RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Update pleaseBecause if it goes better than expected and it takes longer that has to be communicated to investors so the delay doesn't come across as a negative factor on the contrary it could be very positive. Not all the investors Keep going back and read the comments and cross reference them. If the company said initially 28 weeks which is not correct then they have to issue a PR explaining why it might take few more months. For instance that delay could be because of slow enrolment which can also be true but they did add a forth clinic so even so let your investors know there is a mitigation plan for the issue started last August. At the end transparency will be much more appreciated than confusing time lines etc.
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.