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
Authors: Levin-Furtney Samantha , Thomas Michael , Harney Alycen M. , Shan Mengge , Ivliev Alexander , Stefek Adam , Cameron Michael , Prajapati Sudeep , Seiler Michael , Reynolds Dominic , Buonamici Silvia , Kung Charles 
Published: December 2024

The c-MYB (MYB) oncogenic transcription factor is a key regulator of hematopoietic cell differentiation and proliferation. Recurrent genetic lesions or dysregulation of MYB have been identified in a variety of cancers, including adenoid cystic carcinoma (ACC), acute myeloid leukemia (AML), and other hematological malignancies including acute lymphoblastic leukemia (ALL) and lymphoma. AML is characterized by multiple oncogenic abnormalities and high MYB mRNA expression. Evidence from in vitro and in vivo animal studies suggests that MYB may be a key effector of oncogenic abnormalities through the direct regulation of genes such as BCL2, MYC and FLT3. Functional genomics studies reveal MYB dependencies in human leukemia cell lines and mouse models of leukemia. Together, these data suggest that MYB is a master regulator of leukemogenesis and an attractive therapeutic target for AML and other hematological malignancies.

REM-422 is a first-in-class, potent, selective, oral small molecule degrader of MYB messenger RNA (mRNA) being developed for the treatment of AML/HR-MDS (NCT06297941) and ACC (NCT06118086). REM-422 induces the inclusion of a normally unused ‘poison exon’ (PE), which contains a premature termination codon, into the MYB pre-mRNA transcript. Poison exon inclusion activates the nonsense-mediated decay pathway and promotes the degradation of MYB mRNA thereby preventing MYB protein expression. Here we demonstrate that REM-422 has potent activity in AML in vivo models as a monotherapy and in combination with gilteritinib and revumenib.

REM-422 treatment of human leukemia cell lines promoted PE inclusion, leading to degradation of MYB mRNA, a concomitant reduction in MYB protein levels, and decreased expression of MYB regulated genes. In a panel of AML cell lines, REM-422 demonstrated preferential anti-proliferative activity in cell lines with high MYB expression, and in those shown to be MYB-dependent through functional genomics studies.

To demonstrate activity of REM-422 in vivo, AML patient cells were injected into immunocompromised mice. After successful engraftment, mice were dosed orally once daily with 10 mg/kg REM-422. Flow cytometry analysis of bone marrow and whole blood collected after 3 days of dosing demonstrated that REM-422 treatment led to an increase in blasts expressing CD14 and CD11b, known myeloid differentiation markers, as well as an increased frequency of Annexin V+ blasts, a marker of early apoptosis. After 24 days of dosing, REM-422 led to the eradication of human leukemia cells from both compartments and prevented AML cell engraftment-induced body weight loss.

Resistance to targeted therapies in AML can emerge through a number of mechanisms.To assess whether REM-422 can overcome resistance to standards of care, MV411 cells were genetically engineered to be resistant to venetoclax, revumenib, or gilteritinib. REM-422's anti-proliferative activity was unchanged in the resistant models, which is consistent with the differentiated mechanism of action of REM-422 compared to these standards of care.

The activity of REM-422 was assessed in vitro in combination with AML standards of care by co-treating leukemia cell lines with REM-422 and other agents including venetoclax, gilteritinib, revumenib, and azacitidine. REM-422 demonstrated additive and/or synergistic anti-proliferative effects across a panel of AML cell lines.

To evaluate REM-422's combination activity in vivo, MONO-MAC-6 cells, which are FLT3 mutant, were subcutaneously implanted in BALB/c nude mice and REM-422, gilteritinib, or REM-422 in combination with gilteritinib were dosed orally once daily for 21 days. The REM-422 and gilteritinib combination led to improved tumor growth inhibition when compared to either monotherapy. THP-1 cells, which are KMT2A-rearranged, were subcutaneously implanted in NOD/SCID mice and REM-422, revumenib, or REM-422 in combination with revumenib were dosed orally for 21 days. The REM-422 and revumenib combination arm demonstrated more durable activity with delayed tumor regrowth kinetics after cessation of dosing compared to the monotherapy arms.

Altogether, these data support the therapeutic potential for REM-422 in AML patients both as monotherapy and in combination therapy.