jfm1330 wrote: I read the article. Some interesting points. First, they use a linker to attach docetaxel to the micelles and this linker binds docetaxel through an ester bond. The ester bond is the same chemical bond that is used to link docetaxel to TH19P01, to make TH1902, and this is the chemical bond that needs to be selctively cleaved once TH1902 is inside cancer cells by an enzyme called esterase. Marsolais said in the last presentation that there is a higher concentration of esterase inside cancer cells, in comparison to the bloodstream, which would explain the selective cleavage. But I also read that the inside of cancer cells (cytoplasm) is more acidic (lower pH) and that esterases are more active under such a lower pH. So, this is a good thing to see that they use a linker with the same chemical bond to link docetaxel.
Another interesting point is that they give the blood sampling times they used to follow docetaxel levels after injection, it is
In part 1, plasma samples for docetaxel measurement were collected at the following time points during treatment cycles 1 and 2: 0, 5, 15, 30 min, 1, 1.5, 2, 4, 6, 24 h, 2–4 and 7 days after drug infusion What is interesting with that is the fact that Thera likely did a similar blood sampling to dose free docetaxel and TH1902, and they already know the results of that. That's another thing that is probably a part pf the high confidence they were showing in the last presentation.
Other than that, it is interesting to note that the MTD they got in rats during the preclinical work for their IND was 150 mg/m2, and in human in phase I they had to settle for 60 mg/m2 because of unforseen skin toxicity probably driven by their micelle approach. On the other hand, it is interesting to note that they had no problems with neutropenia, the main toxic effect of free docetaxel. They give two possible explainations for that, one similar to mine for TH1902, which is that their micelle minimize the peak concentration of free docetaxel in the bloodstream, the other possible explanation is that the micelle are not bringing much docetaxel to the bone marrow where withe blood cells are produced.
So interesting because it uses docetaxel with a similar linker, but overall, TH1902 seems to be much more promising with a much better mechanism of targeted delivery of docetaxel. We will see, because it also shows that rats and humans are two different things...
SPCEO1 wrote: If THTX's therapeutic window is larger as seems likely, can you explain what that means for the success of TH-1902 from a commercial perspective? I think we can guess but I would rather get a clearer read on that from someone with your background.
Is there anything in the PK or PD info in that article that has any relevance for TH-1902? Hopefully, JFM1330 will weigh in on that as he clearly understands those aspects of it better than most of us.
Micelles are like small spheres that have structures similar to cell membranes that allow them to fuse with the membrane and deposit their content (docetaxel) into the cell. So better delivery of chemo to cell but the problem is it does this to all cells. Just looking at the abstract the results fit that. They can dose lower to get efficacy but seems like some DLTs also appear. It doesn't look like they've increased the therapeutic window size just shifted everything (efficacy and toxicity) to a lower dose. It might be more subtle than that and the toxicity profile might be better, I can't judge, but my first guess is the therapeutic window just moved, it didn't get bigger.
SPCEO1 wrote: My guess is there could be some interesting aspects to this paper for us and am looking forward to any comments JFM1330 and Qwerty might have about it. I could make some uneducated comments but that would likely be wasting everybody's time.
jeffm34 wrote: https://www.sciencedirect.com/science/article/pii/S0168365920303540
This was a phase I dose escalation trial as well. I assume Thera will be monitoring tumour size in each patient after every treatment cycle as well. Which means they should be seeing efficacy data all the way along the trial.
"The total tumour burden measured in this patient decreased from 129 mm at screening to 109 mm in cycle 2, 90 mm in cycle 4, 86 mm in cycle 6 and 85 mm at EOT."