TKM-080301
Small interfering RNAs (siRNAs) can be used as tools to study single gene function both in vitro and in vivo and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. They can be introduced exogenously into the cell or organism in short (21-23 bp) form or in the form of long double-stranded RNA (dsRNA) molecules. These dsRNAs are processed by endogenous RNAi machinery after the introduction into the cell. First, the cytosolic enzyme Dicer cleaves long dsRNAs into shorter fragments (siRNAs). siRNAs are recognized by the AGO2-RISC enzyme complex, where one of the strands is degraded and the other strand is left as a guide to finding target mRNA sequences. Because they can efficiently silence target gene expression in a sequence-specific manner, siRNAs became indispensable tools to study the function of single genes.
Figure 1. Schematic showing a simplified view of siRNA mechanisms.
TKM-080301
The TKM-080301 is a SNALP formulation of a siRNA against Polo-Like Kinase 1 (PLK1), a serine/threonine kinase that regulates key aspects of cell cycle progression and mitosis and is highly expressed in malignant cells. In preclinical models, the anti-tumor activity of PLK1 inhibition through RNA interference has been demonstrated, thus several clinical trials based on the pharmaceutical TKM-080301 were carried out by Tekmira Pharmaceuticals.
- Feasibility
- Safety and Tolerability
The feasibility of administering TKM-080301 via Hepatic Arterial Infusion (HAI) and its pharmacokinetics and pharmacodynamics in patients with unresectable primary liver cancer or liver metastases have been evaluated in a dose-escalation study. The study started in Aug 2011 and was completed in June 2012.
To determine the safety and tolerability of TKM-080301 in adult patients with solid tumors or lymphomas that are refractory to standard therapy, or for whom there is no standard therapy, a phase I/II TKM-PLK1 clinical trial was carried out. The study was completed, the enrollment was of 68 subjects, the starting date was Dec 2010 and the primary completion date was July 2015. Results indicate that TKM-080301 was generally well-tolerated by the majority of patients showing a preliminary antitumor efficacy, supporting PLK1 as a therapeutic target.
Finally, to test the safety and tolerability of TKM-080301 in subjects with advanced hepatocellular carcinoma (HCC) and to find the maximum tolerated dose (MTD) providing a preliminary assessment of anti-tumor activity of TKM-080301, an extended phase I/II TKM-PLK1 clinical trial for HCC was done. The study was completed, the enrollment was of 43 participants, the starting date was Jun 2014 and the primary completion date was May 2016. TKM-080301 was generally well tolerated, lentivirus vector-packaging cell lines have been developed as an alternative method of vector production.
Reference
- Macleod, A. R.; et al. (2017). RNA therapeutics in oncology: advances, challenges, and future directions. The Journal of Clinical Pharmacology. 57.
