An RNA silencer is a drug made from a small piece of RNA (kind of like a DNA) that has been modified to make it more stable and be able to get into cells. They bind to a bigger type of RNA in cells called mRNAs and block mRNA function. That stops production of the viral proteins from the mRNA, blocking viral function.
TLR8 is a “pathogen associated molecular pattern” detector that detects foreign RNA once it gets into the cells (in a part of the uptake pathway called “endosomes”). It normally detects RNA from a pathogen and then triggers the immune system to fight the pathogen. An “agonist” is a molecule that binds to something and turns it on (vs. an “antagonist” that binds to something and turns it off). A TLR8 agonist is therefore a drug that binds to TLR8, turns it on, and triggers the immune response to attack HBV.
In a completely irrelevant but interesting note, TLR stands for “Toll Like Receptor”. TLRs are named after a German word that can be translated as “Cool!”. This is because the first member of the class was identified in studies with mutant fruit flies that looked interesting under a dissecting microscope. The researchers were German, and the lab director looked through the ‘scope and said “Cool!”.
VIR-2218 is an siRNA drug in phase II trials.
Selgantolimod is a TLR8 agonist in Phase II trials.
Combining an siRNA and a TLR8 agonist together in a combination therapy makes sense scientifically. The TLR8 agonist would help turn on the immune system, and the siRNA would help suppress viral replication and reduce the amount of HBV proteins in cells. That is important because some of the viral proteins partially block the immune system. Overall, this strategy focuses on ramping up the immune system to kill HBV infected cells. The risks with this strategy are that if the immune response becomes too vigorous a patient may get ill from killing too many HBV+ cells too fast. However, that does not seem to be very likely to happen as the problem with most siRNAs and the TLR8 drugs when given by themselves is that they did not attack the virus as hard as we had hoped (they worked, just not spectacularly). However, only clinical trials can really find out if a combination works in people.
Note that this is only one of the very many logical drug combinations being considered now.