RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Sad news You can't have it both ways. If anything you say here is true then THTX management ARE incompetent. Fortunately you're wrong and they aren't.
None of what you say here is correct. In SORT+ patients only a tiny proportion of the drug (less than 1% probably) interacts with the tumour. That amount of drug makes little difference to the amount of circulating drug in the blood. And just because drug doesn't enter a cancer cell doesn't mean it degrades to release free docetaxel, in fact the animal work suggests that does not happen, free docetaxel never shows up in the animals blood in any great quantities.
I follow your logic here, it appears to make sense but it's based on wrong assumptions. The first and biggest wrong assumption is that in a patient with SORT expression a large proportion of the drug injected will end up inside the cancer cells, everything flows from that, and that is just not true.
jfm1330 wrote: Contrary to some here I never suggested that people in Thera's management were incompetents. That being said, I don't understand why they are not selecting patients with sortilin overexpression on their tumors, even in the dose escalation part of phase I, because the toxicity of the drug will not be the same depending on sortilin overexpression or not.
If you understand the principles of action of TH1902, this should be obvious to you. If there is no overexpression of sortilin receptors, most of TH1902 injected will stay in the blood stream until enzymatic degradation of the peptide and free docetaxel will be released in the bloodstream and then will passively difuse in any cell, causing toxicity everywhere. If there is sortilin overexpression, TH1902 is supposed to be removed from the bloodstream by affinity interaction with sortilin and endocytosis into the cancer cell. So docetaxel is no longer in the bloodstream, and cannot difuse under free form in healthy cells.
So if your goal is to determine the maximum tolerable dose, the overexpression or not of the sortilin receptor is critical because the pharmacikinetics of the drug and its distribution in the body will be totally different. The simplest way to put it is that the maximum tolerable dose will not be the same depending on the overexpression or not or sortilin receptors. See the sortiln receptor as a drug remover from the bloodstream. If you remove docetaxel, linked to TH19P01 (TH1902) from the boodstream you remove systemic toxicity and you concentrate tumor toxicity. This is the basic principle behind the peptide-drug conjugate approach. So again, if you remove the sortilin overexpression from the equation, you cannot expect the same result.
juniper88 wrote: I have spoken with Christian before and he seems quite serious to me. I believe he and his team know what they are doing. The standard for these Phase I cancer trials is have all comers participate. There is probably a reason for that. As for Mr. Snyder, in the interview he gave, he hinted at his altruistic reason for participating in the trial. Even though we do not know his cause of death, we do not know what organs might already have been damaged in March, we don't know where the cancer had already spread, probably Mr. Snyder and his oncology team knew the extend of his disease and how much time would have had left. Perhaps, for him this was like a 3-point shot from half-court at the buzzer. I admire him for fighting until the end and for helping others in doing so. His death does not shed any light to us how the trial is going, but perhaps Thera has gotten some valuable data from his blood work in his final weeks of life.
jfm1330 wrote: This is the reverse side of the publicity made on the first dosing on this patient. It also put forward the question as to why they are not testing patients for sortilin overexpression on tumors before selecting them? In this case, it was even worse, they took a type of cancer that was never in their list of cancers with possible sortilin overexpression. Also, the doses that he was given are the lowest possible ones, so probably unefficacious even on a patient with the proper cancer. That being said, maybe the patient decided to make an altruistic action knowing it would not change much for him, but it would be his last contribution in helping other. A way to give a purpose to his last weeks on earth, So I thank him for that.
Now, Thera needs to get serious and start testing for sortilin overexpression on the tumors of the patients they will select. Levesque said in his last chat that they will do it later on in the phase I. In my view, they need to start doing it right now! Making sure to keep the whole thing private would also be a good idea.