Iadademstat

Overview

Iadademstat (ORY-1001; RG-6016; RO-7051790) is an oral, highly potent, selective, covalent inhibitor of lysine-specific demethylase 1 (LSD1/KDM1A) in clinical development for hematologic malignancies and small-cell lung cancer (SCLC). Early clinical activity has been reported as monotherapy in relapsed/refractory acute myeloid leukemia (AML) and in combination with azacitidine in newly diagnosed, unfit AML; SCLC studies have explored combinations and are moving to immune checkpoint inhibitor–based regimens. (ascopubs.org)

Mechanism of action

• Target: LSD1/KDM1A, a histone demethylase and chromatin-associated scaffold involved in maintaining leukemic stemness and neuroendocrine programs. Iadademstat forms a covalent adduct with the FAD cofactor, inhibiting demethylase activity and disrupting LSD1’s protein–protein interactions (e.g., with GFI1/SNAG), thereby promoting differentiation. (pubmed.ncbi.nlm.nih.gov)
• Disease biology links: In SCLC models, LSD1 inhibition by ORY‑1001 reactivates NOTCH signaling, suppresses ASCL1, and impairs tumor growth; robust preclinical antileukemic effects and biomarker strategies have also been reported. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Acute myeloid leukemia
- Monotherapy (first‑in‑human, relapsed/refractory AML): Among 27 patients in dose escalation, pharmacodynamic differentiation and blast reductions were observed; one complete remission with incomplete count recovery (CRi) occurred. Recommended monotherapy dose: 140 µg/m²/day (5 days on/2 off, weekly, 28‑day cycles). (ascopubs.org)
- Combination with azacitidine (ALICE, phase 2a; newly diagnosed, unfit AML): Final peer‑reviewed results reported objective responses in 22/27 (82%; 95% CI 62–94), with 14/27 (52%) CR/CRi; 10/11 evaluable CR/CRi achieved MRD negativity. The recommended phase 2 dose with azacitidine was 90 µg/m²/day. Median overall survival exceeded one year in the study population. (pubmed.ncbi.nlm.nih.gov)

Small-cell lung cancer
- CLEPSIDRA (phase IIa, second‑line, platinum‑sensitive ED‑SCLC): Iadademstat plus carboplatin/etoposide showed signals of activity but was limited by hematologic toxicity from the chemotherapy backbone. Across 10 evaluable patients, objective response rate was 40% (4 PRs) with additional durable stable disease (>4 months) in 2 patients; one case maintained prolonged disease control on iadademstat maintenance. The triplet was deemed unsuitable for this setting due to hematologic adverse events. (biotech-spain.com)
- Ongoing direction in SCLC: A National Cancer Institute–sponsored phase I/II is testing iadademstat with atezolizumab or durvalumab as maintenance after initial chemo‑immunotherapy in extensive‑stage SCLC (first patient dosed April 15, 2025). (oryzon.com)

Other ongoing studies
- AML: NCI‑sponsored phase I trial adds iadademstat to venetoclax plus azacitidine in newly diagnosed AML (first patient dosed January 13, 2025). (oryzon.com)
- MDS: Investigator‑initiated phase I dose‑finding study of iadademstat plus azacitidine in myelodysplastic syndromes (first patient dosed January 23, 2025). (oryzon.com)

Safety

• Monotherapy (R/R AML): Most adverse events reflected the underlying disease and included infections and cytopenias; drug‑related events included fatigue, diarrhea, anorexia, dysgeusia, and thrombocytopenia. Differentiation syndrome occurred (including one fatal case considered certainly related). (ascopubs.org)
• Combination with azacitidine (ALICE): Reported as having a manageable safety profile at 90 µg/m²/day with high target engagement; detailed safety outcomes appear consistent with expected myelosuppression from hypomethylating therapy plus LSD1 inhibition. (pubmed.ncbi.nlm.nih.gov)
• Combination with platinum/etoposide in SCLC (CLEPSIDRA): Hematologic toxicity (thrombocytopenia, neutropenia, anemia) was frequent and dose‑limiting for the triplet in second‑line SCLC; iadademstat maintenance alone did not show hematologic, neurologic, renal, or hepatic toxicity in reported cases. (edisongroup.com)

Further reading

• First‑in‑human AML monotherapy study (JCO, 2020). (ascopubs.org)
• ALICE phase 2a final results in newly diagnosed, unfit AML (Lancet Haematology, 2024). (pubmed.ncbi.nlm.nih.gov)
• Preclinical leukemia program and covalent mechanism (Cancer Cell, 2018). (pubmed.ncbi.nlm.nih.gov)
• Mechanistic work in SCLC: NOTCH activation and ASCL1 suppression (preclinical). (pubmed.ncbi.nlm.nih.gov)
• CLEPSIDRA SCLC trial summaries (ESMO 2020 update). (biotech-spain.com)
• Program summary and MOA notes (sponsor). (oryzon.com)

Notes on status as of October 2025: Iadademstat is investigational; no marketing approvals were identified. Multiple NCI‑sponsored trials are active or initiating in AML and SCLC. (oryzon.com)

Last updated: Oct 2025