jfm1330 wrote: Sorry. I am not mixing up anything. I just point out that the data on animal model and cancer patients on the only thing we know, MTD, is very different, and it would be foolish to think that efficacy will be the same as in animal models with their minuscule xenograft tumors genetically homogenous and known to be very high on sortilin expression, in comparison with big genetically heterogenous tumors with unknown sortilin expression.
Also, one thing that is very uncertain is how the PDC stability will be in humans. The whole concept is based on TH1902 being stable enough in the bloodstream to give it time to enter sortilin expressing cells before being cleaved in the bloodstream by enzymes (esterases) and to have a lot of free docetaxel released in the blood and then passively diffuse into all cells no matter how they express sortilin, causing toxicity to healthy cells.
We knew that the jump from nude xenograft mice to real cancer patients would not be straightforward. Yes healthy sortilin expression and affinity of sortilin to TH1902 between mice and humans could be different, but again, TH1902 stability in the bloodstream could also be a problem. If TH1902 is less stable in live human blood, than in live mice blood, it would be a big problem. But again, we know nothing about that. They disclosed nothing about the PK/PD data the gathered on cancer patients they injected. We also don't know if this PK/PD data vary with cancer related sortilin load, i.e.: level of sortilin expression and tumor burden.
So again, all we know is that the MTD will be much lower than what they saw on mice, and lower than their own expectations. Look at their dose escalation diagrams, they were expecting a higher MTD than 300 mg/m2. Again, this could change with further testing on 50 selected patients in phase Ib. My guess is that they reluctantly accepted to go down to 300 mg/m2 at this stage with all comers, but they will test on 50 more suitable patients in phase Ib, collecting all the PK/PD data on those patients and they will test sortilin expression on these patients, before or after treatment. That is not very clear. But they will do biopsies on these patients and do the histological testing. So they will have a clearer picture at the end of it all.
So all I am saying now is that the news we got of a likely MTD at 300 mg/m2 is negative, and we have nothing positive to balance the picture. Maybe they don't have anything positive to release, or maybe they want to realease it only at the end of phase Ia. But Marsolais said that they will not have these results until two or three more months. Again. This is awfully long for a phase Ia they were claiming would last 6 to 8 months. I don't say everything is lost. All I say is that it's clearly not going as planned. And believe me, I also would like it to work for other reasons than investment. I hope for any meaningful progress against cancers. I lost my mother to it, and I know how hurtful it is.
juniper88 wrote: JFM, you are mixing safety with efficacy. Just because MTD (safety) is higher in mice it doesn't mean that efficacy will be lower in humans. Perhaps humans have more sortilin receptors than mice in normal cells. You are right about the fact that we are still in the dark about many things. For example, what where the safety issues. Were they similar to using normal taxol or were the problems in organs that have a higher sortilin expression. Thera knows but they haven't told us. They also know if there has been efficacy but they haven't told us. Maybe they are mum on these things because they are negotiating a partnership. Again, we are in the dark.
jfm1330 wrote: Sorry Wino, you still base you thinking on preclinical data that we now know is irrelevant. We know that because the only thing we know for sure is that they are testing 300 mg/m2 as the MTD. They decided that 420 mg/m2 was not tolerable, so it cannot be the maximun
tolerable dose.
OK. So follow me. In the preclinical data, Thera stated that for TH1902 they reached an equivalent MTD of three times the MTD of docetaxel alone. So they reached a MTD on mice of 690 mg/m2. We now know that the MTD on humans will be at best 300 mg/m2. So the conclusion is that all the data on animal is inflated by a lot, if it really works. We don't know if it works on humans. It also means that the proof of concept established on xenograft mice cannot be taken for granted on humans because the MTDs are so different. So all the other data can no longer be trusted. The difference in MTDs is so huge. So forget about your graphics of efficacy on xenograft mice. It is now worthless. The whole concept may be invalid. We don't know at this point. They gave no hints that would allow to be optimistic. Nothing about any sign of efficacy and proof of concept. So you are down to a MTD that at best will be 30% higher than the MTD of docetaxel alone, and like it or not, the therapeutic window you can now hope for is much smaller that what was hope for. Listen to Marsolais in the KOL presentation Q&A part. For him at that time, the linker would release only 1% of the docetaxel in the bloodstream. So why is it now toxic at 420 mg/m2?
Again, as I also wrote, maybe phase Ib on selected patients and many more patients will allow to better understand how TH1902 is really behaving on patients that are really highly overexpressing sortilin and that it will lead to a revised higher dose for phase II. I don't want to discard this program at this stage. All I say is that it is not going as planned it is taking much, much, longer than expected by the company and all we have is the disapointing side, with nothing on the positive side. Also, their tone is much less enthusiastic about the whole thing. It is beyond understanding that it will take more than a year to complete this trial. Something went wrong at some point and they don't tell us what was the problem. They did not explain how this trial would really be conducted. We know almost nothing about it. Back in June, during the KOL presentation they were expecting results to be published at the beginning of the fall. Now it will something like seven or eight months later. Such a delay would have warranted a much better explaination from them. So if somebody wants to complain about poor communication, complain about that. For once it would be about important stuff.
Wino115 wrote: Sorry JFM, I believe you are wrong on this. Take a look at this chart in the January IP. This is a 1 for 1 comparison of TH1902 vs. docetaxol. So your argument would be the OPPOSITE -- it will be 30 to 50% BETTER since the RP2D will be higher than what this chart shows, not lower as you state. These charts showing tumor suppresion and progression free survival are equimolar, not at the max dose of TH1902. It would only increase, not decrease. There are some charts where they did use more TH1902 vs. docetaxol, but not these.
Also, the step-down to 300 is the final test for the RP2D given the MTD was 460. That is what I understood from Christian.
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