RNA-based therapeutics

The recent development of second generation chemical modifications to stabilize double stranded-RNA (dsRNA) and the ability to deliver these modified RNAs with high specificity to organs such as the liver, has transformed the RNA therapeutics field. The exemplar drug is Patisiran, which is a small interfering RNA (siRNA) therapy that very effectively inhibits the production of a protein in the liver which causes a peripheral nerve disorder.

The success of Patisiran in a large clinical trial in July of 2018, which was reported in the New England Journal of Medicine (full article), resulted in a major milestone for the RNA therapeutics field – approval by the U.S. Food and Drug Administration of the first dsRNA treatment for a human disease. This very successful first-of-its kind targeted RNA-based therapy has set the stage for the development of a range of innovative therapies for other human diseases.

Another example of the success of this technology is the drug called Inclisiran, which is a siRNA against an important target for controlling cholesterol production in the liver. Second generation chemistry enabled Inclisiran to be stable in the blood stream and also to be targeted specifically to the liver. This combination produced a very impressive lowering of cholesterol for many months from a single injection in a phase 2 clinical trial published in the New England Journal of Medicine (full article), which has resulted in the development of ORION-4 a phase 3 clinical trial of 15,000 patients (https://clinicaltrials.gov) to determine how effective it is in preventing heart attacks in people with pre-existing heart disease.

Given that miRNA mimics and siRNAs are structurally very similar (both being small dsRNA molecules) and both utilise the same processing pathway inside cells, miReven has used second generation chemistry to develop novel synthetic miRNA-7 therapeutics for cancer, with mRx-7 being the lead compound.