Theratechnologies Inc T.TH

RE:RE:RE:RE:RE:RE:The Sort1+ Platform

[jfm1330]

I was obviously talking about an hypothetical Ga68-DOTA-TH19P01 imaging PDC, not the approved Ga68 Dotatate for neuroendocrine tumors. Sorry.

jfm1330 wrote: With the actual situation I flushed my ignore list to get as many point of view as possible on the actual situation. I thought maybe some people changed since a placed them there. As I can see this is not your case. If one read my message properly,he will see that I talk about preliminary work and small PET scan machine were you can do a scan on mice. So my message was clear. I was talking about preliminary work on mice before anything else, and the thing is that this step can be done very quickly if Thera would be commited to it.

But establishing relationships with researchers specialized in this field in Sherbrooke and Quebec City would also help Thera understand what is needed to start clinical trial on humans with radionuclides PDCs. With Ga68-Dotatate, you could also inject it to a bigger animal without cancer, an animal genetically closer to human, like a relatively small pig or a monkey and see where the PDC is going in the body without cancer. It would be the best way to get a good idea of what would happen in the human body, where the normal sortilin receptors are, hence predicting toxicity issues

But hey, you proved again that you are a bad faith actor here. You have scientific background, it's clear, but you don't use it properly. So you are back on my ignore list. In my situation I have no time to lose arguing with a bad faith person that put his ego in the way of an honest discussion.

qwerty22 wrote:

Sure just attach some radionucleosides to the peptide and start pumping it into patients. Easy as. I can't see the hospital people at CHUS or CHUM asking if this has gone through the whole R&D and preclinical process. Can't see them needing to develop an SOP, develop the parameters for successful, repeatable conjugation, test it to the hilt before giving it to patients.. Can't see a patient if they got sick asking if the molecule had gone thru the same testing process that every other molecule goes thru before being given to patients, no real lawsuits coming down the track. Just co-opt those hospital departments and away you go!

Just because some hospital departments are set up to handle these materials does not mean that THTX can turn those depertments into their preclinical testing facility. It all sounds lovely but a bit of a fantasy.

jfm1330 wrote: I will repeat myself for maybe the tenth time about that, but the ressources to do a Ga68-DOTA-TH19P01 PDC are available near Montreal, in Sherbrooke, at CHUS. That's where I go for my Ga68 imaging scans. They put the Ga68 on Dotatate in house. Ga68 is emitting only positrons, not radiations. It has very low toxicity. The only thing I don't know is if they have a small PET scan machine for small animals like mice, because half life of Ga68 is only 1 hour, so you would need to do the scan there. If not, they can replace Ga68 with Cu64, which do the same thing, but has a much longer half-life (12.7 hours), so you could have the PDC made in Sherbrooke, and drive to Montrea lfor at PET scan at McGill.

Look at this page, Sherbrooke University is offering the sevice with Ga68 and Cu64. I am quite sure it would be easy to do preliminary work with them. They have the expertise, 2 hours by road from Montreal. And again, in Quebec City, they do the same, but with Lu177 for therapeutic use and they run clinical trials. If Thera would really want to do the preliminary work at relatively low cost, the ressources and expertise are close to them. They just need to reach out.

https://www.usherbrooke.ca/medecine/recherche/notre-caractere-distinctif/infrastructure-et-plateformes-de-la-recherche/synthese-de-peptides-et-sondes-dimagerie

juniper88 wrote: If the toxicity to the eyes is because the eyes have high sortilin expression and the docetaxol is entering the eye cells to the extend that it is causing the side effects then why would a more potent payload that destroys the cell and surrounding cells have less side effects?

Unfotunately we don't have any information of what is causing the side effects in the eyes and how serious those side effects are.  We can only speculate.  I would love to see them putting the GA68 as a payload to actually get a picture of where the payload ultimately ends up.  That would further the science a lot.  I doubt it though that Thera has the resources to do this.

jfm1330 wrote: Sorry, if lower and more frequent doses bring more TH1902 into cells expressing sortilin over time, it will do it for all cells expressing the receptor, not only cancer cells, so I don't see how you increase efficacy without increasing side effects. Unless side effects are related to free docetaxel. But hey! Only 10% of free docetaxel Thera told us. What is this10%? We still don't know.

Also, I don't understand why some are wondering about half-life now, Thera gave us an unclear data of 10% of free docetaxel in the bloodstream, and many thought it meant 90% of docetaxel ended up in the sortilin expressing cells. All that without knowing what this 10% value really was. AUC, Cmax? Nobody really knew. Also, many forgot that as soon as free docetaxel is released in the bloodstream, it passively diffuses into every cells it gets in contact with. So passive diffusion quickly clears the bloodstream from docetaxel. So even if the 10% value was area under the curve (AUC), i.e: total free docetaxel measured over time in the bloodstream after injection. It would not represent the real amount of free docetaxel released in the bloodstream, since part of it diffuses too quickly into cells to be meseared, unless Thera had some compensation factor in their calculations to account for it.

That leads us to the other potential problems that I pointed out here before. First the dimethyl glutaryl linker. A very simple ester linker when you compare with linkers used in ADCs that are far more complex. The question remains about the selective cleavability Thera claims this linker has, especially in humans. We have no proof of that in humans. The other potential problem is the stability of the peptide (TH19P01) within TH1902 (PDC construct). TH19P01, is made of 16 natural amino acids, with natural peptide bonds all easily cleavable by human enzymes (peptidases and proteases). Maybe within the PDC construct the two linkers/docetaxel molecules are stabilzing it through steric hindrance (blocking 3D access to enzymes), but Thera never explained why TH1902 is stable enough tohave the claimed 6 hours half-life in mice.

Wino is talking about other chemo drugs, about siRNA, but again, not about the obvious solution Lu177-DOTA and Ga68-DOTA. Why go with a proven solution and known chemistry that also gives you the ideal imaging tool to easily and properly screen the patients to only treat those suited for the treatment? Also, Lu177 and Ga68 does not need selective cleavage from the DOTA linker.

So proven cytotoxic agent overcoming all chemo possible resistance, no selective cleavage needed, the isotope needs to stay on the linker, and easy imaging tool with very low toxicity that would be of enormous help in the development and then for patient screening once the drug is approved. Also, Lu177 PDCs proven to be the only PDCs that works in humans, and showed no occular side effects. So why think about developing it? Let's stick with chemo that does not work with PDCs uptonow, or let's try to break totally new grounds with enormous siRNA molecules...

Wino115 wrote: The points from JFM, Sabbo and Juniper are important and they really have to discuss this in reasonable depth once they get revised protocol approved. For them to pause enrollment and not outright stop it there must have been something in the totality of all the data collected and what others may know about PDCs, taxols and other dosign approaches to at least have some belief that they can use some part of the function they've observed to the benefit of efficacy. Maybe it's that half life issue that is advantageous in being able to dose more frequently and not take a 3 week pause in getting the chemo agent in to the tumor. I'm totally speculating, but that is the kind of disclosures they need to make to investors once they relaunch the trial. Give us the full logic --what was seen and why a different approach to get from only seeing 2-3 signs of efficacy to something more robust and how dosing is an element they can play with to try to get there. They need to explain to us the parts of the concept they "think" are valid and functioning enough in humans to theorize there should be efficacy with that type of chemo dosing regimin and why. 

It's also encumbant that if they do think it's the chemo, that what they're seeing in their lab with other agents might lead to something more effective like what Sabbo and JFM are speculating on. If there is, that can be the basis for a partnership with someone who's taken those toxins further down the road and is looking for some way to target cells better. But they need to show that with data if it's there, which no one knows at this point.  They've talked about SN38 and SiRNA so give any insights if there are any.  That may be asking for too much, but the point of trying to validate the concept of the peptide and target would be valuable if there's any ability to actually do that from the data. 

Last point, I think their  trial is not a whole lot different than any other trial where you are trying to help the very late stage, heavily treated and resistant enrollees. All of those would face the same difficulties since it's just what happens at that stage unfortunately. I would assume there is always a mix of types of enrollees at the larger cancer centers in cities - some will try but end up deciding to stay at home with hospice and some will stay in centers doing everything they can to get through a trial. And you get everything in between. The unfortunate truth is there aren't many options left at that point and it would only be through a trial, and this is one of them some may try. I would think one advantage would be the side effects and safety issues have all been reported as still well below SAE3 levels. The issue is the robustness of the toxin doing it's thing on the tumors, not so much any treatment effects causing disenrollments.  Anyway, it's incumbant on them to really explain it all in a reasonable depth so there can be a far better understanding based on that collected data and their reasonable theories on the restarted trial. 

 "If they treat patient with 1x docetaxel of TH1902 once weekly, the toxcity might be weaker and efficacy might be better."