RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Update please We are almost a month after this message. It means that they are now likely well into testing the 560 mg/m2 dose of TH1902, which is 2.43 times the MTD of docetaxel alone. At such a dosage, only two things could prevent some efficacy: high resistance to docetaxel that TH1902 cannot overcome, or sluggish linker cleavage inside the cancer cells that would not allow achieving very high concentration of intracellular free docetaxel. At such a high dose, it is hard to think that TH1902 is not internalized in good part into sortilin expressing cells. Remember that TH19P01 is a peptide that is not very stable to enzymatic cleavage in the bloodstream. So in a matter of a few hours it should be dismantled into its amino acids pieces and free docetaxel should quickly accumulate in the blood, then able to diffuse passively into white blood cells (leukocytes) and kill them, causing neutropenia.
So all that to say that they are at a very high dose. Either it will be the limiting dose, or they will go for the next one in January, which would be 740 mg/m2 (3 times the MTD of docetaxel alone). These doses are very likely very toxic if given to a patient not overexpressing sortilin or with a very small tumor burden. Maybe one of the reason for the slower than expected dose escalation process is due to this problem of differential toxicity between patients with different sortilin expression and tumor burden. Maybe they had to sort it out on the fly with the FDA.
jfm1330 wrote: I don't understand why there is a discussion about where the phase Ia is right now. Levesque clearly said in his last video presentation (Credit Suisse), that they were on line to determine the MTD by the end of this year or early in 2022. That is if it goes as they were expecting it at the begining of November. Let's say it goes better than expected, so to a higher dose than expected, then it would push everything by one more month, to February.
In this presentation he also clearly said that they were not allowed to preselect patients based on sortilin expression testing. That this testing including a biopsy, is done only afterward. That being said, I guess it would be easier to have patients with cancer types likely to overexpress sortilin. Also, I still think that the level of expression of sortilin and tumor burden can play a role regarding toxicity. A patient with high sortilin overexpression and high tumor burden is likely to be able to take a higher dose without meaningful toxicity because a good part of TH1902 and its docetaxel will go into cancer cells, and the more cancer cells you have in your body, the more it can internalize TH1902.
The thing that was not explained by Levesque in his presentations or by Marsolais in the last quaterly conference call is to understand why it took them so long to escalate to 2 times the MTD. It took much longer than expected with only one patient per dose level. That I don't understand. But the strange thing in the Credit Suisse presentation, is that Levesque says that they had "many patients", or "at least several patients" that have been dosed over 300 mg/m2 (300 mg/m2 is step 5 of the escalation process). So over 300 mg/m2 is 420 mg/m2. So back in November he said that they had "many, or at least several patients" that have been dosed above 300 mg/m2, so at 420 mg/m2. So probably, back then, the three added patients at step 6, which, again, is 420 mg/m2, were already injected. This presentation was held on November 11. So by now, the 420 mg/m2 should have been completed and cleared. Without any news at this point, it is likely that they are now at step 7, which is 560 mg/m2 or 2.43 times the MTD of docetaxel alone.
Also, the escalation diagram in the presentation has a potential step 8, which would be 740 mg/m2 of TH1902, which is equivalent to 3.2 times the MTD of docetaxel alone. This is in line with what they saw in the animal model, injecting three times the MTD of docetaxel alone, and Marsolais said that what the were seeing on humans, was in line with the preclinical data. Remember that Marsolais has access from the begining to pharmacokinetics data. And Levesque said that the level of free docetaxel in the blood that they see on humans, is in line with what they saw in the preclinical work on animal. From which you can decuct that toxicity on humans should be similar to what they saw on animals.
So all that to say that there is no big mystery there for somebody following what they say and able to put all the pieces together. The question now is to determine if the MTD will be around 2 times the MTD of docetaxel alone or 3 times. If it's 3 times, it will take until Ferbuary to finalize experimentations. If it gets there, they will put out a press realease to clarify the situation.
Also, don't forget one thing, the FDA asked them to take all comers in the trial, including patients that does not express sortilin on their cancer cells, because FDA wanted to see a proof of the necessity of sortilin expression for efficacy. It has been explained that way by Marsolais in the KOL presentation. So in order to see that differential in efficacy, you need to see efficacy in some patients. But where things gets complicated with this "all comers" thing, is that if you take a patient with a cancer not expressing sortilin, he will probably be fine at lower doses of TH1902, doses equivalent to the MTD of docetaxel alone, or slightly higher. But at doses that are clearly higher, I am sure sortilin expressing patients an the non expressing ones won't react in the same way. The non expressing ones will show signs of toxicity like neutropenia, while those expressing sortilin or overexpressing it, and with larger tumor burden, will not show the same toxicity signs at the same dose. Add to that the fact that Levesque said that patients sortilin expression will be determined after treatment, it means biopsies and histological analyses after treatment. So the whole thing is more complicated than it first looks like, and remember that FDA ideally wants to see an efficacy differential between sortilin positive patients and those that does not have the receptor on their tumors, or a very low level of it. All that can maybe explain why the escalation process was so slow.