A Phase 1 Trial of Iadademstat Plus Vidaza Has Dosed a Patient With MDS

The first patient has been administered a dose of iadademstat in a phase 1 clinical trial.

The first participant has been dosed in an investigator-initiated phase 1 dose-finding clinical trial, according to a press release from Oryzon Genomics, S.A., which added that iadademstat (ORY-1001), a potent and selective LSD1 inhibitor, is being investigated in combination with Vidaza (azacitidine) among patients with myelodysplastic syndrome (MDS).

Dr. Guru Subramanian Guru Murthy is leading the investigation at the Medical College of Wisconsin Cancer Center. The study is aiming to evaluate the safety, tolerability and recommended phase 2 dose of iadademstat when given in combination with standard-of-care azacitidine in adult participants with MDS.

“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,” said Dr. Carlos Buesa, Oryzon’s Chief Executive Officer. “MDS is characterized by a block in the normal differentiation of hematopoietic progenitor cells, resulting in the multi-lineage cytopenias which characterize this disease and lead to its morbidity and mortality. The LSD1 enzyme controls this block to differentiation, and in patients with acute myeloid leukemia [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 [patients with] newly diagnosed AML.”

Better Understanding the Treatment Combination

MDS is a hematologic cancer, and in the U.S., over 10,000 new cases of are diagnosed each year. Hypomethylating agents, including azacitidine, are the current standard-of-care for patients who are diagnosed. However, these therapies yield low complete remission rates and are linked to poor long-term outcomes, highlighting the current need for additional therapeutic strategies. Furthermore, higher-risk MDS has proven resistant to both traditional and emerging treatments, creating an unmet need in care.

“MDS is a hematologic neoplasm with limited treatment options and poor prognosis,” Murthy, Principal Investigator of the study, stated “Our study is evaluating a novel combination regimen for the frontline management of patients with MDS using [the] 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.”

The orally administered small molecule, iadademstat, is a highly selective inhibitor of the epigenetic enzyme LSD1, which has a potent differentiating effect in hematologic malignancies. Previously, in a phase 1/2a clinical trial, patients with relapsed or refractory AML had favorable responses to the treatment, including good tolerability and preliminary antileukemic activity, including a complete remission with incomplete hematologic recovery.

Moreover, in the phase 2a ALICE trial of elderly, treatment-naïve patients with AML, encouraging safety and robust clinical activity were observed when iadademstat was combined with azacitidine.

Currently, iadademstat is under investigation in several trials, including the phase 1b FRIDA trial and in investigator-initiated studies assessing its combination with azacitidine and Venclexta (venetoclax) in newly diagnosed AML.

Beyond hematologic malignancies, LSD1 inhibition is being investigated as a therapeutic strategy for several solid tumors, including small cell lung cancer, neuroendocrine tumors and medulloblastoma. Ongoing studies include a phase 2 trial with Fox Chase Cancer Center investigating iadademstat in combination with paclitaxel for refractory or relapsed neuroendocrine carcinomas and a phase 1/2 randomized trial with Memorial Sloan Kettering Cancer Center.

“We are hopeful that Dr. Subramanian Guru Murthy’s trial of this new approach to MDS will benefit patients with this frequently fatal disease,” Buesa concluded in the release.

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