MTL-CEBPA

AW1-51 (also referred to as CEBPA-51), the first small activating RNA therapeutic to enter clinical evaluation, has demonstrated biological activity and safety in Phase II trials for hepatocellular carcinoma, both as monotherapy and in combination with sorafenib, and in Phase 1a/1b in combination with pembrolizumab for patients with advanced solid tumors. In this study, we uncovered the molecular basis for AW1-51-induced transcriptional reactivation of CCAAT enhancer-binding protein alpha demonstrating that by directly promoting DNA demethylation of its promoter restores its expression, protein synthesis, and consequently cell differentiation. These findings unveil AW1-51 as a prototype for RNA-based precision medicine enabling conditional expression of CCAAT enhancer-binding protein alpha in diseases characterized by aberrant gene silencing and extending its potential therapeutic impact beyond cancer.

P1, N=33, Active, not recruiting, National University Hospital, Singapore | Recruiting --> Active, not recruiting

Importantly, MTL-CEBPA enhances the efficacy of commonly prescribed FLT3 inhibitor, gilteritinib, both in vitro and in vivo. All together, these findings support RNAa of CEBPA as a potential adjuvant therapy for FLT3-mutated AML.

Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335).

Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs.

P1, N=75, Active, not recruiting, Mina Alpha Limited | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Jan 2024 --> Jul 2025

P2, N=8, Completed, Mina Alpha Limited | Active, not recruiting --> Completed | N=150 --> 8 | Trial completion date: May 2025 --> Jan 2025

P1, N=50, Completed, Mina Alpha Limited | Active, not recruiting --> Completed | N=108 --> 50 | Trial completion date: Jun 2024 --> Jan 2025 | Trial primary completion date: Dec 2023 --> Jan 2025

P2, N=150, Active, not recruiting, Mina Alpha Limited | Recruiting --> Active, not recruiting

P1, N=75, Active, not recruiting, Mina Alpha Limited | N=51 --> 75 | Trial completion date: Jan 2023 --> Dec 2024 | Trial primary completion date: Nov 2022 --> Jan 2024

In the current study, it was hypothesized that following bone marrow transplant, MPS I mice treated with an saRNA targeting CEBPA (MTL-CEBPA) would increase Idua expression, and thus enzymatic activity...These results demonstrate the power and flexibility that saRNA-based therapies can provide for patients who have previously received HSCT by transiently over-expressing the therapeutic gene in the engrafted and derived cells. This targeted approach by saRNA opens a new avenue of therapeutic development for not only lysosomal disorders such as MPS I, but all disorders where transcriptional activation or enhancement of a gene could provide therapeutic benefits.

MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors.