CEBPA

Findings validate clinical proof of mechanism of MTL-CEBPA as a combination therapy in solid tumor cancers Company to initiate out-licensing activities of its immuno-oncology portfolio, including MTL-CEBPA LONDON--(BUSINESS WIRE)-- MiNA Therapeutics Limited, the pioneer in small activating RNA (RNAa) therapeutics, will present positive updated biomarker data from its Phase 1a/b TIMEPOINT study of MTL-CEBPA in combination with the anti-PD1 checkpoint inhibitor, pembrolizumab, in adults with advanced solid tumors at the annual meeting of the American Association of Cancer Research (AACR) in Orlando, Florida. Findings from the Phase 1b portion of the study validate the clinical proof of mechanism of MTL-CEBPA as a combination treatment and identify a novel predictive biomarker of clinical response. The data will be presented on Tuesday, April 18, during a late-breaking research session beginning at 9:00 am EDT. MTL‑CEBPA is the first therapy that specifically up-regulates CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cells. Dysregulated myeloid cells are implicated in several diseases including solid tumor cancers. MTL-CEBPA is designed to improve the effectiveness of checkpoint inhibitors and other immunotherapies by enhancing the body’s immune response and ability to attack the cancerous cells. Interim data from an open-label, multi-center study demonstrated the safety, tolerability, immunological and clinical activity of MTL-CEBPA in combination with pembrolizumab. “Anti-PD1 checkpoint inhibition has significantly advanced the treatment of cancer, but many patients are resistant to treatment and present with tumors that resemble an ‘immune-desert’,” said Robert Habib, CEO of MiNA Therapeutics. “The updated analysis of TIMEPOINT shows that MTL-CEBPA used in combination with anti-PD1 checkpoint inhibitors profoundly reprograms the tumor microenvironment, reducing resistance and enabling infiltration of disease-fighting T-cells.” The TIMEPOINT study also identified a novel predictive biomarker of clinical response to the combination treatment, presenting an opportunity for further evaluation as a potential companion diagnostic. The novel biomarker predicted clinical response across multiple tumor types. MiNA plans to explore out-licensing opportunities for its immuno-oncology portfolio, which uniquely combines the capability to specifically restore or boost any dysregulated gene target with clinically validated in vivo delivery to myeloid immune cells. MiNA’s immuno-oncology portfolio includes the following programs: MTL‑CEBPA, which has been cleared for evaluation in a global Phase 2 clinical trial in combination with the tyrosine kinase inhibitor, sorafenib, in advanced hepatocellular carcinoma (HCC or liver cancer) and in a Phase 1 clinical trial in pediatric patients with MPS1 Hurler Syndrome MTL-STING currently in pre-clinical development Additional programs currently in discovery About TIMEPOINT TIMEPOINT is a global Phase 1a/b clinical study in patients with solid tumor malignancies to assess the safety and tolerability of MTL‑CEBPA in combination with pembrolizumab in patients who are ineligible or resistant to standard therapies. The study has received clearance from the U.S. Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). To learn more about the TIMEPOINT clinical study, visit ClinicalTrials.gov (NCT04105335). The poster presentation at AACR entitled, “MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade,” will be available on MiNA’s website in the Publications section under "RNA Activation". About MTL-CEBPA MTL-CEBPA is the first therapy that specifically up-regulates CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation. Dysregulated myeloid cells have been implicated in several diseases, and in solid tumor cancers these cells have been identified as a critical barrier to induction of clinical response for many therapies. In pre-clinical studies, MTL-CEBPA has been shown to improve the anti-tumor activity of cancer therapies by targeting dysregulated myeloid cells and reducing or eliminating their suppressive effect on immune response and therapies in the tumor microenvironment. About MiNA Therapeutics MiNA Therapeutics is the global leader in small activating RNA therapeutics or RNAa. Harnessing innate mechanisms of gene activation, RNAa therapeutics are a revolutionary new class of medicines that can restore or boost normal function of genes and thereby protein-modulated pathways in patients' cells. We are advancing a proprietary pipeline of new medicines with an initial focus on genetic medicine, while collaborating with leading pharmaceutical companies to apply our technology platform across a broad range of other therapeutic areas. Based on our unique know-how in RNA activation, we are expanding the possibilities of RNA-based medicine for patients.

Personalized Therapy Biosimulation Uncovers a Spectrum of Genomic Aberrations that Predict Response to HMA in Myelodysplastic Syndrome Patients SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Cellworks Group Inc., a leader in Precision Drug Development and Personalized Therapy Biosimulation, today announced results from a study that examined how Differentiation Scoring (DS) derived from key myeloid biomarkers in individual Myelodysplastic Syndrome (MDS) patients using the Cellworks Platform and Computational Biology Model (CBM) can predict response to Hypomethylating Agents (HMA). In the study, DS predicted HMA response in MDS patients and showed a strong correlation to the treatment efficacy score (ES). Non-responders had lower DS and survival than patients with high DS. Conclusions from the study suggest that DS-low MDS patients should be considered for novel combination therapy at the time of diagnosis. Results from the study were featured in a poster presentation as Abstract 2171 at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition on December 10, 2022 and have been published online at Blood®. “Given that 50% of MDS patients who are treated with HMA as a single agent will have unsatisfactory outcomes, we need to be able to predict therapy response for individual patients prior to treatment,” said Dr. Guido Marcucci, MD, Chair and Professor, Department of Hematologic Malignancies Translational Science, Director, Gehr; Family Center for Leukemia Research, Professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope; and Co-Principal Investigator of the study. “This study demonstrates the power of using Cellworks personalized therapy biosimulation to gain insight into individual patient mutanome, drug resistance pathways and novel biomarkers that determine their drug response and resistance to better inform treatment decisions for MDS patients.” “MDS patients typically have multiple molecular aberrations which impact how they respond to treatment,” said Dr. Scott Howard, MD, MSc, Professor at University of Tennessee Health Science Center and Co-Principal Investigator of the study. “This study showcases the complexity of MDS-related aberrations and provides a metric for identifying beforehand which patients will benefit from HMA as a single agent. By identifying which patients will not respond to HMA, clinicians can consider other options such as a combination therapy or a clinical trial.” “Biosimulation of MDS using differentiation scoring was able to identify patients with minimal benefits from HMA for whom an alternative strategy at the outset of treatment could offer a very meaningful chance to enhance outcomes,” said Dr. Michael Castro, MD, Neuro-oncologist, Medical Oncologist at Beverly Hills Cancer Center; Chief Medical Officer at Cellworks, Group Inc. and Co-Principal Investigator of the study. Cellworks Personalized Therapy Biosimulation The Cellworks Platform biosimulates how a patient's personalized genomic disease model will respond to therapies prior to treatment and can also identify novel drug combinations for treatment-refractory patients. The platform is powered by the groundbreaking Cellworks CBM, a highly curated mechanistic network of 6,000+ human genes, 30,000 molecular species and 600,000+ molecular interactions. As part of the biosimulation process, personalized disease models are created for each patient using their cytogenetic and molecular data as input to the Cellworks CBM. The Cellworks Platform analyzes the impact of specific therapies on the patient’s personalized disease model and predicts the efficacy of specific chemotherapies. Study: ASH Abstract 2171 The purpose of the study was to examine how Differentiation Scoring derived from the Cellworks Platform, Computational Biology Model, and each Myelodysplastic Syndrome patient’s genomic aberrations could serve as a biomarker to predict response to Hypomethylating Agents. Background Differentiation arrest resulting from aberrant methylation represents a key pathogenic and phenotypic feature of MDS. Hypomethylating agents (HMA) can reverse epigenetic dysregulation, but single agents fail to control the disease in approximately 50% of patients, many of whom progress to AML and carry a dismal prognosis. Methods The study included 169 MDS patients treated with azacytidine (n = 86) or decitabine (n = 83) whose genomic aberrations and clinical outcomes were available from public databases. Biosimulation of the disease state was computationally derived from pathways that were up- or down-regulated by individual genomic aberrations. DS was defined as the ratio of the quantified impact of key differentiation biomarkers in myeloid malignancies (CEBPA, GATA1, SPI1 and ITGAM) divided by the impact of HOXA9 transcription, a known repressor of differentiation, and normalized on a log2 scale. The Cellworks Platform and CBM were used to determine the change in DS attributable to HMA to define an efficacy score (ES) as a parameter of drug response. A Pearson correlation coefficient was obtained using the two variables. DS in clinical responders (R) and non-responders (NR) was evaluated with the Student t-test. DS was defined with DS > 1.5 as DS-high and < 1.5 as DS-low. Survival data were available for 101 patients and correlated with DS-high (n=49) and DS-low (n=52) groups using a KM-curve. Results Regarding HMA response, 62 patients were responders, while 107 were non-responders. Prior to therapy, 86 patients had DS-high and 83 had DS-low scores. Post-treatment, DS were correlated with HMA ES (R = 0.58, p < 2.2e-16), and showed a favorable HMA response for DS-high patients. Biosimulation showed the incremental benefit on DS of HMA was greater for people with DS-high than DS-low scores (44% vs 16%, p = 7.51 e-17). Median DS was higher in responders than in non-responders (p=0.00232). Patients with DS-high scores had superior survival compared to those with DS-low scores (log rank p = 0.0016). Different genomic aberrations contributed to the DS scores. DS-high patients had more TP53 mutations, 17p del, 8q amp, and 5q del. On the other hand, DS-low patients more often had mutations in ASXL1, SRSF2, RUNX1, DNMT3A, EZH2, NF1, NRAS, CBL, or 7q deletion. Conclusions This study shows that Cellworks personalized therapy biosimulation, which was based on each patient’s genomic aberrations, reveals a high spectrum of DS among patients with MDS. DS strongly predicted HMA response and in general, non-responders had lower DS and survival than high-DS patients. While patients with DS-low scores might have fared even worse without HMA therapy, this study suggests that DS-low patients should be considered for novel combination therapy at the time of diagnosis given their unsatisfactory outcomes with HMA therapy as a single agent. About Cellworks Group Cellworks Group, Inc. is a leader in Precision Drug Development and Personalized Therapy Biosimulation. The Cellworks Platform predicts therapy response for individual patients and patient cohorts using a breakthrough Computational Biology Model (CBM) and biosimulation technology. Backed by Artiman Ventures, Bering Capital, Sequoia Capital, UnitedHealth Group and Agilent Ventures, Cellworks has the world’s strongest trans-disciplinary team of molecular biologists, cellular pathway modelers and software technologists working toward a common goal – attacking serious diseases to improve the lives of patients. The company is based in South San Francisco, California with a research and development facility in Bangalore, India. For more information, visit . All trademarks and registered trademarks in this document are the properties of their respective owners.