iadademstat (ORY-1001) / Oryzon - LARVOL DELTA

Preliminary safety and efficacy of the frida study: Iadademstat and gilteritinib in FLT3-mutated relapsed/refractory acute myeloid leukemia (ASH 2025) - P1 | "Preclinically, iada is synergistic with gilteritinib in FLT3 mut AML cells and in derivedcell lines resistant to venetoclax, azacitidine or other FLT3is (Sacilotto et al., 2022 Eur J. of Cancer 174S1).More than 140 pts have been treated with iada, including treatment-naïve AML pts in the ALICE studywhere, in combination with azacitidine, iada produced rapid, durable, and deep responses with amanageable safety profile (Salamero et al., Lancet Hematol...The FRIDA Phase 1 study(NCT05546580) aims to establish the safety, tolerability, and the recommended Phase 2 dose (RP2D) ofthe combination of iada plus gilteritinib in FLT3 mut R/R AML.Adult pts with ≤ 2 prior lines of therapy (including quizartinib and gilteritinib if not refractory), receivediada PO at doses of 50 to 100 μg on a 5 days ON- 2 days OFF (5+2) schedule for 3 or 4 weeks (wks), in 28-day cycles with continuous gilteritinib PO at 120 mg/day...The combination of iada and gilteritinib at the tested doses..."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Gene Therapies • Hematological Malignancies • Leukemia • Neutropenia • FLT3

Trial in progress - a randomized study of ASTX727 with or without Iadademstat in accelerated/blast-phase myeloproliferative neoplasms (ASH 2025) - P2 | "Outcomes were similar in patients treated with intensivechemotherapy, DNA methyltransferase inhibitor (DNMTi) + venetoclax-based therapy, and other DNMTi-based approaches (Patel et al, Blood Adv 2024)...The oral LSD1 inhibitor iadademstat has been studiedin combination with the DNMTi azacitidine in de novo acute myeloid leukemia (AML) in the context of thePhase II ALICE study; the complete remission (CR)/complete remission with incomplete count recovery(CRi) rate was 52%...Exclusion criteria of note include IDH1-mutatedMPN-BP (due to the availability of ivosidenib as an approved frontline therapy).The dose escalation phase will follow a 3+3 design...Secondary endpoints include event-free survival, overall survival, and percentage of patients that go onto allogeneic stem celltransplantation. Exploratory endpoints include concordance of response between EuropeanLeukemiaNet (ELN) 2022 response criteria (Dohner et al, Blood 2022) and 2012 MPN-BP criteria,assessment of..."

Clinical • Acute Myelogenous Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • ASXL1 • IDH1 • IDH2 • TP53

Synergistic targeting of KMT2A-rearranged AML with combined LSD1 and menin inhibitors (ASH 2025) - "In MV4-11 (MLL-AF4)and MOLM-13 (MLL-AF9) cells, combination therapy reduced viability with a synergistic IC50 compared tosingle-agent IC50s for revumenib and iadademstat alone.RNA-seq and ATAC-seq were conducted to assess transcriptomic alterations and changes in chromatinaccessibility in MOLM-13 and MV4-11 cells following treatment with each drug individually and incombination. Combining LSD1 inhibition shows promise for a dual-targeted epigenetic strategy for translation into early-phase clinical trials, particularly for patients withR/R KMT2A-rearranged AML. Given the depth of response and low toxicity observed in vivo in our PDX,this combination and dosing strategy may be important for limiting the toxicities of menin inhibition,such as differentiation syndrome or the thrombocytopenia associated with LSD1 inhibition, whenplanning future clinical trials."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Thrombocytopenia • AFDN • CD86 • ITGAM • KAT6A • KMT2A • PTPRC

Preliminary safety and efficacy results of A phase ib investigation of the LSD1 inhibitor iadademstat (ORY-1001) in combination with azacitidine and venetoclax in newly-diagnosed AML (ASH 2025) - P1, P2 | "The novel combination of Iadademstat with AZA+VEN is safe and active in ND-AML, resulting inmanageable AEs and high response rates. Enrollment continues at DL2 in this ongoing clinical trial.Additional outcomes and correlative data will be presented at the meeting."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Dental Disorders • Febrile Neutropenia • Infectious Disease • Ischemic stroke • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • Thrombocytopenia • Xerostomia

Targeting chemoresistance: A phase II study of iadademstat (Iada) with paclitaxel (P) in extrapulmonary neuroendocrine carcinoma (epNEC) and small cell lung cancer (SCLC). (ASCO-GI 2026) - P2 | "Funded by Oryzon Genomics S.A. Clinical Trial Registration Number: NCT05420636 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

P2 data • Gastrointestinal Cancer • Oncology • Solid Tumor

FRIDA (NCT05546580), a Phase Ib clinical study sponsored by Oryzon, was designed to investigate iadademstat in combination with gilteritinib for the treatment of FLT3-mutant relapsed/refractory AML. (Oryzon Press Release) - "The study is in the expansion phase at one selected pharmacologically active dose , with a total of 17 patients enrolled in the study at this dose level per the ASH poster data cutoff. This dose continues to be well tolerated based on continuous safety monitoring, and has achieved the deepest responses which correlate with the target PK and PD values. Preliminary activity at the dose under expansion shows a 67% CCR (10/15 patients) and a 47% CR+CRh (7/15) in 15 patients evaluable for response, which favorably compares with the results of the ADMIRAL trial (CR+CRh 34%), particularly in light of contemporary practice with many patients (47%) treated at this dose after failing venetoclax, a population with markedly decreased response to gilteritinib monotherapy."

P1 data • Acute Myelogenous Leukemia

ORYZON presents data for iadademstat combinations in AML at the American Society of Hematology (ASH) 67th Annual Meeting (Oryzon Press Release) - "The combination treatment resulted in a highly encouraging ORR of 100% and a CCR rate of 90%, with 80% of patients attaining a strict CR. 70% of patients transitioned to allogeneic hematopoietic stem cell transplantation (HSCT). Median overall survival (OS) was not reached, and 6-month OS was 66%. The trial continues to enroll patients at dose level 2 (DL2), with a planned accrual of N=21 MTD-evaluable patients."

P1 data • Acute Myelogenous Leukemia

Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML. (PubMed, bioRxiv) - "This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat...In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK6 • FLT3 • HOXA9 • KMT2A • PBX3

Iadademstat and Gilteritinib for the Treatment of FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia: The Frida Study (ASH 2023) - P1 | "Preclinically, iada produces striking synergy with FLT3is, particularly gilteritinib in FLT3 wild-type and FLT3 mut+ AML cells and in derived cell lines resistant to venetoclax, azacitidine and other FLT3is (Sacilotto et al. At the time of the submission, FRIDA is enrolling a second dose level cohort in escalation phase and plans to have the 15 sites open to accrual in the US by the end of 2023. 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."

Acute Myelogenous Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • FLT3

The LSD1 Inhibitor Ory-1001 (ladademstat) in Combination with Menin Inhibitor SNDX-5613 (revumenib) Has Synergistic in Vitro Activity in KMT2A-Rearranged AML Models (ASH 2023) - "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."

Combination therapy • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HDAC1 • HDAC2 • KMT2A

Effect of the Oral LSD1 Inhibitor Ory-1001 on F-Retics in Baboons (Papio anubis) (ASH 2023) - P1 | "No consistent effects on reticulocyte counts were observed (Table 1). These results show that a single oral dose of ORY-1001 is sufficient to increase HBF in baboons without any adverse hematological effects and provide the necessary dose-response data to pursue further combinatorial studies with oral THU-decitabine"

Acute Myelogenous Leukemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Psychiatry • Sickle Cell Disease • Thrombocytopenia

From mutation to medication: iadademstat and the next era in MDS targeted therapy. (PubMed, Ann Med Surg (Lond)) - No abstract available

Journal

Phase Ib trial (NCT06357182) evaluates iadademstat in combination with azacitidine and venetoclax in patients with newly diagnosed AML. (Oryzon Press Release) - "Preliminary data from the first 8 patients enrolled show the triplet combination is safe and active, resulting in high response rates. The overall response rate (ORR) was 100% (n=8), with 88% achieving complete remission (CR), and 12.5% morphologic leukemia-free state (MLFS). After a median follow-up of 9 months, the estimated 6‑month overall survival (OS) was 88%. No doselimiting toxicities were observed."

P1 data • Acute Myelogenous Leukemia

Oryzon Genomics, S.A…announced that the first patient has been enrolled in RESTORE, its multi‑center, open‑label Phase Ib clinical trial of iadademstat in adults with sickle cell disease (SCD). (Oryzon Press Release) - "The study, to be conducted across several sites in Spain, aims to enroll approximately 40 adult patients. It is designed to evaluate the safety and tolerability of iadademstat in SCD and to establish the recommended Phase 2 dose (RP2D) as well as to evaluate iadademstat’s effect on inducing fetal hemoglobin (HbF) expression."

Enrollment open • Sickle Cell Disease

Curing the Incurable: TP53 Mutated Myeloid Neoplasms. (PubMed, Clin Lymphoma Myeloma Leuk) - "The differential prognosis of the mutation in various chromosomal and VAF settings will be explored. Lastly, we will outline therapeutic options, promising treatments on the horizon, and whether allogeneic stem cell transplant is curative."

Journal • Review • Acute Myelogenous Leukemia • Genetic Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Iadademstat (Oryzon Press Release) - "A new trial, which will evaluate iadademstat in essential thrombocythemia (ET), is currently in preparation, with Clinical Trial Application (CTA, the EU equivalent to an IND) submission to EMA planned for Q425."

New trial • Essential Thrombocythemia

The Phase Ib FRIDA study (NCT05546580) is evaluating the safety, tolerability and recommended Phase 2 dose (RP2D) of the combination of iadademstat plus gilteritinib in FLT3-mutated relapsed or refractory AML. (Oryzon Press Release) - "At the time of abstract submission, 34 patients had been enrolled, with 4 dose level cohorts evaluated in the escalation phase. The combination is tolerable at the tested doses. The study is in the expansion phase at one selected pharmacologically active dose, with a total of 14 patients enrolled in the study at this dose level. At the selected dose for expansion, the combination shows a 67% response rate (8/12 patients) and a 58% complete response rate (CR+CRh+CRi, 7/12 patients) in the 12 evaluable patients. Three patients have undergone HSCT. Updated data will be presented at the congress."

P1 data • Acute Myelogenous Leukemia

Oryzon Genomics, S.A…announced that the European Patent Office (EPO) has issued a Decision to Grant for its patent application EP20712594.9, entitled “Combinations of iadademstat for cancer therapy”. (Oryzon Press Release) - "The allowed claims protect the use of iadademstat in combination with PD1 or PD-L1 inhibitors for the treatment of cancer, including small cell lung cancer (SCLC). Once formally granted, the patent will remain in force until at least 2040, excluding potential patent term extensions."

Patent • Small Cell Lung Cancer

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) | Suspended ➔ Recruiting

Checkpoint inhibition • Enrollment open • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

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 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Checkpoint inhibition • Trial suspension • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

TIARA: Iadademstat + SBRT With Atezo in ES-SCLC (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Yale University

New P1 trial • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids. (PubMed, Cancer Chemother Pharmacol) - "These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem."

IO biomarker • Journal • Preclinical • Oncology • Targeted Protein Degradation • KRAS

ORYZON strengthens patent portfolio for iadademstat...with new Decisions to Grant (Oryzon Press Release) - "The Australian Patent Office has issued a Decision to Grant for Oryzon’s patent application AU2020249493, titled 'Combinations of iadademstat for cancer therapy'. The allowed claims cover combinations of iadademstat with PD1 or PD-L1 inhibitors for the treatment of cancer, including small cell lung cancer (SCLC)....Once formally granted, this Australian patent will remain in force until at least 2040, not including any potential patent term extensions."

Patent • Small Cell Lung Cancer

Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML. (PubMed, EMBO Mol Med) - "While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK6

Tranylcypromine-derived LSD1 inhibitors: Synthetic strategies, structure-activity relationships, and anticancer potential. (PubMed, Eur J Med Chem) - "Clinically evaluated candidates like TCP, ORY-1001, and INCB059872; administered alone or in combination; irreversibly inhibit LSD1 by binding its FAD cofactor. Collectively, these inhibitors demonstrate significant therapeutic promise. We further discuss challenges (e.g., selectivity, resistance), opportunities, and future directions for optimizing LSD1-targeted cancer therapies."

Journal • Review • Breast Cancer • Oncology • Solid Tumor