RE:RE:RE:RE:RE:RE:RE:RE:RE:TH-1902 pause is no reason to blame managementIn the little data that we have from phase Ia, we know that it seemed to work on some tumors and not on others in the same patient. We also know that it can have some effects on cancer cells (reducing PSA in some prostate cancers or other biomarkers like in the case of juniper88's wife), but not killing the cancer cells, just hampering them, maybe stopping or slowing cell division and cancer progression.
So docetaxel will not necessary kill the cells into which it enters with the help of TH19P01, but it will hamper them. This is true for cancer cells, but also true for healthy cells and just hampering healthy cells is enough to cause toxicity, especially in patients that are not really highly overexpressing sortilin on their tumors.
I explained that before here, but I will doit again. With PDCs targeting receptors, the high overexpression of these receptors on the tumors is critical. If you treat a patient that does not have high overexpression of sortilin on his tumors, it leaves the PDC in the bloodstream available to enter healthy cells expressing sortilin, or available for enzymatic cleavage in the bloodstream resulting in free docetaxel being released and able to diffuse passively in any cells in the body, mostly healthy cells.
The idea with PDCs is based on a competition to enter cells expressing the targeted receptor. This competition favors the tumor when you have very high expression of the receptor on the tumors in comparison with healthy tissues. If the receptor expression is not high on the tumors, then the competition favors the healthy cells expressing the receptor and it favors enzymatic cleavage of the free cytotoxic drug in the bloodstream, hence, it leads to more toxicity.
The reality is that Thera's clinical protocol was ill concieved from the beginning by not selecting patients for high sortilin overexpression, and docetaxel was not the right cytotoxic agent. I also have concerns about the stability of TH19P01 to enzymatic degradation in the bloodstream. The peptide itself (TH19P01) is not a stabilized peptide. Its sequence is made only of natural amino acids. I think the level of stabilization it may have in TH1902 is given only by the steric hindrance provided by the two linkers and the two docetaxel molecules loaded onto it. I know this is very technical stuff, but these are valid questions. The same for the stability of the linker in the bloodstream and inside cancer cells in humans, in real patients.
Again, maybe they have the right target, sortilin, the right peptide (ligand), TH19P01, but without the full data they have, I tend to think that they should drop TH1902, and they should go with a new PDC, likely following the path to approval that is already cleared, which is DOTA linker with Ga68 for proof of concept, and Lu177 for therapeutic use.