383P - Clinical experience with TTX-MC138: A first-in-class therapy against metastatic cancer

Background

In our earlier efforts, miRNA-10b was identified as a regulator of the viability of metastatic tumor cells. This allowed us to develop a therapeutic strategy based on miR-10b inhibition. The specific inhibition of miR-10b was achieved using inhibitory oligonucleotides (locked nucleic acid, LNA-based antagomirs) delivered to metastatic sites by aminated dextran-coated iron oxide nanoparticles (termed TTX-MC138). Our research demonstrated that TTX-MC138 could cause complete and persistent regression of metastases in cancer models with no evidence of systemic toxicity.

Methods

On the path to clinical development of TTX-MC138, we conducted critical, exploratory IND enabling studies in rats, dogs, and non-human primates with TTX-MC138. Ultimately, the information generated resulted in FDA authorization under IND163800 allowing for initiation of an ongoing microdosing Phase 0 clinical trial in patients with advanced metastatic cancer.

Results

The Phase 0 clinical trial involves a single injection of a microdose of Cu-64 labeled TTX-MC138 which allows for direct visualization in cancer patients via PET-MR imaging, with a primary endpoint of confirming its localization (%ID/cc) to the metastatic lesions. We have now obtained initial clinical data on drug PK and accumulation in clinical metastases to the lungs, bone, and liver, as well as drug stability, metabolism, and pharmacodynamic activity. We have demonstrated TTX-MC138 uptake by bone, lung, and liver metastases, as well as tumor to blood ratios reflective of selective retention of the drug by tumor tissue. We have established that the drug has a long circulation time of 20 hrs in humans. Remarkably, even at a 100 microgram microdose, the drug showed robust PD activity with a 70% inhibition of the miR-10b target in blood over the full time course of the study.

Conclusions

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 identification

IND 163800.

Editorial acknowledgement

n/a

Legal entity responsible for the study

TransCode Therapeutics.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.