Iadademstat

Iadademstat (ORY-1001) is an orally active, highly potent and selective inhibitor of the epigenetic enzyme Lysine Specific Demethylase-1 (LSD1, also known as KDM1A). LSD1 is a key epigenetic enzyme involved in the regulation of gene expression programs controlling cell differentiation, proliferation, and stemness, processes that are frequently dysregulated in cancer. Elevated levels of LSD1 have been correlated with more aggressive types of cancer and poor prognosis across several malignancies.

In hematological cancers such as acute myeloid leukemia (AML), disease progression is characterized by a block in cellular differentiation and the persistence of leukemic stem cells, a process in which LSD1 plays a central role.

In leukemia, a part of the oncogenic program is sustained by a protein-protein interaction between LSD1 and the transcription factor GFI-1. This interaction is critical for maintaining stemness and blocking differentiation in leukemic blasts. Iadademstat not only blocks the enzymatic (demethylase) activity of LSD1, but also disrupts its scaffolding function through steric hindrance that impairs the interaction of LSD1 with GFI-1. This uncoupling releases the differentiation block, leading to forced differentiation of leukemic blasts, reduction of leukemic stem cell capacity, and inhibition of proliferation. This dual mechanism has been shown to translate into robust antileukemic effects in preclinical models, as reported by Oryzon scientists (1).

A first-in-man Phase I/IIa clinical trial in patients with refractory and relapsed acute leukemia demonstrated the safety and good tolerability of iadademstat. As anticipated in preclinical studies, strong differentiation effects were reported together with preliminary signs of antileukemic activity, including a complete remission with incomplete hematological recovery (CRi).

The favorable safety profile of iadademstat makes it a good candidate for therapeutic combination strategies alongside standard and targeted therapies in different cancers like leukemia or some solid tumors. In the Phase IIa ALICE trial in first-line elderly unfit acute myeloid leukemia patients, iadademstat in combination with azacitidine demonstrated encouraging safety and efficacy, with high response rates. Final resultats from this study were presented at the American Society of Hematology ASH-2022 annual meeting and have been published in The Lancet Hematology (2).

Iadademstat is currently being evaluated in multiple ongoing Phase Ib and Phase II trials across hematological malignancies, including:

  • the Phase Ib FRIDA trial, in combination with gilteritinib in patients with relapsed/refractory FLT3-mutant AML
  • a Phase Ib trial, in combination with azacitidine and venetoclax, in first-line AML (the IIS-ALICE-2 study)
  • additional clinical trials exploring iadademstat in myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and additional AML settings

Encouraging positive preliminary data from the ongoing FRIDA and ALICE-2 studies in AML were presented at the American Society of Hematology ASH-2025 annual meeting, particularly in first line AML (ALICE-2 study), where a 100% Overall response rate (ORR) and 90% complete remission rate was reported, with 70% of patients derived to hematopoietic stem cell transplantation.

Beyond hematological cancers, Oryzon is expanding the evaluation of iadademstat into non-malignant hematological diseases, such as sickle cell disease (SCD). LSD1 is a component of protein complexes that repress the transcription of gamma-globin, a subunit of fetal hemoglobin (HbF). By inhibiting these repressive complexes, iadademstat may restore gamma-globin expression and increase HbF levels. Increased HbF expression is a well-established therapeutic strategy in SCD, as HbF reduces hemoglobin S polymerization and red blood cell sickling. Iadademstat is currently being evaluated in adults with SCD in the ongoing Phase Ib RESTORE trial.

LSD1 inhibition has also been proposed as a therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors, breast, prostate cancer, Merkel cell carcinoma, and also in rare brain tumors such as medulloblastoma, glioblastoma and others.

In SCLC, a very aggressive lung cancer type with limited therapeutic options, LSD1 contributes to tumor stemness and disease progression. In a subset of SCLC tumors, the oncogenic program depends on binding of LSD1 to a transcription factor called INSM1. Recruitment of LSD1 by INSM1 reduces the expression of NOTCH1 and HES1 in SCLC cells, leading to up-regulation of ASCL1 and NEUROD1, which act as oncogenes and drive tumor progression in this cancer type. By disrupting the interaction between LSD1 and INSM1, iadademstat restores NOTCH1 and HES1 expression and reduces that of ASCL1 and NEUROD1, resulting in marked and long-lasting tumor regression in preclinical models (3).

Oryzon has performed a Phase IIa clinical trial with iadademstat in combination with platinum/etoposide in second line SCLC patients (the CLEPSIDRA study).

In addition to its direct antitumor effects, iadademstat also exhibits immunomodulatory activity. In certain AML subtypes, LSD1 inhibition increases the expression of genes of the mayor histocompatibility complex 1 (MHC-1), which can increase the visibility of cancer cells to the immune system. Preclinical studies have shown that iadademstat can synergize with immune check-point inhibitors (ICI), providing a promising avenue to treat so-called immunological cold solid tumors.

Oryzon has entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Cancer Institute (NCI) to collaborate on the clinical development of iadademstat in different types of solid and hematological cancers. Under this CRADA, iadademstat is currently being evaluated in NCI-sponsored clinical trials, including a Phase I/II randomized trial in SCLC combining iadademstat with immune checkpoint inhibitors.

Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU.

 

(1)  Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12. doi: 10.1016 / j.ccell.2018.02.002.
(2)  Salamero et al., The Lancet Haematology, 2024, 11(7): e487-e498. doi: 10.1016/S2352-3026(24)00132-7
(3)  Augert et al., Sci Signal 2019 Feb 5;12(567), doi: 10.1126/scisignal.aau2922