MRX2843 / Meryx, Betta Pharma - LARVOL DELTA

MERTK inhibition regulates tumor-associated myeloid cell phenotypes and potentiates host-versus-lung cancer immunity (AACR 2025) - "MRX-2843 is a novel first-in-class MERTK-selective inhibitor that is currently being tested in phase 1/1b clinical trials...Furthermore, tumors from Mertk KO mice had evidence of increased antigen-presenting capacity with significantly increased numbers of tumor-associated macrophages expressing high levels of MHC-II and increased incidence of dendritic cells. Together these findings suggest that MERTK inhibits anti-tumor immunity by regulating myeloid cell functions and implicate MERTK as an immunotherapeutic target in Kras-mutant non-small cell lung cancer."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • KRAS • MERTK

Pharmacokinetic and Safety Study of MRX-2843 in Adults with Relapsed/Refractory Advanced And/or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: Meryx, Inc. | Trial completion date: Jul 2024 ➔ Apr 2025 | Trial primary completion date: Dec 2023 ➔ Feb 2025

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Pharmacokinetic and Safety Study of MRX-2843 in Adolescents and Adults with Relapsed/Refractory AML, ALL, or MPAL (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Meryx, Inc. | Trial completion date: Dec 2024 ➔ Mar 2026 | Trial primary completion date: Jul 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

MERTK inhibition selectively activates a DC - T-cell axis to provide anti-leukemia immunity. (PubMed, Leukemia) - "Host Mertk knock-out or MERTK inhibitor MRX-2843 increased CD8α+ dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis...Axl-/- did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies."

IO biomarker • Journal • Hematological Malignancies • Leukemia • Oncology • Pediatrics • AXL • CD8 • MERTK

A Phase 1b Study of the MER Tyrosine Kinase Inhibitor, MRX-2843, in Combination with Osimertinib in Advanced EGFR Mutant Non-Small Cell Lung Cancer (IASLC-WCLC 2024) - "Based on suggestion of preliminary evidence of efficacy, expansion cohorts to include both treatment-naïve and osimertinib-resistant patients is currently underway. (NCT # 04762199)"

Combination therapy • Metastases • P1 data • Cardiovascular • Heart Failure • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • AXL • EGFR • MERTK

MERTK Is a Potential Therapeutic Target in Ewing Sarcoma. (PubMed, Cancers (Basel)) - "Combined treatment with MRX-2843 and BCL-2 inhibitors venetoclax or navitoclax provided enhanced therapeutic activity compared to single agents. These data highlight MERTK as a promising therapeutic target in EWS and provide rationale for the development of MRX-2843 for the treatment of EWS, especially in combination with BCL-2 inhibitors."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • MERTK

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML. (PubMed, Leuk Res) - "Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation...Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC...Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • MCL1 • MERTK • MYC

Combining the Novel FLT3 and MERTK Dual Inhibitor MRX-2843 with Venetoclax Results in Promising Antileukemic Activity Against FLT3-ITD AML (Leuk Res, ScienceDirect) - "We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells."

Preclinical • Acute Myelogenous Leukemia

Combining the Novel FLT3 and MERTK Dual Inhibitor MRX-2843 with Venetoclax Results in Promising Antileukemic Activity Against FLT3-ITD AML (Leuk Res, ScienceDirect) - "We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells."

Preclinical • Acute Myelogenous Leukemia

Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma. (PubMed, Nat Commun) - "Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value."

Journal • Acute Myelogenous Leukemia • Ewing Sarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • AXL • GAS6 • JAK1 • MERTK • STAT6

MRX-2843 and Osimertinib for the Treatment of Advanced EGFR Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=69 | Recruiting | Sponsor: Emory University | Phase classification: P1b ➔ P1 | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Combination therapy • Metastases • Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

PIM kinase inhibition synergizes with a MERTK inhibitor to treat osimertinib resistant EGFR-mutant non-small cell lung cancer (AACR 2024) - "Further, two structurally distinct PIM kinase inhibitors, SGI-1776 and PIM447, provided synergistic inhibition of cell expansion and colony formation in osimertinib-resistant cell line cultures when combined with MRX-2843 treatment. Furthermore, knockdown of PIM kinases (PIM1, 2, 3) using nine sets of siRNAs led to various changes in expression of TAM receptor family members (TYRO3, AXL, MERTK), indicating a role for PIM kinases in regulation of TAM kinase expression. These studies suggest a novel treatment strategy for osimertinib-resistant EGFR-mutant NSCLC using a first-in-class MERTK kinase inhibitor that is currently under evaluation in multiple Phase I clinical trials."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • EGFR • MERTK • PIM1

Pharmacokinetic and Safety Study of MRX-2843 in Adults With Relapsed/Refractory Advanced and/or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: Meryx, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Oncology • Solid Tumor

Constitutively Synergistic Multiagent Drug Formulations Targeting MERTK, FLT3, and BCL-2 for Treatment of AML. (PubMed, Pharm Res) - "We developed a nanoscale combination drug formulation that exploits ectopic expression of MERTK tyrosine kinase and dependency on BCL-2 family proteins for leukemia cell survival in pediatric AML and infant ALL cells. We demonstrate ratiometric drug delivery and synergistic cell killing in AML, a result achieved by a systematic, generalizable approach of combination drug screening and nanoscale formulation that may be extended to other drug pairs or diseases in the future."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • BCL2 • FLT3 • MERTK

Pharmacokinetic and Safety Study of MRX-2843 in Adults With Relapsed/Refractory Advanced and/or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: Meryx, Inc. | Trial completion date: Dec 2023 ➔ Jul 2024 | Trial primary completion date: Mar 2023 ➔ Dec 2023

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Pharmacokinetic and Safety Study of MRX-2843 in Adolescents and Adults With Relapsed/Refractory AML, ALL, or MPAL (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Meryx, Inc. | Trial completion date: Jan 2024 ➔ Dec 2024 | Trial primary completion date: Jan 2024 ➔ Jul 2024

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. (PubMed, J Control Release) - "Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL and describe a novel translational agent that could be used to enhance therapeutic responses to vincristine in patients with T-ALL. This broadly generalizable approach could also be applied to develop other constitutively synergistic combination products for the treatment of cancer and other diseases."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • MERTK

Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction. (PubMed, J Dent Res) - "Differentiation of human alveolar bone mesenchymal stem cells with osteogenic media and TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization with pan-TAM or Mertk-specific inhibitors and no change with Axl-specific inhibitor. RNAseq of day 7 extraction sockets showed increased innate immune-related pathways and genes associated with bone differentiation in Mertk mice. Together, these results indicate that TAM receptor signaling, specifically through Mertk, can be targeted to enhance bone regeneration after injury."

Journal • Inflammation • AXL • MERTK

Genetically Engineered Artificial Exosome-Constructed Hydrogel for Ovarian Cancer Therapy. (PubMed, ACS Nano) - "Upon triggering immunogenicity with X-ray radiation, our hydrogel encapsulating efferocytosis inhibitor MRX-2843 enabled a cascade regulation to orchestrate polarization, efferocytosis, and phagocytosis of peritoneal macrophages for realizing robust phagocytosis of tumor cells and powerful antigen presentation, offering a potent approach for ovarian cancer therapy via bridging the innate effector function of macrophages with their adaptive immune response. Moreover, our hydrogel is also applicable for potent treatment of inherent CD24-overexpressed triple-negative breast cancer, providing an emerging therapeutic regimen for the most lethal malignancies in women."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CD24 • SIGLEC10

TAM receptor tyrosine kinase MERTK as a therapeutic target in the tumor immune microenvironment in a murine Kras mutant lung cancer model (P943) (IMMUNOLOGY 2023) - "Treatment with MRX-2843, a MERTK-selective inhibitor currently in Phase 1 clinical trials, also reduced tumor growth in mice. Together, these data demonstrate a critical role for MERTK as a mediator of tumor progression in the tumor immune microenvironment and implicate MRX-2843 as an effective strategy to exploit this finding in the clinic."

Preclinical • Lung Cancer • Oncology • Solid Tumor • ITGAM • KRAS • MERTK

Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC) (AACR 2023) - "MERTK kinase inhibitor MRX-2843 modulates its nuclear translocation...Our analysis of proteins that may interact with MERTK to regulate nuclear localization and function demonstrated co-immunoprecipitation of nuclear MERTK and STAT1. Current studies are underway to further explore nuclear MERTK functions and how these roles may be modulated upon interaction with STAT1."

Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • MERTK • STAT1

Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment. (PubMed, Front Immunol) - "Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1Tim-3 and LAG3 checkpoint expression, and increased CD69CD107a expression. These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD163 • CD86 • HAVCR2 • IFNB1 • IL18 • IL1B • LAG3 • LAMP1 • MERTK • NF-κβ • PD-L1 • PD-L2

Therapeutic Targeting of Mertk and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia (ASH 2021) - P1 | "T-ALL patient samples were cultured with UNC2025, a close analogue of MRX-2843, and relative cell numbers were assessed using MTS reagent. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL, suggest that MRX-2843 may be particularly active alone and in combination with venetoclax in the ETP-ALL subset, and provide rationale for clinical testing of MRX-2843, with the ultimate goal to progress to trials evaluating MRX-2843 in combination with other agents. Toward this end, MRX-2843 monotherapy will be tested in patients with relapsed leukemia in an upcoming clinical trial (NCT04872478)."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • BCL2 • FLT3 • MERTK

MRX-2843 and Osimertinib for the Treatment of Advanced EGFR Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P1b | N=69 | Recruiting | Sponsor: Emory University | Trial completion date: Dec 2024 ➔ Dec 2025

Combination therapy • Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Combining induced neural stem cell therapy and immunomodulation in glioblastoma (SNO 2022) - "Inhibiting MerTK activation via a small molecule drug, MRX-2843 and combining with hiNeuroS-TRAIL demonstrated robust synergistic tumor killing effects in vitro (CDI=0.22) and ex vivo (CDI=0.18)...We think that combining these two therapies could significantly extend the survival in our murine model of GBM. Therefore, we will be optimizing dose concentration and cell counts for single agent therapies, and we will then repeat in vivo y synergy study with optimized therapies and a larger sample size to fully uncover the potential of this combination therapy."

Brain Cancer • Glioblastoma • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor • MERTK