RE:RE:RE:RE:RE:RE:RE:Letter What you are stating is what all the original research around Sort1 done by an assortment of different academic research institutions showed --there was one published one pancreatic, one on TNBC, one on ovarian and one showing sort1 being "high/low" correlated with survivability. All that original research was what they used to theorize and justify to the FDA that targeting sort1 was valid and that it would make sense for late stage given that fact, and the fact sort1 internalization allowed them to get around various resistance mechanisms (theoretically). It made sense to go for those patients where nothing else worked for that reason, and for commercial reasons. If you saw success there, it would be ground-breaking.
But if you look back at the release they made and published back in November or October, after they actually studied a large sample of real human tumor biopsies, it actually showed that sort1 levels were high across all 4 stages of the various cancer tissues they had categorized and that they studied. So those samples were real humans, scored by various oncologists as to what stage they were, and they stained them for sortilin and saw it got to the mid-high or high levels really quickly. Take a look at the one slide the published showing the cancer stages and the readings. It's quite clear sort1 was being overexpressed in way more than just stage 4.
To me, they should give it a rethink and go where the data tells them. Maybe that would be enough to convince someone to partner with you to do a test on very simple stage 1 or 2 patients doing normal docetaxol versus a set doing docetaxol via TH1902. Same with carboplatin for ovarian. If you could show statistically significant results that were well ahead of the normal SOC, but with much better safety signals, you'd have a very commercial product. It would be ok to give away some of that economics for someone designing and paying for it. I realize this thought is way ahead of where they are and their data-based conclusions need to be figured out, but the data definitely showed sort1 was there across the stages of cancer, not just in late stage, last chance situations. Go take a look at that paper on their website and just look for that one chart that shows the cancer stage graphs.
PWIB123 wrote: I thought I remembered reading tumors that were further along expressed greater Sortilin and that was why they were targeting late stage patients. I thought too, that helped the idea that there would be more docetaxol targeting Sortilin in cancer cells rather than healthy cells, like in the eyes. I do remember reading that certain types of tumors express more Sortilin than others, but I still had this idea in my head that Sortilin increases as the tumor grows and metasticizes. I hope I'm wrong on that, because it sure seems like the very sick patients THTX is trying to work with does limit their ability to get good results quite a bit.
I have no science background, and I find it scary from an investment prospect that our scientist here seem to be mostly aligned that THTX needs to just kill TH-1902. It sure seemed like Paul's letter was pointing to a different path forward but still a path forward. I'm confused on the difference between how to describe the "platform" versus a specific peptide/cancer combination when Sortilin remains the target. There were at least partial results with TH-1902, so it seems logical to think that there is a pathway forward if different. Honestly, I have no clue about the science, so I'm trying to absorb as much of everyone's understanding as possible.
Wino115 wrote: They've been pretty data driven throughout the process, so I think you're right. The fact outsiders are on the team too is a positive. I think no one here ever de-risked the efficacy part, so you are right. The only thing I ever checked off was some of the safety issues being de-risked. I still think those are probably de-risked to a large extent --there was never a treatment related issue that stopped moving forward. It was getting that efficacy to "override" whatever normal SAEs there are, which are still rough on these type of patients. In the end, you need to see positive efficacy results as all cancer trials have SAEs of one sort or another that the drug is introducing into a "risky" life situation.
As I've looked back on it, I wonder if the drugs "place" in the treatment regimes is a bit sooner. I realize the original idea pitched to the FDA was that sortilin expression has a positive correlation with the cancer stage --the worse off the patient, the more it's overexpressed. But then in November they showed the research on expression levels in a whole bunch of human biopsy tumor samples based on stage of cancer and it showed the surprising conclusion that this wasn't the case. In fact, sortilin expression was very high in those 6-7 cancer tumor types they studies regardless of the stage of cancer they were in. The correlation was only slightly higher as stages increased. Those slides showed it became pretty high, pretty quickly as the cancer took hold.
The implication is that they shouldn't just deal with these incredibly sick, incredibly hard enrollees where it's likely way harder to both see efficacy and to keep safety issues down. If I were them, I would picke 3-4 cancers and get patients in stages 1 to 4+ and run them through two cycles over 6 weeks with the new regimin and see what the scans tell them. I'm not a scientist, but I think you'd probably see lower safety issues and at least have the same shot to get your toxin in there at a higher rate, it may be beneficial. Their own data showed stage is not correlated with sort1 --they should explore that and take advantage of it. At worse, you might find that for your normal stage 1 or 2 taxol related therapy, on a like-for-like controlled basis, this is a better way to do it --way less safety issues and more toxin in the tumor. Use it at stage 1 or 2 in that case. You could do a taxol alone versus a taxol in PDC as a trial and see if it's multiples better like they did in the carboplatin versus carboplatin + TH1902 where they saw 2-3x more efficacy when they did that.
There's a lot of data driven ideas they can trial pretty simply and fairly cheaply and then go partner up with someone to bring it to commercail stage. Just need to answer those questions around whether they did see parts of the POC, like the multiplier working, there being low bone marrow content, no neutropenia, etc... The original idea of it being a lot safer given internalization and getting more in the tumor. Just play it earlier in the cycle.
qwerty22 wrote: It would be great if they could make a data driven decision based on clinical evidence. My expectation is that it isn't that clear and so there is likely always going to be some element of suck it and see. Ultimately these are empirically driven processes and so you just have to try it. I guess the FDA (and their own professionalism) should be the brake on making overly rash decisions.
The difficult thing to square is the repeated success in multiple animal models not transferring over to patients. Not just that but the preclinical paper they put out last year, I thought, really tested most of the important steps in the MOA and passed. If they don't have a clear answer as to what's going wrong then it must have them so frustrated, both believing there is some technical path out of these at the same time as seeing the increased risk. When you are hitting your goals clinical is clear, when you are failing it can be a nightmare getting to the bottom of it. What I most doubt atm is they have a clear understanding of what the issues are, it's very possible the clinical data won't give them that. I'm not against them having another go with th1902, it's worth put a little in to try rescue all that potential value but we shouldn't fool ourselves about the prospect.
jfm1330 wrote: The analysis of the TH1902 program is quite easy to make, unless they have data showing that it could work in some sub group in a cancer type, or introducing biopsy confirmation of sortilin high overexpression in a new protocol, it should be dropped. And even with the addition of biopsies, I am not sure it would be worth continuing it.
As I wrote previously here, there is no targeted PDC approved in which the warhead is a cytotoxic drug. The one that went the furthest on that path was Aeterna Zentaris' Zoptrex, in which the warhead was doxorubicin, and it failed, despite going up to a pretty large phase III. One of the possible explaination I found for Zoptrex failure in humans was that the linker was not stable enough in the microenvironment of the tumors, outside cancer cells. Zoptex had glorious results in animal models like TH1902. The key is how it behaves in real patients with complex tumors, not a xenograft of a single cancer cell line.
Remember, one of the main difference between sucessful PDCs using radionuclides like Lutathera and candidates using chemo drugs like TH1902 or Zoptrex, is the fact that the former has a stable linker, not a cleavable one. This eliminates a big variable from the equation. No need to have a linker stable enough in the bloodstream, but not stable inside the cells. PDCs with so called selective linker will leak drug in the bloodstream. It's unavoidable, while radionuclides PDCs with a very stable linker won't leak the radionuclide at all. So the toxicity is much easier to control that way. On top of it, imaging capacity allows to exactly know where the PDC is going in the human body, in tumors, but also in healthy organs.
All that to say that I reiterate what I already wrote here after the news on TH1902. If their data is showing that some of TH1902 is going into human cells expressing sortilin, which is the critical part of the proof of concept if you want togo with a new PDC, then they should go back to preclinical, ideally with the radionuclide chemistry. It already exists and it's patent free. So do the preclinical work on that and try to find a partner to push it forward. It would eliminate the Trodelvy blockbuster scenario, but it would still have a lot of value, even with a partner involved.