SRSF2

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.

Exploratory analysis from Cohort 3 of the Phase 2 REFINE study presented in an oral session at ASH NORTH CHICAGO, Ill., Dec. 10, 2022 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced new data from Cohort 3 of its Phase 2 REFINE study of investigational navitoclax in combination with ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (MF). The exploratory analysis suggests the combination of navitoclax and ruxolitinib led to reductions in bone marrow fibrosis (BMF) and variant allele frequency (VAF) for common genetic mutations found in individuals with myelofibrosis that may indicate potential disease modification.1 The findings were shared in an oral presentation (abstract #237) at the 64th American Society of Hematology Annual Meeting & Exposition (ASH). "While the current standard of care for patients with myelofibrosis can improve disease symptoms, impact on underlying disease biology is limited. It is our hope that patients have an option that goes beyond symptom control," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development, AbbVie. "Consistent with previous evidence, these results suggest navitoclax combination may have disease modifying potential, both as an anti-fibrosis agent and by reducing variant allele frequency of driver mutations." REFINE (NCT03222609) is a Phase 2 non-randomized open-label multi-cohort study evaluating the safety and efficacy of navitoclax alone or in combination with ruxolitinib in MF.2 These data build on AbbVie's history of transforming standards of care in blood cancers, including recent presentations of investigational navitoclax data from the REFINE study earlier this year at the American Association for Cancer Research (AACR) Annual Meeting and the European Hematology Association (EHA) Annual Congress. The findings presented at ASH were based on an exploratory analysis of 32 JAK inhibitor-naïve patients with MF from Cohort 3 of the Phase 2 REFINE study. The primary endpoint was spleen volume reduction of ≥35 percent (SVR35) from baseline at week 24.1 Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, MPL or Triple-negative), respectively.1 In this exploratory analysis, SVR35 at week 24 was observed in higher-risk groups, improving over time. The four poor prognosis subgroups were: Type (primary or secondary) of MF (primary MF, 59 percent [n = 10/17]; age (≥75 years, 50 percent [n = 4/8]); prognostic risk score, as measured by Dynamic International Prognostic Scoring System or DIPSS (intermediate-2, 63 percent [n = 12/19]; high, 33 percent [n = 1/3]); and presence of high molecular risk (HMR) mutations (47 percent [n = 9/19].1 In Cohort 3, BMF grade improvement was evaluable in 81 percent (26/32) of patients.1 Of these study participants, 35 percent (9/26) achieved ≥ 1 grade improvement at any time during treatment with a median time-to-improvement of 12.3 weeks.1 Complete resolution of BMF was observed in 22 percent (2/9) of patients.1 Reduction in driver gene mutation VAF > 20% from baseline at week 12 or 24 was observed in 50 percent (14/28) of patients, while 18 percent (5/28) of patients achieved > 50% VAF reduction from baseline. There were no differences in > 20% VAF reductions from baseline to week 12 or 24 between those with or without HMR mutations (47 percent [7/15] versus 54 percent [7/13], respectively). Preliminary safety analysis identified no new safety signals. Twenty-five (78 percent) patients reported one or more adverse events (AE). The most common grade ≥3 AEs were thrombocytopenia (47 percent), anemia (34 percent), and neutropenia (25 percent). 9.4 percent of patients discontinued therapy due to an AE.3 "These results are promising for patients who need a treatment option that goes beyond just symptom control," said Francesco Passamonti, full professor of hematology, University of Insubria and chief, hematology, Varese Hospital, Italy. "The suggestion of disease modification in this analysis from combination therapy with navitoclax is encouraging, particularly when combined with clinical efficacy in terms of SVR35 rates in the higher risk groups that improved over time." About Navitoclax Navitoclax is an investigational, oral BCL-XL/BCL-2 inhibitor. Navitoclax is not approved by any health authority worldwide at this time. Its safety and efficacy are under evaluation as part of ongoing Phase 2 and registrational Phase 3 studies. AbbVie has an extensive late-stage clinical trial program for investigational navitoclax that is currently enrolling. Please visit us here for more information about enrolling in a clinical trial. About the REFINE Study REFINE is a multi-cohort, Phase 2, randomized, open-label, multicenter study evaluating the tolerability and efficacy of navitoclax alone or when added to ruxolitinib in patients with myelofibrosis (MF).2 The primary outcome measure is the percentage of patients who achieve spleen volume reduction of greater than or equal to 35 percent (SVR35) from baseline to week 24.2 Secondary outcomes measures include percentage of participants achieving 50 percent reduction in total symptom score from baseline to week 24; anemia response every 12 weeks up to approximately 96 weeks, measured according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria; and change in grade of bone marrow fibrosis assessed according to the European Consensus Grading System.2 Data presented at ASH 2022 include safety and efficacy results from Cohort 3 of REFINE (n=32). Patients in Cohort 3 had primary or secondary MF with splenomegaly (DIPSS ≥ intermediate-1) and had not received JAK-2 therapy or bromodomain and extra terminal motif (BET) inhibitors prior to enrollment. The primary endpoint of SVR35 was assessed by MRI conducted by central review. Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF obtained from BM biopsies by local evaluation and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, or MPL), respectively. Studied HMR mutations included ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 p.Q157. Driver gene VAF and HMR mutations were determined in whole blood with a 50-gene focus myeloid next-generation sequencing panel. The findings presented at ASH 2022 are representative of data from Cohort 3 of the REFINE study as of February 7, 2022. More information about the REFINE study can be found at (NCT03222609). About Myelofibrosis Myelofibrosis (MF) is a rare, difficult-to-treat blood cancer that results in excessive scar tissue formation (fibrosis) in the bone marrow. Patients living with MF experience symptoms such as an enlarged spleen, fatigue, weakness, and severe anemia which are often debilitating and greatly impact quality of life. MF also carries a risk of transformation to more aggressive disease such as acute myeloid leukemia.4 About AbbVie in Oncology At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit and our Blood Cancer Press Kit page. About AbbVie AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at . Follow @abbvie on Twitter, Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statements Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, failure to realize the expected benefits from AbbVie's acquisition of Allergan plc ("Allergan"), failure to promptly and effectively integrate Allergan's businesses, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, changes to laws and regulations applicable to our industry and the impact of public health outbreaks, epidemics or pandemics, such as COVID-19. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2021 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law. References: Passamonti F, Foran J, Tandra A, et al. The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Mediates Responses Suggestive of Disease Modification. [Oral Presentation #237]. Presented at 2022 American Society of Hematology (ASH) Annual Meeting and Exhibition, December 10-13, 2022. ClinicalTrials.gov. A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis (REFINE). NCT03222609. Available at . Last accessed October 2022. Navitoclax plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: Preliminary safety and efficacy in a multicenter, open-label Phase 2 study. [Oral Presentation S197]. Presented at European Hematology Association 2022 Congress (EHA 2022), June 9-12, 2022. Tsujimoto Y. (1998). Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?. Genes to cells: devoted to molecular & cellular mechanisms, 3(11), 697–707. SOURCE AbbVie

Researchers have discovered a new underlying cause of Wiskott-Aldrich syndrome, a rare genetic disease that leads to bleeding and immune deficiencies in babies. Their findings revolve around how cells cut and paste strands of RNA in a process called RNA splicing. The genetic mutations associated with Wiskott-Aldrich syndrome, they found, disrupt this process which, in turn, prevents numerous immune and anti-inflammatory proteins from being made correctly. Researchers at the Salk Institute and King Abdullah University of Science and Technology (KAUST) in Saudi Arabia have discovered a new underlying cause of Wiskott-Aldrich syndrome, a rare genetic disease that leads to bleeding and immune deficiencies in babies. Their findings, published in the journal Nature Communications on June 25, 2022, revolve around how cells cut and paste strands of RNA in a process called RNA splicing. The genetic mutations associated with Wiskott-Aldrich syndrome, they found, disrupt this process which, in turn, prevents numerous immune and anti-inflammatory proteins from being made correctly. "This study not only suggests new targets for treating Wiskott-Aldrich syndrome with small molecule drugs, but also sheds new light on the basic biology of RNA splicing, an important and not fully understood process," says co-corresponding author Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and holder of the Roger Guillemin Chair. Babies with Wiskott-Aldrich syndrome begin to develop symptoms quickly after birth: itchy, scaly rashes, frequent bruises and nose bleeds are some of the first signs. Over time, they become prone to infections and are more likely than other children to develop autoimmune diseases and cancers. The only potential cure is a bone marrow transplant, which carries a host of complications and only works in some children. Scientists have long known that Wiskott-Aldrich syndrome is caused by mutations in a gene on the X chromosome; the gene and the protein it encodes were named WASP after the syndrome. The WASP protein is found throughout cells in the blood and immune system, and one of its functions is to maintain these cells' cytoskeletons, the microscopic networks of proteins that give cells their shape and organization. But changes to the cytoskeleton couldn't explain all the symptoms. Former Salk Postdoctoral Fellow Mo Li, now the head of KAUST's Laboratory of Stem Cell and Regeneration, and Izpisua Belmonte wondered if WASP plays other roles -- particularly in the nuclei of blood and immune cells, where genetic material is stored and processed. To find out, they removed the WASP gene from stem cells and coaxed the cells to become macrophages or B cells, two types of immune cells impacted by the disease. They also collected cells from two patients with Wiskott-Aldrich syndrome and generated induced pluripotent stem cells (iPSCs) containing the disease-associated mutations in WASP. Then they compared the altered cells to normal macrophages and B cells. "These are powerful models that can help us understand how WASP functions and what the underlying cellular mechanisms of Wiskott-Aldrich syndrome are," says Li. Immune cells lacking WASP, or containing mutations in the WASPgene, appeared different right away; there were many more clusters -- known as nuclear speckles -- in the centers of diseased cells. For a protein to be produced by a cell, the DNA encoding it is first transcribed into a strand of RNA. Often, this initial strand contains more genetic material than is needed; this is where RNA splicing comes in. Proteins in nuclear speckles cut and paste bits of the initial RNA strand into its final instructions for a protein. "When we saw differences in the nuclear speckles of these cells, this is the first time we realized that WASP might be involved in RNA splicing," says Baolei Yuan, a KAUST graduate student and first author of the new paper. The researchers also showed that many proteins related to RNA splicing were present at higher levels in the cells lacking WASP or with mutations in WASP. WASPboth controlled the production of these RNA-splicing factors and directly played a role in RNA splicing itself. The team pinpointed thousands of other genes with altered RNA splicing -- many were related to inflammation, autoimmunity and cancer. Additional experiments revealed that repairing WASP mutations fixes these RNA splicing defects. What's more, lowering levels of an RNA-splicing factor, SRSF2, can prevent the problems. These results suggest that drugs targeting SRSF2 could treat Wiskott-Aldrich syndrome in humans, the researchers say. "These RNA splicing factors could both be a biomarker for monitoring Wiskott-Aldrich syndrome, and a potential target for treatment," says Izpisua Belmonte. More work is needed to understand exactly how WASP is splicing RNA, as well as which symptoms of Wiskott-Aldrich syndrome are associated with the abnormal RNA splicing seen in diseased cells. Izpisua Belmonte is currently Institute Director of Altos Labs Inc., in addition to being a professor at the Salk Institute. Other authors include Keiichiro Suzuki, Sarah Dunn, Reyna Hernandez-Benitez, Tomoaki Hishida, Na Young Kim, Manching Ku, Yuta Takahashi, Ling Huang, Christopher Benner, Emi Aizawa, Zhongwei Li, Fei Yi, Maxim Shokhirev and Concepcion Rodriguez Esteban of Salk; Xuan Zhou, Gerardo Ramos-Mandujano, Mengge Wang , Muhammad Tehseen , Lorena V. Cortés-Medina, Manal M. Andijani, Chongwei Bi, Jinna Xu, Yanal Ghosheh and Samir Hamdan of KAUST; James J. Moresco and John R. Yates of Scripps Research Institute; Jinsong Qiu, Changwei Shao and Xiang-Dong Fu of UC San Diego; Jing Qu and Guang-Hui Liu of the Chinese Academy of Sciences; Patrizia Comoli of Fondazione IRCCS Policlinico San Matteo; and Francesco Frassoni of Instituto G. Gaslini Children Hospital Scientific Institute. The work was supported in part by the KAUST Office of Sponsored Research (BAS/1/1080-01 and URF/1/4716-01), Waitt Advanced Biophotonics Core Facility of the Salk Institute with funding from NIH-NCI CCSG (P30 014195), NINDS Neuroscience Core Grant, Waitt Foundation, National Key Research and Development Program of China (2020YFA0804000), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010000), National Natural Science Foundation of China (81921006, 92149301, 92168201), Moxie Foundation, and G. Harold and Leila Y. Mathers Charitable Foundation.