iadademstat (ORY-1001)

P1, N=24, Not yet recruiting, OHSU Knight Cancer Institute

P2, N=42, Recruiting, Fox Chase Cancer Center | Trial primary completion date: Aug 2024 --> Aug 2025

P1/2, N=45, Not yet recruiting, National Cancer Institute (NCI)

P1, N=50, Recruiting, Oryzon Genomics S.A. | Trial primary completion date: Jan 2024 --> Jan 2025

LSD1 Inhibitor ladademstat in Combination with Menin Inhibitor revumenib has synergistic effect in KMT2A-Rearranged AML models. Surprisingly, we also found that PSIP1, which is essential for inducing MLL-rearranged leukemia, interacts with LSD1. This suggests that PSIP1 may modulate gene expression through its ability to interact with both MLL1 and LSD1.

The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat)...For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

The primary endpoint is ORR per RECIST 1.1; secondary endpoints include rate of ≥ grade 3 toxicities, PFS, OS and DoR. Exploratory endpoints include host inflammatory cytokine and immune profile, and epigenomic and genomic analysis of tumor and peripheral blood samples.

The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.

Preclinically, iada has marked synergy with FLT3i, particularly gilteritinib, in FLT3 wild-type and FLT3 mut+ AML cells and in derived cell lines resistant to venetoclax, azacitidine and FLT3is. Additional sites will be added for a subsequent Phase 2 randomized controlled double-blinded FRIDA 2 study to assess the efficacy of this combination in R/R FLT3 mut+ AML. Clinical trial information: NCT05546580.

P1, N=50, Recruiting, Oryzon Genomics S.A. | Not yet recruiting --> Recruiting

The Phase 3 randomized ADMIRAL trial of gilteritinib revealed a CR rate of 20%; and an event-free-survival (EFS) of 2.8 months (Perl, et al., NEJM 2019).Preclinically, iada produces marked synergy with FLT3i, including gilteritinib, in FLT3 wild-type and mutated (FLT3 mut+) AML cells and in derived cell lines resistant to venetoclax, azacitidine and other FLT3is. Exploratory endpoints include measurable residual disease and gene mutational analysis.Pts who achieve a response can undergo hematopoietic stem cell transplant.The study plans to have 15 sites enrolling in the US. Additional sites will be added for a subsequent randomized controlled double-blinded FRIDA 2 study to assess the efficacy of the iada and gilteritinib combination in R/R FLT3 mut+ AML.

Azacitidine (aza) plus venetoclax has shown an OS of 14.7 months (mo) and a complete remission or complete remission with incomplete hematological recovery (CR/CRi) rate of 66% (VIALE-A trial). The combination of iada with aza produces robust, rapid and durable responses in previously untreated unfit AML patients, including those with high-risk features, with a manageable toxicity profile. Further research with iada in combination with SoC treatments for AML is warranted.

P1, N=50, Not yet recruiting, Oryzon Genomics S.A.

The approval of the FLT3i midostaurin with induction therapy in FLT3mut AML, and of a more specific potent FLT3i, gilteritinib, as monotherapy for relapsed/refractory (R/R) pts have resulted in improved outcomes...More than 100 subjects have been treated with iada, including R/R AML pts with monotherapy and naïve AML pts in combination with azacitidine, revealing a manageable safety profile and encouraging response rates...No results available. Conclusion Study recruiting in Q2 2022 in US.

We employed the inhibitor ORY-1001 and RNA interference to assess changes in MHC-I expression in SCLC cell lines by flow cytometry... Our findings demonstrate potent regulatory roles of LSD1 in MHC-I antigen presentation and provide support for targeting LSD1 to overcome immune evasion in SCLC.

Here investigated the role of LSD1 as a transcriptional regulator of antigen presentation in SCLC. To perturb LSD1 function, we employed the pharmacological inhibitor ORY-1001 and shRNA-mediated knockdown... Our data define a role for LSD1 as a potent negative regulator of MHC-I-mediated antigen presentation and provide rationale for the use of LSD1 inhibitors to augment response to immunotherapy in SCLC.

After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.

Notably, compound 5m showed superior in vitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP-2509 with IC values ranging from 0.23 to 1.56 μM. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.

Further cellular study confirmed that monobenzone could inhibit the proliferation of gastric cancer cell lines MGC-803 and BGC-823 with IC as 7.82 ± 0.55 μM and 6.99 ± 0.51 μM, respectively, and erase the substrate of KDM1A, H3K4me1/2 and H3K9 me2, and inhibit the migration of gastric cancer cell by reversing epithelial-mesenchymal transition (EMT). As the structure of monobenzone is very simple and small, this study provides a novel backbone for the further optimization of KDM1A inhibitor and gives monobenzone potential new application.

Further, the results showed that an LSD1 inhibitor (ORY-1001) combined with anti-CD47/PD-L1 monoclonal antibodies inhibited tumor growth in an established subcutaneous xenograft model more effectively than a single blockade strategy. Collectively, these findings indicate that LSD1 inhibition enhances the therapeutic efficacy of PD-L1/CD47 blockade by reducing CD47 and PD-L1 expression in cervical cancer.

Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

JBI-802 had a much stronger effect in inhibiting the growth of HEL92.1.7 erythroleukemia xenograft by oral administration when compared to ACY-1215, a HDAC6 selective inhibitor or ORY-1001 an LSD1 selective inhibitor. The data obtained to date demonstrate that dual LSD1-HDAC6/8 inhibitors could serve as novel, effective therapeutic agents for treatment of select subset of AML and other cancers. IND-enabling studies are in progress with this inhibitor to be developed as a clinical candidate

Complete and durable tumor regression occurred with ORY-1001-induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.

Iadademstat reduced the expression of SOX2 in luminal-B but not in luminal-A mammospheres, likely indicating a selective targeting of SOX2-driven CSC. The therapeutic relevance of targeting SOX2-driven breast CSC suggests the potential clinical use of iadademstat as an epigenetic therapy in luminal-B and HER2-positive subtypes.