RUNX1

Relapses in a common form of leukemia may be preventable following new research that has identified how the cancer develops resistance to first line treatments. Relapses in a common form of leukemia may be preventable following new research which has identified how the cancer develops resistance to first line treatments. New research published in iScience by researchers from the University of Birmingham, the Institute of Cancer Research (ICR), Newcastle University, the Princess Maxima Centre of Pediatric oncology and the University of Virginia identified changes in a mutated form of acute myeloid leukemia (AML) samples from patients who relapsed after receiving FLT3 inhibitor treatment. The team found that the resistant cancer had up-regulated multiple other signalling pathways to overcome the drug's action, and that the genetic change was able to be replicated in lab tests. These experiments revealed that by targeting RAS family proteins, using a small molecule inhibitor developed from a chemical library screen using the paratope of an inhibitory intracellular antibody by Terry Rabbitts' team at the Weatherall Institute of Molecular Medicine University of Oxford and the ICR, increased signalling no longer rescued the cells from cell death. The team identified that the transcription factors AP-1 and RUNX1 were at the heart of mediating drug resistance. The two factors cooperate and bind to their target genes together, but only in the presence of growth factor signalling. The drugs targeting FLT3 rewire the cell, resulting in the upregulation of other signalling pathway associated genes, which then restored AP-1 and RUNX1 binding. Drugging RAS, which is a key component in multiple signalling pathways, prevented this restoration of RUNX1 binding, and therefore signalling from growth factors no longer rescued the cancer cells from death. Professor Constanze Bonifer from the Institute of Cancer and Genomic Sciences at the University of Birmingham, who has just taken up a position at the University of Melbourne, and is one of the senior authors of the paper said: "The pharmaceutical industry had high hopes that drugs targeting aberrant growth factor receptors such as the FLT3-ITD would prevent people from relapse. However, cancer cells are smart, and rewire their growth control machinery to use other growth factors present in the body. Targeting RAS family members prevents the cancer from rewiring and using different signalling pathways to escape cell death." Targeting RAS blocks rewiring The small molecule inhibitors used to target RAS in this study were developed using intracellular antibody technology. This technology involves screening a large number of antibody fragments to identify those which bind to the target protein in cells and prevent their protein-protein interactions. Small molecule inhibitors are can be screened from chemical libraries that interact with the parts of the target protein where these antibody fragments bind (the paratope). Due to the unparalleled natural specificity of these antibody fragments, this technology (called Antibody derived or Abd technology) can be used to target difficult to drug proteins and identify new parts of the protein which can be targeted to prevent protein-protein interactions. Professor Terry Rabbitts from the Institute of Cancer Research who developed these drugs said: "The strength of the Antibody-derived technology approach is that intracellular antibodies can selected to essentially any protein. In turn, their specific binding sites can be employed to select chemical compounds for drug discovery against hard to drug proteins. Mutant RAS was considered undruggable, but the Abd technology facilitated the development of the RAS-binding compounds used in the current study of cancer cell re-wiring. Abd technology will allow development of a new generation of drugs to hard-to-drug and intrinsically disordered proteins." AML with a FLT3-ITD mutation occurs in nearly 30% of all patients and is a highly aggressive disease with a poor prognosis. This genetic change causes the expression of a mutant growth factor receptor which is always active and therefore cancer cells expressing it grow uncontrollably. While inhibitors which specifically target the FLT3 protein are now in use in the clinic, patients treated with these inhibitors frequently relapse. This work was funded by Leukaemia Research UK, the Medical Research Council, Blood Cancer Research UK, the Royal Society, the Wellcome and Cancer Research UK. The first author, Daniel Coleman is a John Goldman Fellow of Leukaemia UK.

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Cero Therapeutics Holdings, Inc., (NASDAQ:CERO) ("CERo") an innovative immunotherapy company seeking to advance the next generation of engineered T cell therapeutics that employ phagocytic mechanisms today announced the publication in Clinical Cancer Research, a journal of the American Association for Cancer Research, a paper titled “Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia.” The paper details preclinical studies by CERo analyzing its lead clinical candidate CER-1236 in targeting Acute Myelogenous Leukemia (AML) tumor cells from human patients, and the candidate’s killing effects on these tumor cells. The results in the paper found that the target for CER-1236 is found in the large majority (83%) of leukemic cells extracted from the bone marrow from patients, and that more importantly CER-1236 effectively eliminated leukemic cells in the company’s experiments. Finally, the target for CER-1236 was found by CERo to be highly expressed and detectable across common AML genetic classification subtypes, including patient samples with adverse risk mutations in TP53, ASXL1 and RUNX1. “This new publication provides support for our plans to test CER-1236 in AML patients in our planned Phase I clinical trial, and moreover extends the scientific data we have produced showing the target for CER-1236 is present on tumor cells from diverse cancers, including ovarian, non-small cell lung cancer (NSCLC), and B cell malignancies,” said Daniel Corey M.D, Ph.D, CERo’s Founder and Chief Technology Officer. “We’re very pleased with this publication in Clinical Cancer Research supporting our near term plans to advance CER-1236 into the clinic. As we have previously reported, CERo plans to Investigational New Drug (IND) application in the first half of 2024, and is targeting initial treatment of AML patients as well as B Cell lymphoma patients before the end of the year,” said Brian G Atwood, CERo’s Chairman and Chief Executive Officer. About CERo Therapeutics, Inc. CERo is an innovative immunotherapy company advancing the development of next generation engineered T cell therapeutics for the treatment of cancer. Its proprietary approach to T cell engineering, which enables it to integrate certain desirable characteristics of both innate and adaptive immunity into a single therapeutic construct, is designed to engage the body’s full immune repertoire to achieve optimized cancer therapy. This novel cellular immunotherapy platform is expected to redirect patient-derived T cells to eliminate tumors by building in engulfment pathways that employ phagocytic mechanisms to destroy cancer cells, creating what CERo refers to as Chimeric Engulfment Receptor T cells ("CER-T"). CERo believes the differentiated activity of CER-T cells will afford them greater therapeutic application than currently approved chimeric antigen receptor ("CAR-T") cell therapy, as the use of CER-T may potentially span both hematological malignancies and solid tumors. CERo anticipates initiating clinical trials for its lead product candidate, CER-1236, in 2024 for hematological malignancies. Forward-Looking Statements This communication contains statements that are forward-looking and as such are not historical facts. This includes, without limitation, statements regarding the financial position, business strategy and the plans and objectives of management for future operations of CERo. These statements constitute projections, forecasts and forward-looking statements, and are not guarantees of performance. Such statements can be identified by the fact that they do not relate strictly to historical or current facts. When used in this communication, words such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “strive,” “would” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. When CERo discusses its strategies or plans, it is making projections, forecasts or forward-looking statements. Such statements are based on the beliefs of, as well as assumptions made by and information currently available to, CERo’s management. Actual results could differ from those implied by the forward-looking statements in this communication. Certain risks that could cause actual results to differ are set forth in CERo’s filings with the Securities and Exchange Commission, including its Current Report on Form 8-K, as amended, filed on February 27, 2024, and the documents incorporated by reference therein. The risks described in CERo’s filings with the Securities and Exchange Commission are not exhaustive. New risk factors emerge from time to time and it is not possible to predict all such risk factors, nor can CERo assess the impact of all such risk factors on its business, or the extent to which any factor or combination of factors may cause actual results to differ materially from those contained in any forward-looking statements. Forward-looking statements are not guarantees of performance. You should not put undue reliance on these statements, which speak only as of the date hereof. All forward-looking statements made by CERo or persons acting on its behalf are expressly qualified in their entirety by the foregoing cautionary statements. CERo undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

Subgroup analyses showed consistently higher transfusion independence (TI) response rates than placebo across different risk groups regardless of International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) or IPSS molecular (IPSS-M) Robust TI rates with imetelstat treatment compared with placebo in patients with poor prognosis mutational profiles For the nearly 20% of imetelstat-treated patients who achieved greater than 1-year sustained TI, median duration of TI was more than two years and median hemoglobin increase was more than 5 g/dL Consistent with prior imetelstat clinical experience, the most common adverse events were thrombocytopenia and neutropenia that were manageable and of short duration Imetelstat is currently under regulatory review by the FDA and EMA for the treatment of transfusion-dependent anemia in adult patients with lower risk MDS FOSTER CITY, Calif.--(BUSINESS WIRE)--Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, today announced the publication of abstracts from the IMerge Phase 3 clinical trial evaluating its first-in-class investigational telomerase inhibitor imetelstat in patients with lower risk myelodysplastic syndromes (MDS). Four abstracts have been accepted for presentation at the 65th American Society of Hematology (ASH) Annual Meeting taking place from December 9-12 in San Diego, California and virtually. “The 2023 ASH abstracts present data and analyses from the IMerge Phase 3 clinical trial that reinforce the differentiated clinical pro imetelstat in lower risk MDS, and specifically highlight that patients achieve TI irrespective of risk status based on classification systems, or specific poor prognostic mutation pro Of particular importance, the nearly 20% of imetelstat-treated patients who achieved one year or greater transfusion independence with accompanying hemoglobin rises of 5 g/dl and reduction of MDS-associated mutations speak to the potential of this novel therapy to provide clinical benefits to patients that have not been observed before in transfusion-dependent lower risk MDS,” said Faye Feller, M.D., Geron’s Executive Vice President, Chief Medical Officer. Imetelstat is currently under regulatory review by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of transfusion dependent anemia in adult patients with lower risk MDS who have failed to respond or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs). “The data from IMerge Phase 3 being presented at the ASH annual meeting provides important insight into the breadth of effect of TI achieved with imetelstat across different risk subgroups and across the various underlying mutations associated with MDS, suggesting a broad use for imetelstat in patients eligible for the study, including in difficult-to-treat subgroups. Imetelstat also demonstrated efficacy among patients who were reclassified as higher risk using molecular international prognostic scoring system (IPSS-M),” said Rami S. Komrokji, M.D., Vice Chair, Malignant Hematology Department, Moffitt Cancer Center, one of the principal investigators of IMerge Phase 3 and ASH presenter. “Additionally, our abstract showcasing a real-world data population level analysis of over 5,000 lower risk MDS patients adds to the significant literature suggesting a correlation between TI and improvement in survival. These data support the importance of TI to improve outcomes for patients with lower risk MDS.” Abstract #194: “Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence (RBC-TI) Across Different Risk Subgroups in Patients with Lower Risk Myelodysplastic Syndromes (LR MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) in IMerge Phase 3 Study” Oral Presentation on December 9, 2023, at 2:15 p.m. PT This abstract evaluates TI rates in patients treated with imetelstat vs. placebo across different risk subgroups as defined by International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) or IPSS molecular (IPSS-M) risk profiles and shows that patients treated with imetelstat consistently had higher TI response rates than placebo regardless of risk classification. Further, in patients re-classified as high or very high risk using IPSS-M, TI response rates with imetelstat (and not placebo) were similar to TI response rates in lower risk subgroups. This analysis suggests imetelstat has clinical activity in lower risk MDS patients independent of risk categories. Abstract #4603: “Impact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study” Poster Presentation on December 11, 2023, from 6-8 p.m. PT This abstract evaluates the impact of MDS-associated mutations on clinical efficacy of imetelstat for the 165 of 178 patients for whom mutation data were available and shows that RBC-TI response rates in patients receiving imetelstat occurred regardless of the presence of baseline MDS associated mutations that have a poor prognosis (either specific mutations or multiple concurrent mutations). In patients with mutations associated with poor prognosis (TP53, ETV6, RUNX1, ASXL1, or EZH2), ≥8-week and ≥24-week, TI was observed in 31.8% and 9.1% of imetelstat-treated patients vs 0 on placebo. The 8-week TI rate for patients with 3 or more mutations was 55.6% with imetelstat compared to 14.3% with placebo. This analysis suggests clinical benefit of imetelstat across different molecularly defined subgroups and independent of the underlying molecular pattern. Abstract #4605: “Durable Continuous Transfusion Independence (TI) With Imetelstat in IMerge Phase 3 for Patients with Heavily Transfused Non-Del(5q) Lower Risk Myelodysplastic Syndromes (LR MDS) Relapsed/Refractory (R/R) to or Ineligible for Erythropoiesis-Stimulating Agents (ESAs)” Poster Presentation on December 11, 2023, from 6-8 p.m. PT This abstract evaluates the 1-year TI responders in IMerge Phase 3, including 17.8% of imetelstat-treated patients (21/118; 95% CI, 11.4-25.9) and 1.7% of patients on placebo (1/60; 95% CI, 0-8.9). The median duration of TI for imetelstat ≥1-year TI responders was 123 weeks (95% CI, 80.4 to not evaluable); the median increase in hemoglobin during the longest TI interval was 5.18 g/dL (range, 2.67-13.76 g/dL) for the imetelstat group vs 1.67 g/dL for the placebo patient. Of the 18/21 imetelstat-treated 1-year TI responders for whom mutation data were available, 72.2% achieved ≥50% SF3B1 variant allele frequency (VAF) reduction, including 7 patients in whom there was complete elimination of MDS associated mutations. The abstract concludes that the long-term durable TI, robust increases in hemoglobin and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity. Grade 3-4 thrombocytopenia and neutropenia occurred in 14 (67%) and 20 (95%) patients with ≥1-year TI, respectively, and the mean duration of grade 3/4 thrombocytopenia and neutropenia events was 2.25 and 1.78 weeks, respectively. 89% of grade 3/4 thrombocytopenia and 81% of grade 3/4 neutropenia was reduced to grade 1/2 within 4 weeks. Abstract #2440: “Durable Transfusion Independence in Lower Risk Myelodysplastic Syndrome (LR MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database” Poster Presentation on December 11, 2023, from 6-8 p.m. PT This abstract describes a population level analysis of 5,662 lower risk MDS patients identified through Optum Clinformatics® between October 2015 and June 2022. Among these patients, 35% and 49% were transfusion-dependent before first and second lines of therapy, respectively. The median overall survival from start of second line therapy was 23.4 months overall, and 37.9 months vs 9.3 months among responders becoming transfusion independent vs non-responders, respectively (P < .0001). Despite the currently available therapies, transfusion dependence after any line of therapy is associated with poorer outcomes. Achievement of durable TI was associated with improved survival, supporting the clinical benefit of achieving transfusion independence in lower risk MDS. These abstracts are available on the ASH 2023 Meeting website at . About IMerge Phase 3 The Phase 3 portion of the IMerge Phase 2/3 study is a double-blind, 2:1 randomized, placebo-controlled clinical trial to evaluate imetelstat in patients with IPSS Low or Intermediate-1 risk (lower risk) transfusion dependent MDS who were relapsed after, refractory to, or ineligible for, erythropoiesis stimulating agent (ESA) treatment, had not received prior treatment with either a HMA or lenalidomide and were non-del(5q). To be eligible for IMerge Phase 3, patients were required to be transfusion dependent, defined as requiring at least four units of packed red blood cells (RBCs), over an eight-week period during the 16 weeks prior to entry into the trial. The primary efficacy endpoint of IMerge Phase 3 is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, defined as the proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial (8-week TI). Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks (24-week TI), the duration of TI and the rate of hematologic improvement erythroid (HI-E), which is defined under 2006 IWG criteria as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden. A total of 178 patients were enrolled in IMerge Phase 3 across North America, Europe, Middle East and Asia. About Imetelstat Imetelstat is a novel, first-in-class investigational telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from non-clinical studies and clinical trials of imetelstat provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of adult patients with transfusion dependent anemia due to Low or Intermediate-1 risk MDS that is not associated with del(5q) who are refractory or resistant to an erythropoiesis stimulating agent, and for adult patients with Intermediate-2 or High-risk myelofibrosis (MF) whose disease has relapsed after or is refractory to Janus associated kinase (JAK) inhibitor treatment. Imetelstat is currently not approved by any regulatory authority. About Geron Geron is a late-stage clinical biopharmaceutical company pursuing therapies with the potential to extend and enrich the lives of patients living with hematologic malignancies. Our first-in-class investigational telomerase inhibitor, imetelstat, harnesses Nobel Prize-winning science in a treatment that may alter the underlying drivers of disease. The New Drug Application (NDA) for imetelstat for the treatment of transfusion dependent anemia in adult patients with lower risk myelodysplastic syndromes (LR MDS) who have failed to respond or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs), based on the results from the Phase 3 IMerge clinical trial, is currently under review by the United States Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target action date of June 16, 2024. In addition, an MAA is under review in the European Union for the same proposed indication. Furthermore, Geron currently has an ongoing pivotal Phase 3 clinical trial evaluating imetelstat in relapsed/refractory myelofibrosis (MF). To learn more, visit or follow us on LinkedIn. Use of Forward-Looking Statements Except for the historical information contained herein, this press release contains forward-looking statements made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that such statements, include, without limitation: (i) that data from the IMerge Phase 3 clinical trial in the ASH abstracts reinforce the differentiated clinical pro imetelstat in lower risk MDS; (ii)that the nearly 20% of imetelstat-treated patients who achieved one year or greater transfusion independence with accompanying hemoglobin rises of 5 g/dl and reduction of MDS-associated mutations speak to the potential of imetelstat to provide clinical benefits to patients that have not been observed before in transfusion-dependent lower risk MDS; (iii) that data from IMerge Phase 3 associated with the ASH annual meeting suggests a broad use for imetelstat in patients eligible for the study, including in difficult-to-treat subgroups; (iv) that a real-world data population level analysis of over 5,000 lower risk MDS patients adds to the significant literature suggesting a correlation between transfusion independence and improvement in survival and support the importance of transfusion independence to improve outcomes for patients with lower risk MDS; and (v) other statements that are not historical facts, constitute forward-looking statements. These forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. These risks and uncertainties, include, without limitation, risks and uncertainties related to: (a) whether regulatory authorities permit the further development of imetelstat on a timely basis, or at all, without any clinical holds; (b) whether any future safety or efficacy results cause the benefit-risk pro imetelstat to become unacceptable; (c) whether imetelstat actually demonstrates that it alters the underlying drivers of disease and has disease-modifying activity in patients; and (d) whether the FDA and EMA will approve imetelstat for the treatment of transfusion-dependent anemia in patients with lower risk MDS. Additional information on the above risks and uncertainties and additional risks, uncertainties and factors that could cause actual results to differ materially from those in the forward-looking statements are contained in Geron’s filings and periodic reports filed with the Securities and Exchange Commission under the heading “Risk Factors” and elsewhere in such filings and reports, including Geron’s quarterly report on Form 10-Q for the quarter ended September 30, 2023 and future filings and reports by Geron. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made, and the facts and assumptions underlying the forward-looking statements may change. Except as required by law, Geron disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances.