RE:RE:RE:RE:RE:MDGL UpdateFrom the little I read, yes, the challenge with siRNA is much bigger, but I guess they have reasons to believe it's possible. They know much more than me about that. A normal siRNA molecule is about 15 times bigger than a docetaxel molecule. So let's say they would load only one siRNA molecule on TH19P01, instead of two of docetaxeil in TH1902, it would still be 7 or 8 times more load on the peptide. So with such a high load, would the peptide still be able to bind to sortilin? Also, siRNAs are not very stable molecules, they are prone to enzymatic degradation. So the internalization of the PDC by sortilin would need to be very quick. That being said, since free siRNA cannot passively diffuse in cells like docetaxel or other systemic drugs, in theory they could inject much higher doses of the PDC, with the goal that only a fraction of it would make it intact into sortilin expressing cells. My guess is that free siRNA in the bloodstream would be quickly degraded and cleared by the kidneys, also, siRNA in the bloodstream would not be toxic like docetaxel or other cytotoxic drugs since it would not be able to diffuse by itself into lymphocytes to kill them and cause neutropenia.
So looking very quickly at it, it seems to me that using siRNA in a PDC is a much bigger challenge. But again, they have many chemists and biochemists working for them or consulting for them. So if they started the search for a specialist to work on that, it's because they think there is a reasonable possibility that it could work.
SPCEO1 wrote: What are the chances that little TH could acquire the capability to formulate a successful PDC with siRNA as the payload? They were able to put together TH-1902 rather inexpensively. Does it get exponentially harder from this point forward?
jfm1330 wrote: Again, they would not search a siRNA apecialist if they would see nothing on the efficacy side leading to a proof of concept. Making a PDC that would work linking SiRNA to TH19P01 is another ball game than doing it with a rather small, stable and old proven drug like docetaxel.
Wino115 wrote: What the NASH space needs to see -- a successful leader moving to approvall. I think this was the companion NAFLD trial to the main MAESTRO trial they're doing on NASH, but it is also supposed to finish by mid year. Any good news in NASH will help to rebuild sentiment that it's a therapy worth going for.
For THTX news Muslix, from what tidbits came out in the presentations and subsequent discussions is that they are still moving up the dosage. Means they may still have to keep going to find DLTs, then back down one level and test six patients at that. Then we have MTD. I think my "ready-reckoner" was if its the 320mg (1.5x taxel SOC) it would have been finished Jan, 400-ish level would be Feb, 500-ish level would be Mar. If it keeps going up to the 700-ish level, maybe even beyond Mar. So looks like we're at least past the 400 level, so Feb at best and maybe Mar. WHile it's painful to wait, this waiting does actually have financial implications if you believe the higher the does, the higher the probabilitiy of something special in efficacy.
Be patient, it's a wait around good news, not bad.
muslix1 wrote:
one day it's going to be our turn pop up 20%...
but not today there's no news at 7.30 well see you tomorrow at 7.30 for news i hope