RUNX3

Researchers used various sequencing technologies to explore the molecular characteristics of myeloid/natural killer cell precursor acute leukemia (MNKPL). They observed activation of the NOTCH1 and RUNX3 genes, with lower expression of the BCL11B gene. MNKPL cells were also highly sensitive to a drug called L-asparaginase. Collectively, these qualities make MNKPL distinct from other leukemia types. These insights will assist with more accurate clinical diagnoses and therapeutic development for MNKPL. Leukemia is a common term used to refer to a form of blood cancer. However, there are different types of leukemia depending on the cell type involved. One unique form is myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL). Because of its rarity, there is no consensus on the specific characteristics needed to clinically identify this disease. In a recent article published in Science Advances, a team led by researchers at Tokyo Medical and Dental University (TMDU) used various approaches to better assess the molecular pro drug sensitivity characteristics of MNKPL. MNKPL was only first proposed as a leukemia subtype in 1997. Extramedullary involvement is one of the hallmarks of MNKPL. It is prevalent in East Asian countries. Although the immunological phenotype of MNKPL was explored previously, a full genetic characterization of this cancer type had not been performed. These details would help support more accurate diagnoses for patients, which would lead to more appropriate therapeutic decisions. Therefore, the TMDU group aimed to investigate MNKPL on a single-cell level. "A single-cell exploration of MNKPL would not only help us better understand its clinical and genomic features, but also clarify the specific cellular origin of this disease," says Dr. Akira Nishimura, lead author of the study. The team first used what is known as a multiomics approach to investigate MNKPL patient samples. They used various sequencing technologies to determine if there were any relevant mutations in specific genes, look for expression differences in certain signaling pathways at the RNA level, and examine any unique DNA methylation patterns. "Our results demonstrate that MNKPL has molecular qualities that are distinct from other similar cancers, such as acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia," explains Dr. Masatoshi Takagi, senior author. "Specific hallmarks of MNKPL include activation of the NOTCH1 and RUNX3, as well as lower expression of the BCL11B." Further work at the single-cell level in MNKPL cells showed that NK cells and myeloid cells come from a common progenitor cell type. The researchers also conducted in vitro drug sensitivity assays where they measured MNKPL cell responses to 79 individual anti-cancer drugs. "We observed that MNKPL cells were highly sensitive to a drug called L-asparaginase, which has already shown clinical effectiveness for this disease," says Dr. Nishimura. "Mechanistically, we found that this was from low expression of asparagine synthetase, a quality that was distinct from other similar types of leukemia." Overall, the robust and comprehensive analysis performed in this study provides crucial molecular details for characterizing MNKPL. This work will undoubtedly help clinicians more effectively diagnose MNKPL and choice of therapeutic option. Additionally, this work provides data that will assist with novel therapeutic target identification and drug development in this leukemia.

SOUTH SAN FRANCISCO, Calif. and WATERTOWN, Mass., Aug. 2, 2022 /PRNewswire/ -- Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) and Forma Therapeutics, Inc. (Nasdaq: FMTX) today announced that they have entered into an exclusive, worldwide license agreement to develop, manufacture and commercialize olutasidenib, an oral, small molecule inhibitor of mIDH1 being investigated for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML) and other malignancies. In a Phase 2 registrational study of olutasidenib in patients with mIDH1 R/R AML, olutasidenib demonstrated a robust composite complete remission rate and duration of response and was well-tolerated. The U.S. Food and Drug Administration (FDA) has accepted Forma's New Drug Application (NDA) for olutasidenib. The Prescription Drug User Fee Act (PDUFA) target action date is February 15, 2023. "Olutasidenib is a potential market-leading treatment that we believe, based on the registrational Phase 2 data, can improve outcomes in patients with mIDH1+ relapsed or refractory acute myeloid leukemia, and is a strategic fit for our business," said Raul Rodriguez, Rigel's president and CEO. "This transaction expands our hematology-oncology portfolio and enables us to leverage our strong commercial capabilities to provide a potential new therapy for these patients who remain underserved despite currently available therapies." "The compelling efficacy and safety data generated to date highlight the potential for olutasidenib to transform the treatment of mIDH1+ R/R AML. The development and approval of olutasidenib, pending a favorable FDA decision, would represent an important milestone for Forma that highlights our R&D capabilities," said Frank Lee, Forma's president and CEO. "Given Rigel's focus on hematologic diseases and cancers and the strength of their commercial infrastructure, we believe they are well-positioned to execute on our shared objective of delivering olutasidenib to patients in need." The registrational cohort of the open-label Phase 2 study evaluated olutasidenib as monotherapy in 153 mIDH1+ R/R AML patients. The primary efficacy-evaluable population of the cohort was comprised of 123 R/R AML patients, who received olutasidenib 150 mg twice daily at least six months prior to the interim analysis cutoff date of June 18, 2020 and had a centrally confirmed IDH1 mutation. The primary endpoint was a composite of a complete remission (CR) plus a complete remission with partial hematological recovery (CRh), defined as less than 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter). Results from the interim analysis of the trial1 demonstrated a 33% CR+CRh in mIDH1+ R/R AML patients. Among those with CR+CRh, the estimated 18-month survival was 87% and the median duration of CR+CRh was not yet reached, with a more conservative sensitivity analysis indicating a median duration of 13.8 months. Importantly, these data provide compelling evidence of clinical efficacy with a durable response and a favorable tolerability profile, both of which we believe differentiates olutasidenib from other currently available treatment options for mIDH1+ R/R AML patients. Olutasidenib was well-tolerated, with adverse events (AEs) being consistent with the late stage of disease and the heavily pre-treated population. A safety analysis for all 153 patients enrolled in the registrational Phase 2 study found the most common grade 3/4 (≥ 10%) treatment-emergent adverse events (TEAEs) were febrile neutropenia (20%), anemia (19%), thrombocytopenia (16%), and neutropenia (13%). Updated data from the registrational study will be presented at an upcoming medical congress. "The data from the Phase 2 registrational trial of olutasidenib demonstrated encouraging results, particularly on durability and survival, with median duration of response that appears to be longer than currently available treatment options and an 18-month survival rate among those with CR+CRh of 87%," said Jorge E. Cortes, M.D., Director, Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, and Phase 2 trial investigator. "Given the trial's compelling efficacy data in duration of response, the favorable tolerability profile, and the still limited treatment options of patients with mIDH1+ R/R AML, olutasidenib has the potential to be an important new treatment option for patients." Under the terms of the agreement, Forma will receive an upfront payment of $2.0 million, and is eligible to receive an additional $17.5 million upon the achievement of certain near-term regulatory, approval, and first commercial sale milestones. In addition, Forma is eligible to receive a total of up to an additional $215.5 million in connection with the achievement of certain development and commercial milestones. Forma is also eligible to receive tiered royalties in the low-teens to mid-thirties. Moving forward, Rigel will be responsible for the potential launch and commercialization of olutasidenib in the U.S., and intends to work with potential partners to further develop and commercialize olutasidenib outside the U.S. Conference Call and Webcast Today at 4:30 p.m. Eastern Time, with KOL and Olutasidenib Phase 2 trial investigator, Jorge E. Cortes, M.D. Rigel will host a live conference call and webcast today at 4:30 p.m. Eastern Time (1:30 p.m. Pacific Time) to discuss financial results, provide an update on the business, including the licensing agreement for olutasidenib. The conference call will also feature a presentation of the olutasidenib Phase 2 interim results by Jorge E. Cortes, M.D., Director, Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, and Phase 2 trial investigator. Participants can access the live conference call by dialing (877) 407-3088 (domestic) or (201) 389-0927 (international). The conference call will also be webcast live and can be accessed from the Investor Relations section of the company's website at www.rigel.com. The webcast will be archived and available for replay after the call via the Rigel website. About Olutasidenib and AML Olutasidenib is an oral, small molecule investigational agent designed to selectively bind to and inhibit mutated IDH1 enzymes. This targeted treatment has the potential to provide therapeutic benefit by reducing 2-HG levels and restoring normal cellular differentiation. IDH1 is a natural enzyme that is part of the normal metabolism of all cells. When mutated, IDH1 activity can promote blood malignancies and solid tumors. IDH1 mutations are present in 6 to 9 percent of patients with AML2. AML is a rapidly progressing cancer of the bone marrow and blood3. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that about 20,940 new cases, most in adults, arose in 2021 in the United States alone.4 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need. About Rigel Rigel Pharmaceuticals, Inc., is a biotechnology company dedicated to discovering, developing, and providing novel small molecule drugs that significantly improve the lives of patients with hematologic disorders, cancer, and rare immune diseases. Rigel's pioneering research focuses on signaling pathways that are critical to disease mechanisms. The company's first FDA-approved product is TAVALISSE® (fostamatinib disodium hexahydrate) tablets, the only oral spleen tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. The product is also commercially available in Europe (TAVLESSE), the United Kingdom (TAVLESSE) and Canada (TAVALISSE) for the treatment of chronic immune thrombocytopenia in adult patients. Fostamatinib is currently being studied in a Phase 3 clinical trial (NCT03764618) for the treatment of warm autoimmune hemolytic anemia (wAIHA)5; a Phase 3 clinical trial (NCT04629703) for the treatment of hospitalized high-risk patients with COVID-195 and an NIH/NHLBI-sponsored Phase 3 clinical trial (ACTIV-4 Host Tissue Trial, NCT04924660) for the treatment of COVID-19 in hospitalized patients. Rigel's other clinical programs include its interleukin receptor-associated kinase (IRAK) inhibitor program, and a receptor-interacting serine/threonine-protein kinase (RIPK) inhibitor program in clinical development with partner Eli Lilly and Company. In addition, Rigel has product candidates in development with partners BerGenBio ASA and Daiichi Sankyo. For further information, visit www.rigel.com or follow us on Twitter or LinkedIn. Please see www.TAVALISSE.com for full Prescribing Information. About Forma Therapeutics Forma Therapeutics is a clinical-stage biopharmaceutical company focused on the research, development, and commercialization of novel therapeutics to transform the lives of patients with rare hematologic diseases and cancers. Our pipeline is led by etavopivat, an investigational, once-daily, selective pyruvate kinase-R (PKR) activator designed to be a disease-modifying therapy with the potential to improve red blood cell (RBC) health and transform the lives of people living with sickle cell disease, thalassemia, and lower risk MDS. Our R&D engine combines deep biology insight, chemistry expertise and clinical development capabilities to create drug candidates with differentiated mechanisms of action focused on indications with high unmet need. Our work has generated a broad proprietary portfolio of programs with the potential to provide profound patient benefit. For more information, please visit www.FormaTherapeutics.com or follow us on Twitter @FORMAInc and LinkedIn. De Botton, S., et al. Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 7006-7006. NCCN Clinical Practice Guidelines in Oncology, Acute Myeloid Leukemia. Version 2.2022 – June 14, 2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411 Leukemia & Lymphoma Society. Accessed July 25, 2022. https://www.lls.org/leukemia/acute-myeloid-leukemia The American Cancer Society. Key statistics for acute myeloid leukemia (AML). Revised January 12, 2021. Accessed Dec. 2, 2021 at https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. The product for this use or indication is investigational and has not been proven safe or effective by any regulatory authority.