Initial clinical experience with the first-in-class anti-metastasis therapeutic TTX-MC138.

e15072 Background: TransCode is focused on developing nucleic acid-based cancer therapies. Through scientific discovery efforts, miRNA-10b was identified as a master regulator of the viability of metastatic tumor cells. This knowledge allowed development of a therapeutic strategy based on miR-10b inhibition. miR-10b was targeted using antagomirs delivered to metastatic sites by an iron oxide nanocarrier, termed TTX-MC138. Results demonstrated that TTX-MC138 could cause complete and persistent regressions of metastases in cancer models. Methods: TransCode has an active eIND and is conducting a Phase 0 clinical study with radiolabeled TTX-MC138 in patients with advanced metastatic cancer of multiple tissue origins. TTX-MC138 was radiolabeled with Cu64 through a NODAGA chelator. IND enabling studies were conducted in rats and non-human primates to support FDA activation (eIND163800) for the Phase 0 clinical study. In the trial, a single intravenous microdose of Cu-64 labeled TTX-MC138 is administered, which allows for direct visualization of drug tissue distribution in cancer patients via PET-MR imaging. Results: Non-clinical studies were conducted to support the TTX-MC138 clinical development program. In rats, when TTX-MC138 was infused intravenously at a dose of 27 mg/kg, results displayed a blood half-life of 16.7±9.35 hrs. At 24-h, concentrations were highest in the liver and spleen. In non-human primates injected with Cu64-labeled TTX-MC138 at a dose of 100 microg, the organs with the highest uptake were the liver, heart, lung and spleen. The mean whole blood half-life was 12.2 ± 2.3 h (mean ± standard deviation). RadioHPLC analysis of plasma samples showed that the drug is very stable with respect to metabolism. A study in rats involved a single injection with 0, 0.5 or 1 mg/kg followed by a 2-day or 14-day observational period. The drug was well-tolerated at levels up to 1 mg/kg, which was considered to be the no-observed-adverse-effect-level (NOAEL). Preliminary results from the Phase 0 clinical study showed that the first patient tolerated the dosing with no reported adverse reactions, the drug remained stable in circulation, and circulated with a long half-life of 20 hours. Lesion to blood ratios of radioactivity in the region of the metastatic lesions was consistent with accumulation of TTX-MC138. Enrollment, data monitoring, and analysis is ongoing. Conclusions: The results of the non-clinical studies and Phase 0 clinical study have the potential to address the question of delivery to the target tissue. The process leading to the implementation of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX delivery platform to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Clinical trial information: NCT05908773 .