A Phase 1/2, Open-label, Multicenter Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of CC-90011 in Combination With Venetoclax and Azacitidine in R/R Acute Myeloid Leukemia (AML) and Treatment-naïve Subjects With AML Who Are Not Eligible for Intensive Induction Chemotherapy

CC-90011-AML-002 is a Phase 1/2, open-label, multicenter study to assess the safety, tolerability, and preliminary efficacy of CC-90011 given concurrently with Venetoclax and Azacitidine. This study will include 3 parts: a dose escalation part in R/R AML, a dose escalation part in ndAML (treatment-naïve participants with AML who are ≥ 75 years of age or are ≥ 18 to 74 years of age and otherwise not eligible for intensive induction chemotherapy), and a randomized dose expansion part in ndAML of Venetoclax and Azacitidine with or without CC-90011.

Start Date14 Oct 2021

Sponsor / Collaborator

Celgene Corp.

NCT04628988 / CompletedPhase 1

A Phase 1, Open-label, Functional Imaging Study to Assess Whether CC-90011 Reverses the Castration Resistance Due to Lineage Switch in Subjects With Metastatic Castration-resistant Prostate Cancer (mCRPC) Who Have Failed Enzalutamide as Last Prior Therapy, Followed by a Dose Finding Study of CC-90011 Combined With Abiraterone and Prednisone

This is an open-label, positron emission tomography (PET) imaging Proof of Biology (POB) study to determine whether CC -90011 reverses, by the induction of androgen receptor (AR) expression, the castration resistance, due to lineage switch, in participants with mCRPC that have failed enzalutamide as last prior therapy. This study aims to assess whether CC-90011 can induce AR expression and, consequently, re-sensitize tumors to anti-hormonal therapy.

Start Date28 Jul 2021

Sponsor / Collaborator

Celgene Corp.

NCT04350463 / CompletedPhase 2

A Phase 2, Multicenter, Open-label, Multi-cohort Study to Assess Safety and Efficacy of CC-90011 in Combination With Nivolumab in Subjects With Advanced Cancers

This is a Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-90011 in combination with nivolumab in subjects with small cell lung cancer or squamous non-small cell lung cancer who have progressed after 1 or 2 lines of therapies.
The primary objectives of the study are to evaluate the overall response rate of subjects treated with CC-90011 in combination with nivolumab in three cohorts:
Cohort A: SCLC in ICI naïve subjects
Cohort B: SCLC in ICI progressor subjects
Cohort C: sqNSCLC in ICI progressor subjects Overall response rate is defined as the proportion of subjects in the treated population who had complete response (CR) or partial response (PR) as assessed by Investigator review per RECIST v1.1.
In Cohort A, expected ORR for nivolumab monotherapy is 14% while target ORR is 30%. To achieve at least 80% power with one-sided type 1 error 0.1, 39 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 12 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 2 or more subjects responding, Cohort A will continue to enroll an additional 27 subjects. If 1 or less subjects respond in stage 1, Cohort A will stop for futility.
In Cohort B and C, expected ORR for nivolumab monotherapy is 5% while target ORR is 15%. To achieve at least 80% power with one-sided type 1 error 0.1, 48 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 14 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 1 or more subjects responding, Cohort B and C will continue to enroll an additional 34 subjects each. If 0 subjects respond in stage 1, Cohort B and C will stop for futility.

Start Date14 Jul 2020

Sponsor / Collaborator

Celgene Corp.

100 Clinical Results associated with Pulrodemstat

100 Translational Medicine associated with Pulrodemstat

100 Patents (Medical) associated with Pulrodemstat

Literatures (Medical) associated with Pulrodemstat

04 Jun 2024·BIOCHEMISTRY

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates

Article

Author: Deniz, Emre ; Uren, Aykut ; Helmbreck, Joceline ; Schneider, Owen ; Mardikar, Aashay ; Zeng, Danyun ; Reiter, Nicholas J. ; Priyankara, Indunil K. ; Senanayaka, Dulmi

Lysine specific demethylase-1 (LSD1) serves as a regulator of transcription and represents a promising epigenetic target for anticancer treatment. LSD1 inhibitors are in clinical trials for the treatment of Ewing's sarcoma (EWS), acute myeloid leukemia, and small cell lung cancer, and the development of robust inhibitors requires accurate methods for probing demethylation, potency, and selectivity. Here, the inhibition kinetics on the H3K4me2 peptide and nucleosome substrates was examined, comparing the rates of demethylation in the presence of reversible [CC-90011 (PD) and SP-2577 (SD)] and irreversible [ORY-1001 (ID) and tranylcypromine (TCP)] inhibitors. Inhibitors were also subject to viability studies in three human cell lines and Western blot assays to monitor H3K4me2 nucleosome levels in EWS (TC-32) cells, enabling a correlation of drug potency, inhibition in vitro, and cell-based studies. For example, SP-2577, a drug in clinical trials for EWS, inhibits activity on small peptide substrates (K_i = 60 ± 20 nM) using an indirect coupled assay but does not inhibit demethylation on H3K4me2 peptides or nucleosomes using direct Western blot approaches. In addition, the drug has no effect on H3K4me2 levels in TC-32 cells. These data show that SP-2577 is not an LSD1 enzyme inhibitor, although the drug may function independent of demethylation due to its cytotoxic selectivity in TC-32 cells. Taken together, this work highlights the pitfalls of using coupled assays to ascribe a drug's mode of action, emphasizes the use of physiologically relevant substrates in epigenetic drug targeting strategies, and provides insight into the development of substrate-selective inhibitors of LSD1.

25 Jan 2024·Journal of medicinal chemistryQ1 · MEDICINE

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

Q1 · MEDICINE

Review

Author: Wang, Shu-Wu ; Wang, Bo ; Hou, Wen-Qing ; Fu, Meng-Jie ; Ji, Shi-Kun ; Shen, Liang ; Liu, Hong-Min ; Dai, Xing-Jie ; Wang, Shao-Peng

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

11 Jan 2024·The journal of physical chemistry. B

Uncovering New Conformational States of the Substrate Binding Pocket of LSD1 Potential for Inhibitor Design via Funnel Metadynamics

Article

Author: Yang, Kecheng ; Liu, Hongmin

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target for cancer therapy. So far, over 80 crystal structures of LSD1 in different complex states have been deposited in the Protein Data Bank, which are valuable resources for performing structure-based drug design. However, among all of the crystal structures of LSD1, the substrate binding pocket, which is the most efficient druggable site for designing LSD1 inhibitors at present, is very similar no matter whether LSD1 is in the apo or any holo forms, which is inconsistent with its versatile demethylase functions. To investigate whether the substrate binding pocket is rigid or exhibits other representative conformations different from the crystal conformations that are feasible for designing new LSD1 inhibitors, we performed funnel metadynamics simulations to study the conformation dynamics of LSD1 in the binding process of two effective LSD1 inhibitors (CC-90011 and 6X0, CC-90011 undergoing clinical trials). Our results showed that the entrance of the substrate binding pocket is very flexible. Two representative entrance conformations of LSD1 counting against binding with the substrate of histone H3 were detected, which may be used for structure-based LSD1 inhibitor design. Besides, alternative optimal binding modes and prebinding modes for both inhibitors were also detected, which depicted that the key interactions changed along with the binding process. Our results should provide great help for LSD1 inhibitor design.

News (Medical) associated with Pulrodemstat

17 Jun 2024

·www.globenewswire.com

Clinical Data on Salarius Pharmaceuticals’ Seclidemstat in Patients with MDS and CMML Presented at the 2024 European Hematology Association Annual Meeting

Patients were treated in the dose-escalation portion of the Phase 1/2 study evaluating seclidemstat in combination with azacitidine Investigators reported a 43% overall response rate among 14 predominantly higher risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) patients who previously failed or relapsed after hypomethylating agent therapy Median overall survival was 18.5 months (95% CI, range 6.1-30.9 months) with median event-free survival of 7.2 months (95% CI, range 6.3-8.2 months) HOUSTON, June 17, 2024 (GLOBE NEWSWIRE) -- Salarius Pharmaceuticals, Inc. (NASDAQ: SLRX), a clinical-stage biopharmaceutical company using protein inhibition and protein degradation to develop cancer therapies for patients in need of new treatment options, today announced that investigators at the University of Texas MD Anderson Cancer Center’s Leukemia department presented clinical data on seclidemstat in patients with MDS and CMML at the 2024 European Hematology Association (EHA) Hybrid Congress. The meeting was held in Madrid and virtually from June 13-16, 2024. Seclidemstat is a novel oral, reversible, targeted LSD1 inhibitor. The poster was presented by Guillermo Montalban-Bravo, M.D. on June 14th, and is available on Salarius’ website, in the Investors, Events and Presentations section here. The objective of this investigator-initiated Phase 1/2 dose-escalation study is to evaluate the safety, tolerability, maximum tolerated dose and overall response of seclidemstat in combination with azacitidine in adult patients with higher-risk MDS or CMML who previously failed or relapsed after hypomethylating agent therapy. As of May 2024, 16 patients were enrolled in this study with 14 patients evaluable for efficacy. As presented at EHA, of the 14 evaluable patients for efficacy, 6 (43%) had an objective response including 1 complete response, 3 marrow complete responses, 1 marrow complete response plus hematological improvement and 1 hematologic improvement. The median overall survival was 18.5 months (95% CI, range 6.1-30.9 months), median event-free survival was 7.2 months (95% CI, range 6.3-8.2 months) and median follow-up time was 18.9 months (95% CI, range 0-48 months) from treatment initiation. As reported, overall survival after failing therapy with hypomethylating agents typically is 4-6 months. 15 patients were evaluable for toxicity, with a dose-limiting toxicity observed in 1 patient in the 750mg BID cohort. Per protocol, the cohort was expanded to 3 additional patients. Based upon reported data, Salarius believes adverse events observed were manageable. The Phase 1 dose-escalation portion of this study will evaluate up to six dose levels of seclidemstat. Cohort 5 (dose level 750mg BID seclidemstat in combination with azacitidine) is currently enrolling and cohort 6, the final cohort, will receive 900mg BID seclidemstat in combination with azacitidine. The maximum tolerated dose, which will inform the Phase 2 portion of the study, has not yet been reached. “We are encouraged by these promising results at this early stage of the study when seclidemstat is combined with azacitidine at doses below what we believe will be the recommended Phase 2 dose,” said William McVicar, Ph.D., Chairman of the Salarius Pharmaceuticals Board of Directors. “Patients who have failed prior treatments including hypomethylating agents have a poor prognosis and are in desperate need of new treatment options. With a 43% overall response rate, median overall survival of 18.5 months and median event-free survival of 7.2 months, we agree with the investigators that these results show promising early signs of activity in a high-risk MDS and CMML treatment failure population.” About Salarius PharmaceuticalsSalarius Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing therapies for patients with cancer in need of new treatment options. Salarius’ product portfolio includes seclidemstat, its lead candidate, which is being studied as a potential treatment for pediatric cancers, sarcomas and other cancers with limited treatment options, and SP-3164, an oral small molecule protein degrader being developed for the treatment of non-Hodgkin’s lymphoma. Salarius has received financial support from the National Pediatric Cancer Foundation to advance the Ewing sarcoma program and was a recipient of a Product Development Award from the Cancer Prevention and Research Institute of Texas (CPRIT). For more information, please visit salariuspharma.com or follow Salarius on Twitter and LinkedIn. In August 2023 Salarius announced a comprehensive review of strategic alternatives focused on maximizing shareholder value. While these efforts are ongoing, the Company continues to support its clinical programs, as appropriate, which includes the work being performed by the investigators at MD Anderson Cancer Center. Forward-Looking StatementsThis press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this press release are forward-looking statements. These forward-looking statements may be identified by terms such as “will,” “believe,” “developing,” “expect,” “may,” “progress,” “potential,” “could,” “look forward,” “encouraging,” “might,” “should,” and similar terms or expressions or the negative thereof. Examples of such statements include, but are not limited to, statements relating to the following: Salarius’ expectations regarding the exploration of strategic alternatives, opportunities to extend Salarius’ resources, the Company’s expected cash runway, the Company’s expectations that the cost-savings measures will support the generation of additional data from the ongoing Phase 1/2 clinical trials in hematologic cancers and Ewing sarcoma; the future of the Company’s operations and product candidates; the future of the Company’s preclinical studies and clinical trials and development activities; the advantages of protein degraders including the value of SP-3164 as a cancer treatment; the value of seclidemstat as a treatment for Ewing sarcoma, Ewing-related sarcomas, and other cancers and its ability to improve the life of patients. Salarius may not actually achieve the plans, carry out the intentions or meet the expectations or objectives disclosed in these forward-looking statements. You should not place undue reliance on these forward-looking statements. These statements are subject to risks and uncertainties which could cause actual results and performance to differ materially from those discussed in the forward-looking statements. These risks and uncertainties include, but are not limited to, the following: the risk that exploration of strategic alternatives may not result in any definitive transaction or enhance stockholder value and may create a distraction or uncertainty that may adversely affect our operating results, business, or investor perceptions; the potential for the Company to seek other alternatives for restructuring and resolving its liabilities, including bankruptcy proceedings, a dissolution and orderly wind-down of operations; expectations regarding future costs and expenses; our product candidates being in early stages of development; the uncertainty about the paths of our programs and our ability to evaluate and identify a path forward for those programs, particularly given the constraints we have as a small company with limited financial, personnel and other operating resources (including with respect to the allocation of our limited capital and the sufficiency of our capital in the near term for any path we do select); Salarius’ ability to continue as a going concern; the sufficiency of Salarius’ capital resources; availability of suitable third parties with which to conduct contemplated strategic transactions; whether the Company will be able to pursue a strategic transaction, or whether any transaction, if pursued, will be completed successfully and on attractive terms or at all; whether our cash resources will be sufficient to fund the Company’s foreseeable and unforeseeable operating expenses and capital requirements; changes in the Company’s operating plans that may impact its cash expenditures; the uncertainties inherent in research and development, future clinical data and analysis; the risks associated with reductions in workforce, including reduced morale and attrition of additional employees necessary for the strategic reprioritization; the risk of not having a full-time chief executive officer; future clinical trial results and the impact of such results on Salarius; that the results of studies and clinical trials may not be predictive of future clinical trial results; the competitive landscape and other industry-related risks; and other risks described in Salarius’ filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2023, as revised or supplemented by its Quarterly Reports on Form 10-Q and other documents filed with the SEC. The forward-looking statements contained in this press release speak only as of the date of this press release and are based on management’s assumptions and estimates as of such date. Salarius disclaims any intent or obligation to update these forward-looking statements to reflect events or circumstances that exist after the date on which they were made. CONTACT: LHA Investor RelationsKim Sutton Golodetz kgolodetz@lhai.com212-838-3777

Clinical ResultPhase 1Phase 2

14 Jun 2024

·www.globenewswire.com

ORYZON Presents Preliminary Data From Ongoing Phase Ib FRIDA Trial with Iadademstat Plus Gilteritinib in Relapsed/Refractory FLT3-mut AML Patients at EHA-2024

Data from the first two cohorts demonstrated that combination of iadademstat plus gilteritinib was safe and showed strong antileukemic activityA third cohort is ongoing following FDA’s OPTIMUS guidance MADRID and CAMBRIDGE, Mass., June 14, 2024 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, today presents preliminary data from its ongoing Phase Ib FRIDA study investigating iadademstat in combination with gilteritinib in relapsed/refractory acute myeloid leukemia (AML) patients harboring a FMS-like tyrosine kinase mutation (FLT3 mut+) at the European Hematology Association (EHA) 2024 congress, being held in Madrid (Spain) on June 13–16. Dr. Amir Fathi, from the Massachusetts General Hospital and Principal Investigator of the study, will present a poster communication entitled “Preliminary results of the FRIDA study: iadademstat and gilteritinib in FLT3-mutated R/R AML”. Dr. Carlos Buesa, Oryzon’s CEO, stated, “We are very excited with these preliminary results, which showed in a mostly refractory patient population a higher-than-expected antileukemic activity in the first two cohorts. We, and others, have previously described the strong synergism of the combination of iadademstat with gilteritinib, and these clinical data confirm this synergism. The observed LSD1 full occupancy data in the first two cohorts outlines that we need to reduce the dose to optimize the marrow recovery and achieve a higher degree of complete responses. With the capability to quantify the levels of LSD1 occupancy, we are in an optimal situation to follow the FDA’s OPTIMUS guidance. The safety profile is so far adequate as expected and recruitment continues.” Summary of the main results reported at EHA-2024 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).Encouraging antileukemic activity observed, with 9 out of 13 patients (69%) achieving bone marrow (BM) blast clearance in the first cycle. 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). Of note, 11 out of 13 patients were refractory to prior standard regimens including venetoclax, 7+3 and midostaurin. Two patients have undergone hematopoietic stem cell transplantation.Platelet count recovery has been slow in most patients, limiting so far a rapid transition from morphologic leukemia-free state (MLFS) to CR/CRh. Since LSD1 plays a key role in hematopoiesis and both iadademstat doses evaluated in the first two cohorts (starting dose and DL-1) showed full LSD1 target engagement (≈90%), lower doses are being investigated with the aim of maintaining efficacy and improving platelet recovery, in accordance with the FDA’s Optimus Project requiring to identify the minimum safe and biologically active dose.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. FRIDA (NCT05546580) is an escalation/expansion, open-label, single arm, multicenter Phase Ib trial to establish the safety, tolerability, and the recommended Phase II dose (RP2D) of the combination of iadademstat with gilteritinib. The study has been designed according to the FDA’s Project Optimus and consists of 2 parts: a dose finding part to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic and emerging activity of the combination, and to determine the pharmacologically-active dose (i.e., the minimum safe and biologically active dose) of iadademstat in combination with gilteritinib, and an expansion part at the specific dose(s) selected to evaluate the activity of iadademstat in combination with gilteritinib in patients with FLT3-mutated R/R AML. The trial is conducted in the US and plans to accrue up to approximately 45 patients. Oryzon is further expanding the clinical development of iadademstat in AML through an Investigator-initiated study (IIS) led by Oregon Health & Science University (OHSU). This trial is a Phase Ib dose-finding study to evaluate iadademstat in combination with the SoC, venetoclax and azacitidine, in first line AML patients and is expected to begin enrolling patients in the coming weeks. In addition, in neuroendocrine tumors, in the context of the CRADA agreement between Oryzon and the NIH, the NCI is sponsoring a randomized Phase I/II trial in 1L extensive disease small cell lung cancer combining iadademstat with immune checkpoint inhibitors. The IND for this trial was recently approved by the FDA. A copy of the EHA-2024 poster is available here. About Oryzon Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS and iadademstat in oncology, in several Phase II clinical trials. The company has other pipeline assets directed against other epigenetic targets like HDAC-6, where ORY-4001 has been nominated as clinical candidate for the treatment of certain neurological disorders such as CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About Iadademstat Iadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and efficacy data in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing 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 valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is being evaluated in a collaborative Phase II basket study with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and the company is preparing a new trial in combination with immune checkpoint inhibitors (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; a first trial in combination with ICI in SCLC has recently received FDA IND approval. In total iadademstat has been dosed so far to more than 130 cancer patients in four clinical trials. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events, or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzon’s securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzon’s securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements. IR, USIR & Media, EuropeSpainOryzonAshley R. RobinsonSandya von der WeidPatricia Cobo/Mario CorderaEmili TorrellLifeSci Advisors, LLCLifeSci Advisors, LLCAtreviaChief Business Officer+1 617 430 7577+41 78 680 05 38+34 91 564 07 25+34 673 33 97 65+34 93 515 1313arr@lifesciadvisors.comsvonderweid@lifesciadvisors.compcobo@atrevia.commcordera@atrevia.cometorrell@oryzon.com

Phase 2Clinical ResultPhase 1Orphan DrugImmunotherapy

03 Jun 2024

·www.globenewswire.com

ORYZON Announces Journal Publication of Final Phase IIa ALICE Results with Iadademstat in The Lancet Hematology

The Phase IIa study ALICE evaluated the combination of iadademstat plus azacitidine in newly diagnosed, unfit patients with acute myeloid leukemia (AML)The combination showed substantial antileukemic activity with deep responses and a manageable safety profile, including in patients with high-risk prognostic factorsIadademstat continues to be studied in 1L unfit AML patients through an investigator-initiated study with Oregon Health & Science University (OHSU) MADRID and CAMBRIDGE, Mass., June 03, 2024 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the final results of the Phase IIa ALICE study evaluating iadademstat in combination with azacitidine in unfit patients with newly diagnosed acute myeloid leukemia (AML) were published online in The Lancet Hematology. A summary of the final data from this study had been previously released in an oral presentation at the 2022 American Society for Hematology (ASH) annual meeting, where it was selected as one of the 25 most relevant communications in AML. This notable publication is a continuation of Oryzon’s previous pioneering research featured in the Journal of Clinical Oncology (First-in-Human study in AML with iadademstat) and Cancer Cell (Characterization of iadademstat as a potent and selective LSD1 inhibitor), cementing the company’s position at the forefront of epigenetics in oncology and LSD1 innovation. Dr. Carlos Buesa, Oryzon’s CEO, stated, “We are thrilled to publish these groundbreaking results in one of the most prestigious journals in clinical oncology. Our study demonstrates that targeting LSD1 is a completely novel anti-leukemic mechanism of action in AML, potentially offering a new therapeutic approach, especially for patients with hard-to-treat forms of the disease such as myelomonocytic leukemias, DNMTs mutations, or TP53 mutations. These patients currently respond poorly to available treatments and may benefit from the innovative treatment option of iadademstat. We want to reiterate our gratitude to the patients, their families and the researchers involved in this study.” Summary of the main results reported in the publication The combination of iadademstat with azacitidine induced a high proportion of responses, with 22 (82%) of 27 patients in the efficacy analysis set having an objective response. Notably, 52% of patients had either a complete remission (CR) or complete remission with incomplete hematological recovery (CRi) in the ALICE trial. For comparison, the percentage of patients who experienced a CR/CRi in the intention-to-treat azacitidine populations was 28% in the acute myeloid leukaemia-001 trial, 28% in the VIALE A trial, and 27% in the Monarch trial.Most of the responses occurred rapidly (87% by the second assessment) and 36% lasted 12 months or longer. At database lock (1 year after the last patient was enrolled), nine patients were alive and as of February, 2024, five patients remain alive, with three continuing treatment (and in complete remission) under compassionate use after four years.The CR/CRi responses in ALICE were generally deep, as determined by the high rate of measurable residual disease (MRD) negativity (91% in the evaluable samples), which is associated with improved survival.Remarkably, responses were seen across the entire adverse prognostic mutational landscape. Of note are the responses in specific subgroups: Three patients with M5 AML (a population primary refractory to venetoclax and azacitidine) had CR/CRi with iadademstat plus azacitidine, with 100% measurable residual disease negativity.In patients with AML with TP53 mutations in combination with a complex karyotype or high variant allele frequency, or both, CR/CRi was reached in 63%, with a duration of response of 7.9 months and a median overall survival of 10 months.Responses in leukemias harboring other poorer-prognosis mutations were also encouraging. All seven patients harboring a mutation or mutations in the RAS pathway responded, with a median overall survival of 467 days. Patients harboring mutations in DNM3TA (n=7), NPM1 (n=4), and RUNX (n=3) had 100% response rates, mostly CR or CRi. A temporary link to access the online publication for free can be found here. As a continuation of ALICE, Oryzon is further expanding the clinical development of iadademstat in 1L unfit AML through an Investigator-initiated study (IIS) led by Oregon Health & Science University (OHSU). This trial is a Phase Ib dose-finding study to evaluate iadademstat in combination with the SoC, venetoclax and azacitidine, in first-line AML patients and is expected to begin enrolling patients in the coming weeks. Iadademstat is currently being evaluated also in combination with gilteritinib in relapsed/refractory AML patients harboring a FLT3 mutation in the FRIDA study, an open-label, multicenter Phase Ib trial being conducted in the US and which plans to accrue up to approximately 45 patients. The first two cohorts have been completed (thirteen patients), and the combination was safe and showed strong antileukemic activity. Following the FDA’s new OPTIMUS doctrine, the company continues to explore the minimal dose with clinical activity, and a third cohort has been started and is recruiting. Preliminary results from this trial will be presented at the upcoming European Hematology Association (EHA) 2024 congress in June. In addition, in neuroendocrine tumors, in the context of the CRADA agreement between Oryzon and the NIH, the NCI is sponsoring a randomized Phase I/II trial in 1L extensive disease small cell lung cancer combining iadademstat with immune checkpoint inhibitors. The IND for this trial was recently approved by the FDA. About OryzonFounded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS and iadademstat in oncology, in several Phase II clinical trials. The company has other pipeline assets directed against other epigenetic targets like HDAC-6, where ORY-4001 has been nominated as clinical candidate for the treatment of certain neurological disorders such as CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About Iadademstat Iadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and efficacy data in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing 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 valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is being evaluated in a collaborative Phase II basket study with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and the company is preparing a new trial in combination with immune checkpoint inhibitors (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; a first trial in combination with ICI in SCLC has recently received FDA IND approval. In total iadademstat has been dosed so far to more than 130 cancer patients in four clinical trials. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events, or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzon’s securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzon’s securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements. IR, USIR & Media, EuropeSpainOryzonAshley R. RobinsonSandya von der WeidPatricia Cobo/Mario CorderaEmili TorrellLifeSci Advisors, LLCLifeSci Advisors, LLCAtreviaChief Business Officer+1 617 430 7577+41 78 680 05 38+34 91 564 07 25+34 673 33 97 65+34 93 515 1313arr@lifesciadvisors.comsvonderweid@lifesciadvisors.compcobo@atrevia.commcordera@atrevia.cometorrell@oryzon.com

Phase 2Clinical ResultASHOrphan DrugPhase 1

100 Deals associated with Pulrodemstat

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 2	US	Celgene Corp.	14 Jul 2020
Advanced cancer	Phase 2	FR	Celgene Corp.	14 Jul 2020
Advanced cancer	Phase 2	IT	Celgene Corp.	14 Jul 2020
Advanced cancer	Phase 2	PL	Celgene Corp.	14 Jul 2020
Advanced cancer	Phase 2	ES	Celgene Corp.	14 Jul 2020
Advanced cancer	Phase 2	GB	Celgene Corp.	14 Jul 2020
Acute Myeloid Leukemia	Phase 1	US	Celgene Corp.	14 Oct 2021
Acute Myeloid Leukemia	Phase 1	BE	Celgene Corp.	14 Oct 2021
Acute Myeloid Leukemia	Phase 1	FR	Celgene Corp.	14 Oct 2021
Acute Myeloid Leukemia	Phase 1	ES	Celgene Corp.	14 Oct 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04350463 (WCLC2023) Manual	Phase 2	Advanced Lung Adenocarcinoma	88	CC-90011+Nivolumab (ICI-naive patients with ES SCLC)	oiaenyscef(qfvbkvrnph) = nzdilhysoc suyufpzryp (onlbozzflp, 2.9 - 24.2)	Negative	12 Sep 2023
NCT04350463 (WCLC2023) Manual	Phase 2	Advanced Lung Adenocarcinoma	88	CC-90011+Nivolumab (patients with ES SCLC)	-	Negative	12 Sep 2023
NCT02875223 (CC-90011-ST-001, Pubmed) Manual	Phase 1	Neoplasms	69	CC-90011 (dose-escalation)	vujqlugljv(ytebvddhpi) = aeuphrdlki ytfjqlocxj (ljkwhcjcdd )	Positive	23 Jun 2022
NCT02875223 (CC-90011-ST-001, Pubmed) Manual	Phase 1	Neoplasms	69	CC-90011 (dose-expansion)	fnheqzvlke(mzsqssdtlj) = anmapztkkk xkclleffwy (dwcshbdybe )	Positive	23 Jun 2022
NCT02875223 (CC-90011-ST-001, Pubmed \| Clin Cancer Res)	Phase 1	Non-Hodgkin's lymphoma refractory \| HR-positive/HER2-low Solid Tumors	-	CC-90011	srgwiuazjf(msjsajdwac) = jyeegofijd cwakpxltby (keahmhiqrb ) View more	-	15 Jan 2021
NCT02875223 (CC-90011-ST-001, ESMO2020)	Phase 1	Non-Hodgkin's lymphoma refractory \| Advanced Malignant Solid Neoplasm	-	CC-90011	wlzjiaffbu(swmegavwxm) = ntdnfbmipc suaccwbhip (ugnyurodqi, 10.0 - 33.7)	Positive	20 Sep 2020
NCT03850067 (ESMO2020) Manual	Phase 1	Extensive stage Small Cell Lung Cancer First line	13	CC-90011+etoposide+cisplatin	xljdihyjce(imlrgreznn) = hlsxavzgmk lwjyfuhpvh (tltzkcvsni ) View more	Positive	17 Sep 2020
NCT02875223 (ESMO2019) Manual	Phase 1	Non-Hodgkin's lymphoma refractory \| HR-positive/HER2-low Solid Tumors	50	Pulrodemstat	dbzuijjihg(ueakgdxkhn) = digydlqejx hbqamjhsxl (egyqguuojw ) View more	Positive	01 Feb 2019

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