一种一流的抗 miRNA（antagomir）疗法治疗晚期实体瘤的 1 期临床试验

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. 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 clinical study with TTX-MC138 is a Phase 1a Multicenter, Open-Label, Dose-Escalation and Expansion Study of TTX-MC138 in Subjects with Advanced Solid Tumors. The study employed a Bayesian Optimal Interval (BOIN) design to inform dose escalation among patients with previously treated advanced solid tumors. The BOIN design incorporated four dose levels: 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg and 4.8 mg/kg. Patients received a once monthly administration of TTX-MC138. The study met its primary safety endpoint and helped define a recommended Phase 2 dose, enabling advancement of TTX-MC138 into the next stage of clinical evaluation to assess its efficacy across selected metastatic diseases and for multiple indications. Primary objectives of the trial focused on safety, tolerability, pharmacokinetics ("PK") and establishment of a Phase 2 dose (RP2D). A total of sixteen patients were treated across four escalating dose levels. No significant treatment-related safety events or dose limiting toxicities were observed. TTX-MC138 was administered to 16 patients with positive pharmacodynamic effects over all four administered dose range levels. Currently three patients remain on trial receiving TTX-MC138. The median treatment duration was four months. Importantly, the duration of treatment for all patients ranged from two to 12 cycles, indicative of tolerability and disease control. Forty-four per cent or seven out of sixteen patients were classified as having stable disease lasting 4 months or longer. Preliminary data in 16 patients showed positive pharmacodynamic effects over a wide dose range, consistent with preclinical models and TransCode's Phase 0 clinical trial. Of note, one patient diagnosed with thyroid cancer and historic evidence of an increase in thyroglobulin levels, demonstrated a reversal of the trend during treatment and presented at the most recent measurement with undetectable thyroglobulin levels. 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.