jfm1330 wrote: Where the docetaxel is going is related to sortilin expression in the whole body and especially tumor burden, and the rate of degradation and hepatic elimination. The higher the tumor burden is in a patient and the higher sortilin is expressed on these tumors, the more the share of the injected dose going in the tumors will be high.
We don't have that data in humans for TH1902 since it's too early in the process and there is no imaging tool that has been developed, but for Dotatate conjugates imaging exist with Ga68. Dr. Beauregard in Quebec City made a study in 2008 on that subject and he clearly proved that the higher the tumor burden load of a patient is, the less radiation goes in other organs, and in the case of somatostatin receptors, two organs are expressing somatostatin receptors highly, spleen and kidney. So the higher the tumor burden of a patient is, the less radiation goes in these two organs because more goes in the tumors.
So I still think that the smaller the tumors of a patient are and if they do not overexpress sortilin a lot, you will end up with more docetaxel elswhere and more toxicity in the end. That's another aspect of the use of TH1902 this phase Ia was unable to assess. It's noemal, it's too early, but it is important to remember, there is very likely a correlation dose to tumor burden involved all linked to sortilin overexpression. I will give the link to the article once again, it is pretty technical, but results and conclusions are easy to understand, The more tumors you have overexpressing the target receptor, the more it will drain the drug out of the rest of the body, that's why they call it a "sink effect". It's proven for Dotatate based PDCs, but there is no reason why it should not be the same for TH1902/sortilin.
https://www.researchgate.net/profile/Michael-Hofman/publication/51656132_The_tumour_sink_effect_on_the_biodistribution_of_68Ga-DOTA-_octreotate_Implications_for_peptide_receptor_radionuclide_therapy/links/00463515fe5c38f1ef000000/The-tumour-sink-effect-on-the-biodistribution-of-68Ga-DOTA-octreotate-Implications-for-peptide-receptor-radionuclide-therapy.pdf
SPCEO1 wrote:
1.) Were you expecting a report on the percentage of free docetaxel in the patient's bloodsteam - I didn't and the 11% seen versus the amount seen in a normal straight docetaxel dose is pretty encouraging. THTX is putting 150% of the normal dose in and getting 11% of it floating freely in the bloodstream. Clearly, the vast majority of the docetaxel is going elsewhere and it seems reasonable to assume most of that is going to the sortilin overexpressing tumors as the drug was devised to do and as the pre-clinical tests showed it would. I don't think that is some huge leap of faith.