Theratechnologies Inc T.TH

MTD and the FDA

[qwerty22]

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.

[Wino115]

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

[scarlet1967]

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

[qwerty22]

I think you are right safety and toxicity issues are becoming less tolerated by patients, docs and the fda so the bottom end of you're efficacy widow, the furthest from toxicity, is as important as the top end. Certainly looks like you can kill a drugs revenue potential by dosing too high.

[juniper88]

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

[scarlet1967]

I agree and I believe they should get better efficacy point is I think they shouldn't ignore the importance of safety for the great efficacy. I read somewhere they needed to use lower dosage of docetaxel from 100mg/m2 to 60mg/m2 due to toxicity issues for earlier stages of cancers. Those late stage patients couldn't cope with increased toxicity. They need to balance cons and pros for their

[scarlet1967]

Of course their technology has to work first...

[AMoschitto]

On this point, with patients who may have developed resistance to taxol based on their previous treatment history... would bypassing the MDR pump still be effective in the way they talked about in the June presentation? I went to look back at that slide but they have taken it out of the current presentation.  Curious if people here have thoughts about that as a potential disadvantage of this

[Wino115]

I have no answer for you, but I wonder if there's a clue in the colorectal study that showed despite taxel not even working as normal chemo on the tumor, it worked when delivered via TH1902.  I know lack of efficacy is not resistance. I'm actually ignorant on what causes resistance to a particular chemo.    

[jfm1330]

Resistance to docetaxel can come from multiple modifications in gene expression. The MDR efflux pump involving p-glycoprotein seems to be the main one, and the one Thera claim Th1902 allows to bypass, but there are other mechanism of resistance at the tubulin level, which is the target of docetaxel. Also, some inefficacy can be related to dose limitation, or, in other words, the impossiblity to

[juniper88]

Jfm1330, I like your actinium-225 idea. It can probably overcome any resistance mechanisms as long as it goes in the cancer cell.

[jfm1330]

Yes but we are still a few years away to see an ADC or a PDC using it being approved. It's on trial with many ADC, and that's in line with the fact that ADC needs more potent cytotoxic agents since they have a low loading rate, and also low tumor penetration and cell internalization. But if it works for ADC, it should be a killer in a good PDC system (peptide + target). On the PDC front

[Wino115]

Dies that mean the competitor will have the peptide+Actinium patent for all cancers?  Or would you still be able to conjugate it with something using different target than they use?  

[jfm1330]

There is no patent on isotopes or atoms. In the case of Lutathera, they have no patent on the peptide, the linker and the isotope. I think their patent is on the way to manufacture the PDC. I think they have a patent on use, but I am not sure it is valid since Lu177-Dotatate is used in Europe since at least 15 years. Many cancer centers in Europe were offering it a bit like a generic drug within

[jfm1330]

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

[jfm1330]

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

[qwerty22]

I wasn't suggesting wrench throwing and you're right this is about the therapeutic window and the space in which thtx can play with this drug. Things like that are as important as getting a strong indication of efficacy at this point in the process. Even though the fda is exploring alternatives MTD is still the benchmark. I was mostly just trying to plug my old, general idea that the