Iadademstat

Iadademstat (ORY-1001) is a small oral molecule, which acts as a covalent and highly selective inhibitor of the epigenetic enzyme Lysine Specific Demethylase-1, LSD1 (KDM1A).

Among other biological roles, LSD1 is involved in stemness in cancer and high levels of LSD1 are known to correlate with more aggressive types of cancer and poor prognosis for patients.

In leukemia, a blood cancer where differentiation stops and stemness is massive, a part of the oncogenic program is sustained by the protein-protein interaction occurring between LSD1 and another transcription factor called GFI-1. This mutual anchoring occurs through a “molecular hook” in GFI-1 denominated SNAG-domain.

Iadademstat does not only block the demethylating activity of LSD1, but also its scaffolding function. As the molecule binds covalently to the FAD cofactor in LSD1’s catalytic center, it protrudes in a way that impairs the anchoring of LSD1 with GFI-1 (a phenomena denominated steric hindrance). This uncoupling produces a strong effect forcing undifferentiated blasts to differentiate. This reduces leukemic stem cell capacity and proliferation and induces leukemic blast differentiation, and may produce therapeutic benefit, as has been reported by Oryzon scientists (1).

A first in man Phase I/IIa clinical trial with iadademstat in refractory and relapsed acute leukemia patients demonstrated safety and good tolerability of the drug. 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 good safety profile of iadademstat makes it a good candidate for therapeutic combinations in different cancers like leukemia or some solid tumors.

In a Phase II clinical trial in first line elderly unfit acute myeloid leukemia patients (ALICE trial), iadademstat has shown promising safety and efficacy results in combination with the hypomethylating agent azacitidine, with an objective response rate (ORR) of 81%, of which 64% were complete remissions and 36% partial remissions. The final resultats of the ALICE trial were presented at the American Society of Hematology congress, ASH-2022 (see Salamero et al., ASH-2022 oral presentation).

Iadademstat is currently being evaluated in combination with gilteritinib in the Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations.

Beyond hematological cancers, the inhibition of LSD1 has 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 that continues to resist to most of the current antitumor drugs, LSD1 plays an important role on its stemness. This may also offer an angle for using LSD1 inhibition as a therapeutic option for these patients.

In part of the SCLC tumors, the oncogenic program depends on binding of LSD1 to a transcription factor called INSM1. Again, anchoring occurs through the SNAG-domain. Recruitment of LSD1 by INSM1 reduces the expression of NOTCH1 and HES1 in SCLC cells. This in turn leads to up-regulation of ASCL1 and NEUROD1, which act as oncogenes and drive tumor progression in this cancer type. Iadademstat impairs the binding between LSD1 and INSM1 and allows for the restoration of NOTCH1 and HES1 expression and reduces that of ASCL1 and NEUROD1. This can produce strong and long-lasting tumor regression (2).

Oryzon has performed a Phase IIa clinical trial with iadademstat in combination with platinum/etoposide in second line SCLC patients (CLEPSIDRA study). Iadademstat is currently being evaluated in a collaborative Phase II basket study with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in relapsed/refractory neuroendocrine carcinomas.

Iadademstat also acts as an immunomodulator and was found to enhance the expression of genes of the mayor histocompatibility complex 1 (MHC-1) in some AML types, which can increase the visibility of cancer cells to the immune system. Combination of iadademstat with immune check-point inhibitors (ICI) was also shown to be a promising avenue to treat so-called immunological cold solid tumors, and the company is preparing a new trial in combination with ICI in SCLC.

Oryzon has entered into a Cooperative Research and Development Agreement (CRADA) with the U.S. National Cancer Institute (NCI) to collaborate on potential further clinical development of iadademstat in different types of solid and hematological cancers.

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)  Augert et al., Sci Signal 2019 Feb 5;12(567), doi: 10.1126/scisignal.aau2922