MRX2843

P1, N=50, Recruiting, Meryx, Inc. | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Jul 2024 --> Dec 2025

P1, N=42, Active, not recruiting, Meryx, Inc. | Trial completion date: Jul 2024 --> Apr 2025 | Trial primary completion date: Dec 2023 --> Feb 2025

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.

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.

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.

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.

P1, N=69, Recruiting, Emory University | Phase classification: P1b --> P1 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=42, Active, not recruiting, Meryx, Inc. | Recruiting --> Active, not recruiting

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.

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.

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.

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.

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.

P1b, N=69, Recruiting, Emory University | Trial completion date: Dec 2024 --> Dec 2025

Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.

Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naïve and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

No abstract available

These data validate MERTK as a promising therapeutic target in EWS and support development of MRX-2843 for treatment of EWS and OS, with potential to directly inform and enable a clinical trial in pediatric patients and, ultimately, to improve both outcomes and quality of life for patients with these diseases.

Enhanced therapeutic efficacy and synergistic interactions were also observed in AML cell cultures treated with MRX-2843 and navitoclax, a BCL-2 and BCL-XL inhibitor, implicating BCL-2 inhibition as a mechanism of synergy. Synergy was optimal when MRX-2843 and venetoclax were administered in a 1:20 ratio. Our data (i) implicate combined treatment with MRX-2843 and a BCL-2 inhibitor, such as venetoclax, as a promising new strategy for treatment of both AML and ETP-ALL, (ii) define optimized dosing strategies for MRX-2843 and venetoclax combination therapy, and (iii) support further evaluation of MRX-2843 in combination with venetoclax in murine models and potentially in upcoming clinical trials.

To evaluate a potential mechanism of PD-L1/PD-L2 downregulation when efferocytosis is inhibited, we evaluated for IL-4, IL-10 and IL-6 – all previously associated with checkpoint ligand expression – in serum samples of C57Bl/6 mice inoculated with a syngeneic MLL-ENL AML, and treated with a MerTK efferocytosis inhibitor (MRX-2843, n=15) or vehicle (PBS, n=14)...Taken together, these data demonstrate a mechanism by which MerTK inhibition alters antigen presentation through decreased co-inhibition and augmented activating cytokine production. Given that MerTK inhibitors are currently in clinical trials for relapsed/refractory malignancies, these data are relevant, timely, and could provide additional justification for their use in acute leukemias.

P1/2, N=104, Not yet recruiting, Betta Pharmaceuticals Co., Ltd.

Furthermore, treatment with PIM447, a structurally distinct PIM kinase inhibitor, and MRX-2843 decreased cell expansion more effectively than either agent alone. Additionally, combined treatment with MRX-2843 and SGI-1776 prevented colony formation, while single agents had limited effect. In all, these data indicate that combining MRX-2843 and a PIM TKI may control osimertinib resistant tumor growth, providing a potential treatment strategy for osimertinib resistant EGFR-mutated NSCLC patients for whom the choices are still limited.

P1b, N=69, Not yet recruiting, Emory University