Abstract PS1-09-17: Phase 1 Clinical Testing of a First-in-Class Antisense Oligonucleotide Therapeutic against Advanced Solid Tumors of Multiple Tissue Origins

Abstract Background: TransCode Therapeutics, Inc. is developing TTX-MC138, an antisense oligonucleotide (ASO) therapeutic targeting miR-10b, a critical driver of metastatic disease progression. Several in vivo preclinical studies with TTX-MC138 have successfully demonstrated its delivery to metastatic lesions, its ability to eliminate metastasis, and its capacity to elicit complete regression without recurrence. Thus, TTX-MC138 holds the potential to improve patient outcomes over currently approved and available treatment options. Methods: The first clinical study with TTX-MC138 was a first-in-human single-center, Phase 0, microdose study to demonstrate delivery of TTX-MC138-NODAGA-Cu64 to radiographically confirmed metastases in patients with advanced solid tumors. Preliminary analysis indicated accumulation of TTX-MC138 in metastatic lesions in a patient with metastatic breast cancer. Metabolite analysis demonstrated drug stability in circulation and a blood half-life of 18.7 hours. At a 100 microgram microdose, the drug showed robust PD activity in blood over the full-time course of the study. Clinical Study: NCT05908773.The second, ongoing clinical study with TTX-MC138 is a Phase 1/2 Multicenter, Open-Label, Dose-Escalation and Expansion Study of TTX-MC138 in Subjects with Advanced Solid Tumors. The study is employing a Bayesian Optimal Interval (BOIN) design to inform dose escalation among patients with previously treated advanced solid tumors. The BOIN design incorporates four dose levels: 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg and 4.8 mg/kg. Patients receive a once monthly administration of TTX-MC138. Preliminary data review in 16 patients indicates no dose-limiting toxicities or serious adverse events. To date, all cohorts have enrolled. Preliminary analyses suggest that TTX-MC138 demonstrates a PK/PD profile consistent with preclinical results and results from TransCode’s Phase 0 clinical study. Specifically, results confirmed the Phase 0 observation that TTX-MC138 shows evidence of pharmacodynamic activity in the presence of high baseline expression of miR-10b (PCR), reaching a 66% inhibition at 24 hours after infusion, similar to that seen in the Phase 0 clinical study. Additionally, the level of TTX-MC138 increased with the increase in dose and remained consistent with repeated administration of TTX-MC138, suggesting a favorable pharmacokinetic profile. The process leading to use of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX drug design engine to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Clinical Study: NCT06260774. Citation Format: Z. Medarova, S. Fu, A. Varkaris, M. McKean, M. Barve, A. Spira, D. Vlock, L. Fortin, S. Dugan. Phase 1 Clinical Testing of a First-in-Class Antisense Oligonucleotide Therapeutic against Advanced Solid Tumors of Multiple Tissue Origins [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-17.