Oryzon Genomics, S.A. has announced the first patient dosed in a Phase I clinical trial evaluating iadademstat in combination with azacitidine for the treatment of myelodysplastic syndrome (MDS). The trial, led by Dr. Guru Subramanian Guru Murthy at the Medical College of Wisconsin (MCW) Cancer Center, aims to determine the safety, tolerability, and recommended Phase II dose of iadademstat when administered with azacitidine, a standard-of-care treatment for MDS. This investigator-initiated study marks a significant step in exploring new therapeutic options for this challenging hematological malignancy.
Addressing Unmet Needs in MDS Treatment
Myelodysplastic syndromes are a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, resulting in cytopenias and a significant risk of transformation to acute myeloid leukemia (AML). The incidence of MDS increases with age, with over 10,000 new cases diagnosed annually in the United States. While hypomethylating agents like azacitidine and decitabine are commonly used, they offer low complete remission rates (less than 20%) and are associated with poor long-term outcomes. Higher-risk MDS, in particular, has shown resistance to many conventional and emerging cancer therapies, highlighting the urgent need for novel treatment strategies.
Iadademstat: An Epigenetic Approach
Iadademstat (ORY-1001) is an orally available, highly selective inhibitor of lysine-specific demethylase 1 (LSD1), an epigenetic enzyme that plays a crucial role in regulating gene expression and cell differentiation. By inhibiting LSD1, iadademstat aims to reverse the block in normal differentiation of hematopoietic progenitor cells, a hallmark of MDS. Preclinical and early clinical data suggest that iadademstat can promote differentiation and restore normal function in immature blood cells.
Dr. Carlos Buesa, Oryzon’s CEO, stated, "We believe that the addition of iadademstat, an inhibitor of the epigenetic LSD1 enzyme, to MDS standard-of-care, represents a new approach to this disease... The LSD1 enzyme controls this block to differentiation, and in patients with AML, a closely-related malignancy, iadademstat irreversibly and safely inhibits LSD1 and allows immature hematopoietic cells to differentiate and function, which translated in deep and durable responses in newly diagnosed AML patients."
Clinical Trial Design and Objectives
The Phase I trial (NCT06502145) is designed as a dose-finding study to evaluate the safety and tolerability of iadademstat in combination with azacitidine in adult patients with MDS. The primary objectives include determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of iadademstat. Secondary endpoints will assess preliminary efficacy signals, including complete remission rate, overall response rate, and duration of response.
Dr. Guru Murthy, Principal Investigator of the study, commented, "MDS is a hematologic neoplasm with limited treatment options and poor prognosis. Our study is evaluating a novel combination regimen for the frontline management of patients with MDS using LSD1 inhibitor iadademstat, in combination with hypomethylating agents, given the encouraging results of this combination in AML. We are excited to start the study and offer this option to our patients with MDS in need of novel therapies."
Prior Clinical Experience with Iadademstat
Iadademstat has previously demonstrated promising activity in AML. In a Phase IIa trial (ALICE trial) in elderly, treatment-naïve AML patients, the combination of iadademstat and azacitidine showed encouraging safety and clinical activity (Salamero et al., The Lancet Haematology, 2024, 11(7):e487-e498). Iadademstat is also being evaluated in combination with gilteritinib in the ongoing Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations, and in combination with azacitidine and venetoclax in 1L AML in an investigator-initiated study led by OHSU and in a trial sponsored by the U.S. National Cancer Institute (NCI).
Future Implications
The initiation of this Phase I trial represents a significant step forward in the development of iadademstat as a potential treatment for MDS. If the combination of iadademstat and azacitidine proves safe and effective, it could provide a valuable new option for patients with this challenging disease, particularly those with higher-risk MDS who have limited treatment alternatives.
