RE:RE:RE:RE:RE:MTD and the FDA Another thing, from the animal model, we know that at an equivalent dose, TH1902 shows more efficacy than docetaxel alone, which likely means that TH1902 allows higher concentration of docetaxel inside the cancer cells expressing sortilin. That is leading us to a much higher therapeutic window. At this point, all we know leads to think the therapeutic window of TH1902 will be much better than the therapeutic window od docetaxel alone. It will be much wider. We know that the therapeutic window of docetaxel alone is 60 mg/m2 to 100 mg/m2. I think that the therapeutic window of TH1902, on docetaxel equivalent, could be at least 30 mg/m2 to 200 mg/2. These number are docetaxel equivalent, in terms of TH1902 numbers, it would be 115 mg/2 to 460 mg/m2.
This is based on the assumption that the MTD of TH1902 would be the equivalent of twice the MTD of docetaxel alone, and that half MTD of docetaxel alone would still be efficacious to some extent. We still don't know what the MTD of TH1902 will be, it could be more than twice the MTD of docetaxel alone. But even with twice the MTD of docetaxel alone, it would allow for a very flexible use, where toxicity should not be an issue, In fact, at this point, toxicity is low on the list of question marks about TH1902. The main question mark, and by a huge margin, is its efficacy on humans with real tumors. In my mind, at this point, this is where we have no real clue. I mean by that, that at this point in the phase Ia, we know that they are well above the MTD of docetaxel alone. So, we can assume that toxicity is not a problem, but that does not allow to assume there is efficacy. We will have to wait for the real results to know something about that. That being said, the longer the phase Ia goes on, the better the odds are that there is efficacy on some patients in some type of cancers.
jfm1330 wrote: As I said many times, the step from nude mice, with a grafted human tumor, to real humans, with real tumors, much bigger tumors and more complex tumors, is a very big step, and we cannot expect TH1902 to exactly replicate efficacy shown on mice on humans. That being said, all this endeavour is based on what was seen on xenograft mice. That's the basis, and this basis showed that on those xenograft mice, TH1902 was much better than docetaxel alone.
Also, Marsolais said in the Q&A section of the KOL presentation that they will do patient derived xenografts (PDX), which is grafting the cancer cells from an actual patient on a nude mice and after that, test different drugs on these mice to see which ones are effective and which ones are not. So with that tool, they should be able to understand better how than can correlate efficacy on PDX and on the real patient. So they have tools in their hands going forward to better understand how TH1902 works in humans on different types of cancers compared to what they see on the mice.
Also, again, Oncopeptides melphalan flufenamide (Pepaxto) is not a PDC, it's a small molecule, and has nothing in common with real PDCs like TH1902. It's totally irrelevent.
juniper88 wrote: In order to be commercially successful TH-1902 will have to have better efficacy. They are enrolling patients who are out of options. So, taxol and even other chemos aren't working anymore for these patients. If efficacy of TH-1902 is not better then those patients will die.
Most phase 3 clinical trials wouldn't accept these patients because those trials have an exclusion criteria for anyone who has had more than 3 lines of treatment. The theory is that TH-1902 would actually work better on these patients because sortilin increases as the patient progresses.
scarlet1967 wrote: I think THTX needs to pay close attention to oncopeptid's situation, their PDC commercialization seems to be going nowhere due to the mortality issues. Now they haven't clarified what is the reason for the mortality but it seems to be an element of lack of safety reading between the lines! They seems to have included lower stages of cancers in their other trials now to expand the label for their drug, some are speculating that could be the reason for mortality.
Point is if the safety is due to wider therapeutic window for various stages of cancer then high dose high efficacy approach can backfire later on causing serious issues which can't be reversed during the trial and post potential approval of the drug. So all the speculations to less go higher thus better efficacy to me is a risky approach. Late stage cancer fragil patients shouldn't be exposed to drugs with safety issues, I believe if their PDC shows better safety and even equal efficacy compared to traditional chemotherapy there is an advantage right there.
Wino115 wrote: It could be why they added in a few months to the Phase2 timeline. I think you're right about the advantage of a known toxin. If you have safety all the way to your chosen MTD ( like Kuras Menin-inhibitor) and a wide therapeutic window as THTX has suggested, then maybe you explore high/low dose. The Menin-Inhibitors are new so that's valuable. Docetaxel in tumors is old and they probably know how to use it with low vs high dose like you say. But whatever the FDA works out for TH1902, it shouldn't be throwing a wrench in the works. Add a few more patients to each of the 4 tumors and do a low (or normal taxel equivalent) and MTD. On the other hand, since the normal therapeutic dose of taxel is below where they are, they know a lot about the low dose environment, although not delivered via SORT1.
qwerty22 wrote: Scarlett brought this news to the board about the fda seeking alternatives to MTD.
https://www.fiercebiotech.com/biotech/fda-s-renewed-focus-oncology-dosing-spooks-investors-but-companies-say-they-were-ready It got me thinking about how thtx might handle this (if they had to), I'm not suggesting they have to atm. Anyway it's pretty well known how normal docetaxel accumulates in tumours. You can use that concentration as your target concentration for dosing. So rather than rely on MTD to find the maximum dose based on safety you use a tumour accumulation number to get a dose based on efficacy. You can only do this because you have the long experience of using docetaxel in patients. I'm not saying this is what they'll do, to me it's just another example of how it might help the drug development process to be using an old, well-understood chemo.
Hopefully they get tumour material and are able to measure drug (and released docetaxel) in the tumour. It will be a good number to have for many reasons. If investors were truly spooked by the FDA's shift from MTD, it would be good for thtx to have a pre-prepared solution.