Weer een belangrijke bijdrage van BioBoyScout: het toont aan dat de anti sense benadering van rna therapie een belangrijk nadeel heeft tov rnai. TRIM is in feite een tailor made constructie die leidt tot (waarschijnlijk) minder bijwerkingen dan het nieuwste anti sense platform.
Citaat ontleend aan het Yahoo forum:
Additional observations on the Ionis ENaC news. If you go to the Ionis webpage and look under the tab "Ionis Innovation" and select "Optimizing Antisense", you'll see an explanation of the technology that Ionis uses for its drugs. There are four different technologies: Gen 2+, Gen 2+ LICA, Gen 2.5, and Gen 2.5 LICA. What is LICA? Ionis explains it on that page, it's basically their antisense drugs with targeting ligands (LIgand Conjugated Antisense).
If you recall, Arrowhead in its presentations well over a year ago showed plenty of data on how using targeting ligands with their triggers was much more effective than without using targeting ligands. This is because you're able to target drug into areas where you want it to go. Without a targeting ligand, the drug ends up being much more dispersed throughout the body. The drug may "work" without a targeting ligand, but it will be much less effective because less of the drug gets to where you're wanting it to go (i.e. the liver, or the lung).
With that said, if you go to Ionis's pipeline page, head down to their ENaC drug and click on it, it will expand to show additional information about the drug. This additional info states that the technology used for its ENaC drug is Gen 2.5. It is NOT Gen 2.5 LICA or Gen 2+ LICA, therefore Ionis's ENaC drug is without a targeting ligand. What does this mean? It means that the drug is not specifically targeted like Arrowhead's is to the lung. No doubt Ionis's drug will get absorbed by the lung, but it will also get dispersed elsewhere and will most likely not get the same concentration of to the lung as Arrowhead can.
The benefit of having a ligand-less drug is that it's easier and cheaper to manufacture and test. The downside is that you're probably not getting most of your drug where you want it to be. The result can be a higher risk of side effects and off-target effects.
So given the fact that Ionis was able to effectively knock down and target the ENaC gene with a ligand-less drug, this should bode much better for Arrowhead's targeting ligand conjugated drug, not just in terms of effectiveness, but also in terms of safety.
BTW, I haven't seen any other analyst jump on this issue. IMO, they probably should
@JJ my understanding is that identifying and developing the proper targeting ligand for the lung takes considerable time and money, as there are no readily available ones to use like there are for the liver (i.e. GalNAc). Arrowhead not only took the time and effort to identify the best possible lung targeting ligand, but they also patented their specific formulation (can you say "pulmonary franchise"). It is also my understanding that it is more difficult and more costly to incorporate a targeting ligand with your trigger, but it is also probably less safe, as your drug will be more freely distributed elsewhere.
Have to add the following comment, as I believe it's pretty amazing. Arrowhead's ability to identify a targeting ligand for the lung was so effective that the conclusion they came to was that the "Targeting ligand increases trigger potency 10x and improves uniformity of aENaC mRNA silencing in the lung."
If that isn't exciting, I don't know what is. Arrowhead has to be licking their chops after seeing Ionis's interim data. IMO, extrahepatic to the lung is alive and well - it doesn't take an analyst that's a biologist to come to that conclusion.
Just as an FYI, I actually covered this exact issue in the report that I issued on August 14, 2019. I am realizing that much of the info in that report applies more today than it did back in 2019. If you have a copy, it is referenced in pages 5-7 and specifically cites the studies with hyperlinks.
@zhiyilinnj go see Arrowhead's poster presentation on it's ARO-ENaC drug at the North American Cystic Fibrosis Conference on October 18, 2018. After seeing that presentation, you'll understand that an inhaled drug with a targeting ligand is much more effective than one without it.