On November 20, 2024 Remix Therapeutics (Remix), a clinical-stage biotechnology company developing small molecule therapies to modulate RNA processing and address the underlying drivers of disease, reported an upcoming oral presentation at the 66th ASH (Free ASH Whitepaper) Annual Meeting taking place from December 7-10, 2024, in San Diego, CA (Press release, Remix Therapeutics, NOV 20, 2024, View Source [SID1234648531]). Results demonstrate oral dosing of REM-422, a selective mRNA degrader of the MYB oncogene, leads to robust anti-leukemic activity observed both as a monotherapy and in combination across a genetically diverse set of preclinical models of acute myeloid leukemia (AML), including eradication of AML blasts in engrafted patient-derived xenograft (PDX) models of AML. The presentation also highlights the differentiated mechanism of action of REM-422 as it can be combined effectively with other agents used in the treatment of AML/MDS and retains activity in cell models engineered with mutations known to confer resistance to other targeted agents.
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"The preclinical data for REM-422 provide strong therapeutic rationale for our ongoing Phase I study in AML and High-Risk MDS," said Peter Smith, Ph.D., President and Chief Executive Officer of Remix Therapeutics. "REM-422 is the first compound from our REMaster platform to enter clinical development. Its unique mechanism of action, coupled with the robust anti-leukemic activity observed both as a monotherapy and in combination, positions REM-422 as a promising candidate to address the unmet needs in these patient populations."
The MYB oncogenic transcription factor plays a crucial role in hematopoietic cell differentiation and proliferation. Its dysregulation and aberrant activity have been identified in various cancers, including adenoid cystic carcinoma (ACC), AML, acute lymphoblastic leukemia (ALL), and lymphoma. In AML, functional genomics studies have demonstrated a lineage-wide dependency on MYB, consistent with its involvement in disease driven by multiple oncogenic abnormalities (e.g. MLLr, NPM1, FLT3, p53, etc.).
REM-422 is a first-in-class, potent, selective, oral small molecule degrader of MYB mRNA currently in clinical development for AML/HR-MDS (NCT06297941) and ACC (NCT06118086). It functions by inducing the inclusion of a normally unused ‘poison exon’ (PE) in the MYB pre-mRNA transcript, activating the nonsense-mediated decay pathway and preventing MYB protein expression.
Details for the oral presentation are as follows:
Title: REM-422, a Small Molecule MYB mRNA Degrader, Demonstrates Anti-Leukemic Activity As Monotherapy and in Combination with Standards of Care in Preclinical Models of AML
Speaker: Samantha Levin-Furtney, Scientist, Remix Therapeutics
Session: 604- Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: New Targets and Drugs
Date: Monday, December 9, 2024
Time: 3:30 PM (Session time: 2:45-4:15 PM)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom ABCD
About REM-422
REM-422 is a first-in-class, potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression. REM-422 functions by facilitating the incorporation of poison exons within the mRNA transcript, leading to nonsense-mediated decay (NMD) of the transcript. REM-422 addresses MYB dysregulation, a driver of oncogenesis, upstream of protein expression.
About AML/HR-MDS
Acute myeloid leukemia (AML), a rare cancer of the blood and bone marrow, is the most common type of acute leukemia in adults. AML is caused by genetic mutations within bone marrow cells, which in turn causes the production of leukemic white blood cells that crowd out healthy blood cells. This may cause problems with bleeding, infection, and anemia. Myelodysplastic Syndromes (MDS) are disorders of blood-forming units in the bone marrow. High-risk (HR)-MDS patients have a higher percentage of blast cells in the bone marrow and that, in many cases, progresses to AML. There are several approved agents to treat AML, however, many patients relapse after achieving a response, underscoring the need for new therapies.