Preliminary safety and efficacy results of A phase ib investigation of the LSD1 inhibitor iadademstat (ORY-1001) in combination with azacitidine and venetoclax in newly-diagnosed AML

Abstract Background: Azacitidine combined with venetoclax (AZA+VEN) is the standard of care treatment for older and/or unfit patients (pts) with newly diagnosed acute myeloid leukemia (ND-AML), yet most pts ultimately relapse. For pts without targetable mutations, additional therapies are needed to improve response and survival. Iadademstat (IADA), a lysine-specific demethylase 1 (LSD1) inhibitor, demonstrated synergy with VEN or AZA in pre-clinical models and increased clinical activity with AZA in pts with ND-AML in the Phase 2 ALICE study (EudraCT 2018-000482-36). Whether the triplet therapy of IADA+AZA+VEN is safe and active in ND-AML remains unknown. Herein, we present preliminary safety and activity data from an ongoing Phase 1b study of IADA+AZA+VEN in ND-AML (NCT06357182). Methods: Eligible pts were 75 years old with ND-AML or MDS/AML overlap (10-19% blasts) and ELN 2022 intermediate- or adverse-risk disease. Adult pts 75 with ECOG status ≤ 3 were permitted if they had comorbidities precluding the use of intensive chemotherapy. To identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), pts were enrolled in cohorts of n=3 according to a Bayesian optimal interval (BOIN) dose-finding design with a 20% target toxicity rate. Four dose levels (DLs) of IADA were pre-specified, with a starting DL1 of 100 mcg PO qd, an escalation DL2 of 150 mcg qd, and two de-escalation DLs (-1 and -2), all administered 5 days on, 2 days off. In 28-day (D) cycles (C) of triplet therapy, IADA (D1-5, 8-12 and 15-19) was combined with AZA (75 mg/m² IV or SubQ, D1-7) and VEN (400 mg PO qd, D1-21). The first 6 pts received a 7-day IADA lead-in cycle (C0) before protocol amendment removed this planned correlative C0. The primary endpoint was incidence of dose-limiting toxicities (DLTs), defined as grade (Gr) 4 or 5 non-hematologic adverse events (AE) related to study drug and not related to underlying disease or intercurrent illness occurring in C0 or C1 as well as Gr ≥ 4 neutropenia or thrombocytopenia at 42 days from C1D1 in the absence of disease. MTD-evaluable pts had a DLT and/or took ≥75% of study drug doses during C0-C1. Secondary endpoints included rates of composite complete remission (CRc: complete remission CR + CR with partial hematologic recovery CRh + CR with incomplete recovery CRi), overall response (ORR: CRc + morphologic leukemia-free state MLFS + partial remission PR), and Gr ≥ 3 AEs. Results: As of July 2025, 8 pts (7 ND-AML, 1 MDS/AML) have enrolled: n=3 on DL1 and n=5 on DL2. Median age was 70 years (range: 64-81), 75% were male and 100% White, and median ECOG was 2 (range: 1-2). ELN 2022 risk was adverse in 88% (n=7) and intermediate in 12% (n=1); 4-gene risk was higher-benefit in 88% (n=7), and intermediate-benefit in 12% (n=1). In 6 MTD-evaluable pts, there were 0 DLTs. Among all 8 pts, Gr ≥ 3 AEs included febrile neutropenia (25%; n=2), neutropenia (13%, n=1 Gr 4), tumor lysis syndrome (13%; n=1), and xerostomia (13%, n=1). One Gr 5 event deemed unrelated to study drugs occurred at 1-month in a pt treated at DL2 who had prolonged neutropenia before enrollment on protocol and developed septic shock from presumed fungal pneumonia complicated by ischemic stroke and cerebral edema. The median number of treatment cycles was 2 (range: 1-4). All pts but 1 have discontinued protocol therapy: due to transitioning to allogeneic hematopoietic cell transplantation (n=5), relocation (n=1), and death secondary to septic shock (n=1). ORR was 100% with a CR rate of 88% (n=7/8); One patient attained MLFS as best response. After a median follow-up of 9 months, the estimated 6-month OS was 88%. Median time to ANC ≥ 500/μL and platelets ≥ 50,000/μL amongst responding pts was 32 days in C1 (DL1 n=2: 31 vs. DL2 n=4: 37 days) and 37 days in C2 (DL1 n=3 30 vs. DL2 n=3 39 days). Median number of cycles to best response was 2 (range: 1-4). PK analysis in 8 pts demonstrated increased IADA concentrations at 150 vs. 100 mcg dosing. LSD1-target engagement was higher during C0 with 150 vs. 100 mcg (89% vs. 70%, p 0.05); however, no significant difference was observed by C1D19 (89% vs. 85%, p: ns), indicative of a saturation effect. Conclusion: The novel combination of Iadademstat with AZA+VEN is safe and active in ND-AML, resulting in manageable AEs and high response rates. Enrollment continues at DL2 in this ongoing clinical trial. Additional outcomes and correlative data will be presented at the meeting.