Abstract 450: Preclinical development of FTX-001: first in class inhibitor of the long non-coding RNA MALAT1

Abstract Long non-coding RNAs (lncRNAs) have emerging roles in many aspects of biology. In the context of cancer, it has been reported that lncRNAs can act as cancer oncogenes and are altered in various cancer types. Among them, MALAT1 is a lncRNA highly expressed in multiple cancer types and associated with disease progression in patients. MALAT1 is highly upregulated in metastatic lesions of breast cancer patients. Both genetic and pharmacologic inhibition of MALAT1 suppressed tumor epithelial to mesenchymal transition, resulted in the differentiation of breast cancers and had a dramatic impact on tumor metastasis. MALAT1 is a nuclear retained lncRNA, and as such MALAT1 is highly sensitive to RNaseH1-dependant Antisense Oligonucleotide (ASO) degradation, because RNaseH1 is also predominantly localized to the nucleus. Thus, MALAT1 represents an attractive novel therapeutic target uniquely tractable to ASOs with the potential to impact metastatic cancer progression. Here, we describe the identification and characterization of FTX-001 leading to its selection as a clinical drug candidate for the treatment of human cancers. Preclinical pharmacology, tolerability, and toxicity studies conducted in rodents and non-human primates demonstrated the safety and potency of FTX-001. FTX-001 ASO contains constrained ethyl (cEt) chemistry Gen 2.5 and was identified by screening over 2700 ASOs against MALAT1. FTX-001 showed a consistent potent inhibition of MALAT1 RNA expression in human cancer cell lines in vitro as well as in human xenograft tumor models in vivo upon systemic delivery. Good exposure, tissue distribution and tolerability profile were observed in mice, rats and non-human primates (NHP) after repeated subcutaneous (sc) administrations. Genotoxicity studies including the bacterial reverse mutation assay and in vivo micronucleus assays demonstrated that FTX-001 did not cause mutagenic or chromosome alterations at doses up to 2000 mg/kg in mice. Preliminary results from 6-weeks nonclinical toxicity testing in mice (sc administration up to 45mg/kg) and NHP (intravenous administration up to 24mg/kg) revealed no significant adverse events observed during dosing and recovery phases. No major variation of blood markers or blood count were observed. Ongoing histopathological evaluation will complete the health hazard evaluation of FTX-001. Taken together, these results demonstrate the high potency and good preclinical safety profile of FTX-001 which supports the potential to achieve good target engagement (MALAT1 RNA knock down in human tumors) at well tolerated clinical doses in cancer patients. Citation Format: Marie-Aline C. Neveu, Alexey Ravenko, Tae-Won Kim, Xiaolin Luo, Youngsoo Kim, Joanna Schmidt, Robert A. MacLeod. Preclinical development of FTX-001: first in class inhibitor of the long non-coding RNA MALAT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 450.