On October 24, 2023 TransCode Therapeutics, Inc. (NASDAQ: RNAZ), the RNA oncology company committed to more effectively treating cancer using RNA therapeutics, reported preliminary results with its lead therapeutic candidate, TTX-MC138, in the first patient enrolled in its Phase 0 clinical trial aimed at demonstrating delivery of TTX-MC138 to metastatic cancer, including metastases beyond those found in the liver (Press release, TransCode Therapeutics, OCT 24, 2023, View Source [SID1234636304]). These preliminary data showed that radioactivity consistent with accumulation of TTX-MC138 was detected by noninvasive imaging in the regions of the metastatic lesions previously identified by fluorodeoxyglucose (FDG)/positron emission tomography (PET) (FDG/PET). In addition, radiolabeled TTX-MC138 had pharmacokinetic behavior consistent with that expected based on non-clinical IND-enabling studies. The patient tolerated the dosing with no reported adverse reactions. Metabolite analysis indicated circulation of intact radiolabeled TTX-MC138 for more than 20 hours, equivalent to that predicted by Drug Metabolism and Pharmacokinetics (DMPK) modelling, and that the drug candidate analyzed in the blood was identical to that of the manufactured drug candidate, demonstrating in vivo stability. Complete analysis of data from this first patient is in process and will be included in the final report for all patients enrolled in the study.
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TransCode’s Chief Technology Officer, Zdravka Medarova, PhD, commented, "We believe these preliminary clinical data support our thesis that TTX-MC138 can be delivered successfully to metastatic lesions for the potential treatment of metastatic cancer. Preclinical evidence pointing towards miRNA-10b’s critical role in metastatic progression across a number of major cancer types suggests that inhibition of miRNA-10b in patients with advanced disease could have a dramatic impact on their disease."
The Phase 0 trial is an open-label, single-center, microdose study intended to demonstrate delivery of the radiolabeled version of TTX-MC138 to radiographically-confirmed metastases in subjects with advanced solid tumors. Up to 12 subjects may be enrolled in this clinical study, each of which is expected to receive a single microdose of radiolabeled TTX-MC138 followed by positron emission tomography/magnetic resonance imaging (PET-MRI) and blood analyses. The trial is intended to quantify the amount of TTX-MC138 delivered to metastatic lesions, especially beyond the liver, and the pharmacokinetics of the therapeutic candidate in those patients. The trial is intended to yield important data regarding TTX-MC138 delivery to clinical metastases that could inform dose selection and frequency, for further clinical development. The trial is not intended to demonstrate a therapeutic effect.
In the earlier IND-enabling studies conducted in non-human primates (NHP), TTX-MC138 demonstrated long circulation and tissue distribution consistent with hepatic clearance. Data from the NHP study were incorporated into a DMPK model, intended to model the pharmacokinetics and tissue distribution of TTX-MC138 in humans. The model predicted circulation and tissue distribution in humans consistent with results from TransCode’s nonclinical studies in which numerous complete regressions of metastatic disease were observed.
TTX-MC138 consists of an iron oxide nanocarrier conjugated to a nucleic acid specifically designed to inhibit the oncogenic RNA, microRNA-10b. MiRNA-10b has been described as the master regulator of cancer progression in a number of advanced solid tumors. TransCode believes that TTX-MC138 has the potential to become a treatment for many of these cancers. Administration of TTX-MC138 has demonstrated complete regression of metastatic disease in a number of mouse models of pancreatic and breast cancer. In addition, TTX-MC138 was successfully delivered and demonstrated bioactivity in a case study of spontaneous feline mammary carcinoma.
"Our Phase 0 trial involves a single microdose of radiolabeled TTX-MC138 followed by noninvasive PET-MRI imaging and metabolite analysis. Given the similarities between humans and non-human primates relative to anatomy, physiology, and molecular biology, we anticipated results in trial patients comparable to those observed in the DMPK model based on our NHP studies, as evidenced by the preliminary data we announced today," added Michael Dudley, Chief Executive Officer of TransCode.
This study was done in collaboration with Andreas Varkaris, MD, PhD, an attending physician and investigator for the Termeer Center for Targeted Therapies at Massachusetts General Hospital and the principal investigator of TransCode’s study.