RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Any comments on this from Leede's Doug Loe?One thing I forgot to say about the siRNA option is that logically you invest in research about that only if you have a proof of concept with TH1902, otherwise it would be very aggressive for a small company. Also, imagine that they hire somebody well qualified for that job, but in a few months they end uo without a proof concept and release that person. Ethically it does not make sense.
So this hiring is still one indirect hint that they see some efficacy in some patients, but it is just guessing on my part. Nothing is sure about that. I still think something is not going as planned in this phase Ia trial and it's more speculative than it was. If you are in for oncology, at this point it's believe or sell. The problem is that it is harder to believe in the management now with this phase Ia that will take twice the time expected to complete it. And in the last CC, they gave nothing, not a positive hint, no context, nothing.
jfm1330 wrote: 300 mg/m2 is only a 30% higher MTD. Puting aside efficacy and proof of concept, without PK/PD data, and "cancer sortilin load" it is hard to understand what it could mean. Add to that the enormous delay in finishing phase Ia. To me it is a black box at this point with only negative output. To give publicly the likely MTD without any context is problematic. Also, no explainations about the very long delay in finishing the trial is also problematic because last summer a short phase Ia was a slam dunk for them. Again, this program was always speculative, now it is highly speculative.
In the light of all that, another thing I thought about is the fact that hiring a siRNA expert could have been misinterpreted. At first I thought it was a sign of optimism for their SORT1 technology based on what they were seeing in the phase Ia. But there is another way to look at it now for me. If they have problem with TH1902 stability in the human bloodstream, hence lower MTD and toxicity problems. Using siRNA would be a way to overcome that since siRNAs are not toxic outside of cells and cannot passively diffuse into cells.
So let's say the PDC concept with TH19P01 really works, in the sense that a small part of it is internalized by sortilin expressing cells, but that internalization is too slow to avoid the release of a lot of toxic free docetaxel in the boodstream that will diffuse passively into healthy cells. Then, using siRNA would be a way to overcome this problem because siRNA is not toxic in the bloodstream and cannot diffuse passively through cell membranes. So a PDC with siRNA could be given at very high doses and even if only 1% of it would make it inside sortilin expressing cells, the 99% that would not would be non toxic, and would be degraded in the bloodstream to non toxic amino acids and nucleotides (building blocks for peptides/proteins and RNA/DNA).
These amino acids and nucleotides would end up into cells as building blocks to make proteins, peptide and DNA/RNA. So maybe they saw that carrying highly toxic hydrophobic drugs like docetaxel and SN38 would have toxicity limitations (hydrophobic drugs, also called lipophilic drugs are soluble in lipids, and cell membrannes are mostly made of phospholipids, so these drugs easily diffuse through cell membranes. RNAs are hydrophilic molecules, you can also called them lipophobic, and are soluble in water, but not in lipids (fat) so cannot diffuse passively through cell membranes).
So siRNA used with TH19P01 in a PDC would be an approach eliminating the toxicity concern. The breakdown of the PDC in the bloodstream would be non toxic, even at very high doses, so you would need only a small fraction of the injected dose to make it inside sortilin expressing cells. That is probably the reason why they want to develop that. The problem is that it won't be easy. It will be much harder than carrying docetaxel, but the fact that you don't need to worry about the toxicity related to PDC degradation in the bloodstream would be the great advantage allowing the use of massive doses. But first you need to find a way to attach big siRNA to the peptide, then it needs to be stable enough for a part of it to make it inside sortilin expressing cells. You also need an hypothetical siRNA PDC made with TH19P01 to retain good affinity with sortilin. Finally, you need to identify a siRNA that would be cytotoxic to cancer cells by blocking the expression of a key protein critical to cell survival, preferably critical to cancer cell survival. So it is is a nice idea on paper. There is a lot of hrdles to jump before it could be a reality. Sorry if it's too technical and too long.