RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Sad news If you're unwilling to engage with some ideas that might explain why they do this then maybe we should just live with the fact that you "don't understand" and move on.
You assume so much, and so much of what you assume is wrong. There is absolutely no evidence that the drug distribution will differ all that much between SORT1+ and SORT1- patients. That's your assumption, for which there is no evidence. When drugs have been measured in the past no more than 0.1% of the drug that is injected in the patient interacts with the tumour, that's not measured directly but is the implication from indirect measurement. So that means you are talking about a difference in drug distribution to the rest of the body of 100% of the drug compared to 99.9% of the drug. Can you say that difference will have a substantial impact? I understand 0.1% of drug actually doing the job it's designed for is ridiculously low but those appear to be the facts with other drugs and there is no reason to believe it won't be the same with TH1902.
If your idea was correct, that targeted therapy drug distribution is significantly affected by the presence or absence of targeted antigen on the tumours, then not just THTX's trial would be compromised but every other ADC or PDC trial would suffer as well if they didn't pre-screen their patients. The fact that MOST of these trials don't pre-screen in their first-in-human trial should be telling you something.
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.