose showing greater target engagement than 405 mg/². Conclusions ABD-3001 demonstrated an acceptable safety profile across all dosing regimens in this first-in-human Phase 1 study. Preliminary evidence of anti-leukemic activity was observed, including blast reduction in nearly half of evaluable patients and one CR. PD data confirmed target engagement and biological activity in peripheral blasts. These findings support continued evaluation of ABD-3001 in order to select a potentially optimal dose for further clinical development.