Wino115 wrote: All very good questions and you, as well as all of us, are right to be skeptical until we see the human data…coming shortly! You’ve identified the biggest problem —size— with trying to put too much in on a 1a that is really only there to assess safety and dosage level. We get a dosage, but everything else is just secondary bits of data that can help us see if the whole POC of the peptide and the chemo-bomb is working. Maybe they’ll talk some of the pharmacokinetic, some signals on POC or efficacy. I’m hopeful there will be something else beyond just MTD, but maybe not. As you say, in something this small you actually could be really unlucky and get nothing but Stage 5 prostate or lung and no mTNBC or ovarian. It’s just the luck of the draw. I would certainly hope they’d get at least one or more mTNBC given the expressions there. In fact, since trying to understand the sortilin/efficacy correlation per FDA request, you’d hope they built in some level of tumor type distribution or at least MD Anderson would request and push the other partners to find a few candidates with differing tumor types.
But we can use all the preclinical and research to answer some of these questions you pose though and move our own “probability” view upwards or downwards. There is independent objective science done on the topics you mention, and it’s not all just what THTX and UQAM have done. Here’s a few facts for you to consider to maybe increase your optimism a tad.
- So, is it possible as we learn more that SORT1 is not really as highly expressed in these cancers as what is assumed right now?
I don’t think they are doing this trial based on an assumption SORT1 is highly expressed in certain tumors. There is valid scientific evidence from multiple medical researchers that it is highly expressed on the cells in certain cancer tumors based on a large number of actual cancer tumor patient biopsy data, not just cultivated cancer cell lines. You can look up these PDFs online if you want to read them yourself.
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Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion, Oncotarget, 2015, Severine Roselli, Jay Pundavela.
They reviewed all the studies based on cell lines that showed sortilin expression in colon tumor cells, melanoma, prostate, breast tumors. But their study was to see if this was the same in breast cancer using actual human tumor cells from patients. They studied 318 breast cancer patient tissues and 53 normal breast patient tissues.
Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer , BMC Cancer, Karoline Berger, Sara Rhost, et al.
They studied 560 tissue microarrays from randomized breast cancer patients to evaluate aggressiveness of cancers expressing sortilin.
Overexpression of sortilin is associated with 5-FU resistance and poor prognosis in colorectal cancer, Jour of Cellular & Molecular Medicine, Sabrina Blondy, Hugo Talbot.
Their study used human cell lines for tumors and then also obtained 6 primary cultures from humans suffering from colorectal cancer at different stages.
That’s just a few articles showing outside labs validating with data and facts based on actual human tumor cell biopsy tissue versus normal healthy tissue samples. There’s a slew more of these and you can find them in the various biographies.
I’m not sure why sortilin wouldn’t be highly expressed in the advanced cancer tumors they will be studying. All the science says it is. Now, could this first 1a be a slew of bad luck, as you say, and they get no one with a tumor significantly over expressing it. Absolutely, that could happen with a small probability. But I don’t think that would actually stop it as this would be a much more important factor for the basket trial and Phase 2 and not dose escalation studies. It’s not quite as big a problem for reading safety signals and figuring the MTD. In fact, those would be the kinds of patients to perhaps show the worst symptoms since the chemo-bomb is not going off in the tumor cells and is circulating around causing havoc for a few hours. They would be the toughest to get to that MTD and if you got to the highest level (which is this week), then you have one heckuva safe drug for these purposes since the receptor didn’t even get much. So you won’t see a lot of efficacy, but for anyone with SORT1 over expression like seen in the human tissue samples, you’ll certainly get a lot of the chemo into the cell.
- Or is it possible that even though the Taxol now enters the tumor it doesn't actually do much (seems unlikely).
This would be a worse situation for them and also a possibility. I would assign it a fairly low probability simply because the chemo is used now and not targeted, but only spreading it throughout your body to kill any newly forming cells. So it’s potency even in a rifle shot approach of entering all growing cells shows it works. I think we saw there was another study recently where someone had a target-type ADC and it validated taxol doing well even when it’s just deposited in the neighborhood of tumor cells. It was posted here within the last 4-6 weeks. So the idea is being done elsewhere, but with different targets (I think that target was a lot less over expressed than SORT1 and it worked ok for them). So I put this as a highly unlikely probability.
The one you didn’t put which is the real issue that could create a return to the design lab is, what if the peptide doesn’t target SORT1 very well, missed a lot of it, and it doesn’t really get internalized like in the pre-clinical, so just has very little efficacy because of the mis-targeting, bad cleavage, low amount of the overall chemo actually getting to on to the tumor cell. This would be the most negative thing in my mind. That’s why JFM and Qwerty have said just seeing the POC that sortilin is a plentiful target and the peptide does bind, get internalized and drops the chemo is really the POC that we need to see. The toxin working POC is not that important since we know it works. It’s the peptide and ligand we need to see work — then we have a highly effective PDC —all the parts of it work.
Why should we believe it works? We have seen it gets internalized very quickly —in a matter of minutes not hours or days. We have seen that it worked on colorectal where taxol has never worked at all very well —so that leads you to believe sortilin is expressed in advanced cancers and receiving the TH1902 peptide. We all know, human environment is different and that’s what we’ll learn.
So I hope that provides you some more data to put around your own skeptical view, which I’m not trying to dissuade you from. But I do think you should take into account the scientific trials and consensus around sort1 being both expresses, important to cell elasticity and tumor metastases. These aren’t THTX’s ideas and assumptions, they are based on the scientific data coming from experiments around these things. Could it be wrong? I guess, but it seems highly improbable when numerous medical studies have shown otherwise.
On your other question — I believe in Phase 1a if you hit your MTD early in the trial (meaning there were dose limiting toxicities seen and you stepped it down a notch), you’d only have 15 patients. If you see no DLTs and you go to the max they have specified, it would be 25 patients. Given we are at the highest level Oct 6th and haven’t heard anything, we should be at a minimum of 19-20 patients and moving to 25 at the end MTD dose if next weeks is safe. Then you do the 40 and maybe based on results they’ll change that around or expand it. The big trial will be Phase 2 in order to be powered for statistical significance. But cancer trials aren’t like NASH or COVID trials where you need high 100’s and 1,000’s of participants.
Hope this helps you get your head around the probabilities and provides you at least a glimmer of optimism!
juniper88 wrote: Personally, I am not feeling very optimistic about the trial. From what I understood (and what PL has mention before) if there is a strong efficacy signal then they will share it will Wallstreet. Which tells me they don't have a strong efficacy signal yet. The question is why? When you look at all the different cancers and the percentage of patients that over express SORT1 (for example, ovarian cancer 90%+) then it seems to me plausible that at least some would have highly expressed SORT1, or did THTX just get extremely unlucky with enrollement? So, is it possible as we learn more that SORT1 is not really as highly expressed in these cancers as what is assumed right now? Or is it possible that even though the Taxol now enters the tumor it doesn't actually do much (seems unlikely).
Also, if TH1902 is safe for patients with SORT1 not over expressed but not efficacious , then why should we assume that TH1902 is efficacious in highly over expressed patients just because it is safe?
Frankly, it would be pretty eye opening just to say our PDC was safe when we delivered 4x the normal docetaxel dose into solid tumors across 4-5 cancer types. That's pretty astounding news in and of itself when you think of the implications those that know oncology would surmise.
What good is 4x delivery of the normal docetaxel if it does not produce efficacy? How many patients would there be in the Phase 1a part of the trial? None of them had highly over expressed SORT1? Did Mr. Murphy return.
Sorry, just asking honest questions to things I don't seem to be able to connect the dots with.