iadademstat (ORY-1001) / Oryzon - LARVOL DELTA

In Silico Identification of LSD1 Inhibition-Responsive Targets in Small Cell Lung Cancer. (PubMed, Bioengineering (Basel)) - "This study demonstrates that RG6016 may exert its antitumor effects through the modulation of additional molecular targets such as MYC, UCHL1, and TSPAN8 in SCLC. The combined bioinformatic and molecular docking analyses provide new insights into the potential multi-target profile of RG6016 and indicate the need for further experimental validation."

Journal • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MYC • TSPAN8 • UCHL1

A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs) (clinicaltrials.gov) - P2 | N=62 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2027 ➔ Dec 2027 | Initiation date: May 2025 ➔ Feb 2026 | Trial primary completion date: Jun 2027 ➔ Dec 2027

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis

THE MOLECULAR BACKGROUND DETERMINES THE EXTENT BY WHICH LSD1 INHIBITORS SENSITIZE AML CELLS TO KINASE AND RAS INHIBITORS (EHA 2025) - "These cells present FLT3, NRAS and JAK2 activating mutations, respectively.Independently of FLT3 and RAS mutations, Iadademstat, sensitized 10, 8, 8 and 7 AML cell lines to gilteritinib, trametinib, pictilisib and RMC-7977, respectively...These included the phosphorylations of pNIBAN2(Ser692) and pNFIL3(Ser287)...Remarkably, gilteritinib reduced STAT5A/B phosphorylation, and iadademstat sensitised HEL cells to the JAK inhibitor ruxolitinib. In summary, the heterogeneity by which LSD1 inhibition sensitizes AML cells to FLT3, PI3K, RAS and MEK inhibitors can be rationalised by differences in how LSD1 regulates the wirings of kinase signalling networks irrespective of FLT3 and RAS mutations."

Acute Myelogenous Leukemia • FLT3 • NRAS • STAT5

ORYZON Reports Financial Results and Corporate Update for Quarter Ended March 31, 2025 (GlobeNewswire) - "FRIDA, an open-label, multicenter Phase Ib clinical trial of iadademstat in combination with gilteritinib in patients with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) harboring a FMS-like tyrosine kinase mutation (FLT3mut+), continues to enroll patients....The company plans to present the next data update from this trial at ASH-2025."

P1 data • Acute Myelogenous Leukemia

Synergistic growth-inhibitory efficacy of LSD1 and BCL-XL inhibitors in JAK2+ AML/MPN cells (AACR 2025) - "We explored the synergy between the LSD1i Iadademstat (Selleckchem), and BCL-2/BCL-XL inhibitor, Navitoclax, or the platelet-sparing BCL-XL degrader, DT2216 (Dialectic Therapeutics). In summary, JAK2+-mutant post-MPN AML cell lines and isogenic Ruxolitinib-resistant lines showed sensitivity to BCL-XL inhibitors and a synergistic increased sensitivity to these compounds when combined with low dose LSD1 inhibitor, Iadademstat. Mechanisms behind the synergy are being studied and will be reported.Summary of Glo Titer Assays and Annexin 5 Flow Cytometry Data with mean Synergy ScoresGlo Titer AssayNavitoclaxDT2216LSD1iLSD1i+NavitoclaxLSD1i+DT2216Hel ParentalIC501.3±0.2µM2±0.8µMNot Reached6.5±3 nM0.25±0.08 µMHel RRIC500.5±0.3µM1.8±0.7µMNot Reached6±3nM0.3±0.15 µMSet 2 ParentalIC500.4±0.4µM2.5±1 µMNot Reached6.5±02.5nM2±1.3 µMSet 2..."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • BAX • BCL2 • BCL2L1 • JAK2

ORYZON announces first patient dosed in NCI-sponsored Phase I/II clinical trial of iadademstat plus immune checkpoint inhibitors in 1L extensive stage Small Cell Lung Cancer (Oryzon Press Release) - "Oryzon Genomics, S.A...announced today that the first patient has been dosed in a Phase I/II trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with immune checkpoint inhibitors (ICI) in first line small cell lung cancer (SCLC) patients with extensive disease, sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. This is the first clinical trial testing the combination of iadademstat with ICI...The trial plans to enroll 45-50 patients and will be carried out under a Cooperative Research and Development Agreement (CRADA) that Oryzon has in place with the NCI."

Trial status • Small Cell Lung Cancer

Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

Recapitulation and reversal of neuropsychiatric phenotypes in a mouse model of human endogenous retrovirus type W expression. (PubMed, Mol Psychiatry) - "Importantly, pharmacological inhibition of LSD1 through oral ORY-1001 treatment normalized abnormal H3K4 methylation and rescued the behavioral and cognitive deficits in HERV-W ENV mice. In conclusion, our study suggests that the expression of HERV-W ENV has the capacity to disrupt various behavioral and cognitive functions and to alter the brain transcriptome in a manner that is highly relevant to neurodevelopmental and psychiatric disorders. Moreover, our study identified epigenetic pathways that may offer avenues for pharmacological interventions against behavioral and cognitive deficits induced by increased HERW-W expression."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Genetic Disorders • Infectious Disease • Mental Retardation • Psychiatry • Schizophrenia • ANK3 • KMT2A • KMT2B • KMT2D • SETD1A

Super-enhancer-hijacking RBBP7 potentiates metastasis and stemness of breast cancer via recruiting NuRD complex subunit LSD1. (PubMed, J Transl Med) - "Together, our results establish that the SE-RBBP7-LSD1 axis represents a potential therapeutic target for BCa treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • CCND1 • POU5F1 • RBBP7 • SOX2 • SOX9

Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML (clinicaltrials.gov) - P1 | N=45 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

IO biomarker • Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BAX • BCL2 • BCL2L1 • MCL1 • NF1 • TP53

Iadademstat with Hypomethylating Agent in Patients with Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Medical College of Wisconsin | Not yet recruiting ➔ Recruiting | Initiation date: Oct 2024 ➔ Jan 2025

Enrollment open • Trial initiation date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Oryzon obtains orphan designation for ORY-1001 for the treatment of Acute Myeloid Leukemia from the European Medicines Agency (Oryzon Press Release) - "Oryzon has received from the Committee for Orphan Medicinal Products (COMP), the committee at the European Medicines Agency that is responsible for reviewing applications for 'orphan-medicinal-product designation', the positive opinion on its application for orphan designation of ORY1001 for the treatment of Acute Myeloid Leukemia (AML) after the meeting held by the COMP in London on July 9-11."

Orphan drug • Acute Myelogenous Leukemia

Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Jul 2025 ➔ Dec 2024

IO biomarker • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BAX • BCL2 • BCL2L1 • MCL1 • NF1 • TP53

ORYZON announces first patient dosed in an Investigatorinitiated Phase I study of iadademstat in myelodysplastic syndrome (Oryzon Press Release) - "Oryzon Genomics, S.A...announced today that the first patient has been dosed in an investigator-initiated Phase I dose-finding trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with azacitidine in myelodysplastic syndrome (MDS), led by the Medical College of Wisconsin (MCW). Under the direction of Dr. Guru Subramanian Guru Murthy at the Medical College of Wisconsin Cancer Center, the trial...will evaluate the safety, tolerability, and recommended Phase II dose of iadademstat when administered together with the standard-of-care azacitidine in adult subjects with MDS."

Trial status • Myelodysplastic Syndrome

A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs) (clinicaltrials.gov) - P2 | N=56 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Jan 2025 ➔ May 2025

Trial initiation date • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis

ORYZON announces first patient dosed in NCI-sponsored iadademstat in combination with venetoclax and azacitidine clinical trial in first line acute myeloid leukemia (Oryzon Press Release) - "Oryzon Genomics, S.A...announced today that the first patient has been dosed in a Phase I dose-finding clinical trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with venetoclax and azacitidine in newly diagnosed acute myeloid leukemia (AML), sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. The trial...will evaluate the safety, tolerability, and optimal dose of iadademstat when administered together with the standard-of-care venetoclax and azacitidine in treatment-naïve AML patients."

Trial status • Acute Myelogenous Leukemia

NCI-2024-01398: Testing the Combination of an Anti-cancer Drug, Iadademstat, With Other Anti-cancer Drugs (Atezolizumab or Durvalumab) at Improving Outcomes for Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Trial completion date: Jan 2026 ➔ Jul 2029 | Initiation date: Oct 2024 ➔ Aug 2025 | Trial primary completion date: Jan 2026 ➔ Jul 2029

Checkpoint inhibition • Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Autophagy Attenuation-Induced LSD1 Enrichment Promotes Renal Tubular Cell Senescence and Kidney Aging (KIDNEY WEEK 2024) - "However, the role of LSD1 in senescence and kidney aging remains unknown. To explore the role and mechanisms of LSD1 in renal tubular senescence and kidney aging, we treated renal tubular epithelial cells with oxidative stress injury agent D-Gal and DNA damaging agent etoposide (ETO) and wild type mice with ionizing radiation (IR) plus an LSD1 specific inhibitor, ORY1001. The protein level of LSD1, but not its mRNA, was increased in 22-month-old mouse kidneys compared to that in 2-month-old mouse kidneys. This study indicates a role of LSD1 in promoting senescence and kidney aging, and a mechanism of that the upregulation of LSD1 is subjected to impaired autophagy in these processes. Our study places an emphasis that LSD1 has potential as a therapeutic target for the delay of kidney aging."

Chronic Kidney Disease • BECN1 • CDKN2A

Lysine-Specific Demethylase 1A Is a Targetable Kidney Disease Causal Gene (KIDNEY WEEK 2024) - "We analysed these mice at baseline and following kidney injury by cisplatin or unilateral ureteral obstruction. Our studies propose that lysine specific demethylase 1A could be a therapeutic option to combat kidney disease."

Acute Kidney Injury • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • CST3 • KDM1A • TGFB1

A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs) (clinicaltrials.gov) - P2 | N=56 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

Metastases • New P2 trial • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis

Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Oct 2024 ➔ Jul 2025

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BAX • BCL2 • BCL2L1 • MCL1 • NF1 • TP53

ORYZON Reports Financial Results and Corporate Update for Quarter Ended September 30, 2024 (GlobeNewswire) - "The Phase I/II trial with iadademstat plus immune checkpoint inhibitors in first line SCLC patients with extensive disease under the CRADA agreement with the NCI, already approved by the FDA, is now ready to start enrolling patients....The trial plans to enroll 45-50 patients and is expected to start enrolling patients in 4Q2024."

Trial status • Small Cell Lung Cancer

ORYZON Reports Financial Results and Corporate Update for Quarter Ended September 30, 2024 (GlobeNewswire) - "...'We have since completed enrollment of the third cohort...[in the] ongoing FRIDA Phase Ib trial..., and as the data matures, we plan to present additional results at the EHA Conference next June'....Iadademstat will also be evaluated in combination with venetoclax and azacitidine in first-line AML patients in a trial under the Cooperative Research and Development Agreement (CRADA) signed with the National Cancer Institute (NCI) in the United States....The trial plans to enroll 45 patients and, according to NCI, is expected to start enrolling patients in 4Q2024....The Company is further expanding the clinical development of iadademstat in hemato-oncology through a new IIS led by the Medical College of Wisconsin, which will evaluate iadademstat in combination with azacitidine in adult subjects with myelodysplastic syndrome."

Enrollment status • New trial • P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

ORYZON presents preliminary data from ongoing Phase Ib FRIDA trial with iadademstat plus gilteritinib in relapsed/refractory FLT3-mut AML patients at EHA-2024 (Oryzon Press Release) - P1b | N=50 | FRIDA (NCT05546580) | Sponsor: Oryzon Genomics S.A. | "The combination of iadademstat and gilteritinib appears safe and well-tolerated, with no dose limiting toxicities (DLTs) reported in the 28-day DLT evaluation period in the first two cohorts: initial cohort (n=6, iadademstat 100 μg) and DL-1 cohort (n=7, iadademstat 75 μg). There were no unexpected Treatment Emergent Adverse Events (TEAEs)....Five out of 13 patients (38%) achieved complete remission (CR), complete remission with partial hematological recovery (CRh) or complete remission with incomplete blood count recovery (CRi)...FRIDA is currently accruing patients to the third cohort, DL-2 (iadademstat 75 μg, 3 weeks treatment per cycle). Two patients have been enrolled, with no reported DLTs to date...Pharmacokinetic (PK) data support there is no drug-drug interaction between iadademstat and gilteritinib."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

ORY-1001 inhibits glioblastoma cell growth by downregulating the Notch/HES1 pathway via suppressing lysine-specific demethylase 1 expression (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • HES1 • KDM1A • NOTCH1 • NOTCH3