RE:RE:RE:Some more random thoughtsYep, the market has not liked the uncertainty that continues around the trial and it's crushed our investment value over the last 4 months. It's to be expected, so we read the tea leaves. Here is one from the discussion a few weeks ago that hints the first 3 patients at 300 were fine through at least one cycle, if not two. I would think if they've continued on through April/May, those initial 3 will have gone through at least 2 and maybe 3 cycles. That information will be very, very helpful to discuss with investors. But, at least we do know the 300 dose didn't have any SAEs for it's initial cycle with those 3 patients, whatever that's worth since we don't know what kind of tumors they were or what shape the patient was in.
I am hopeful we get a further read at the B&B conference next week and then the annual, so that by the time they finish and jump in to 1b, they have plenty to tell us around the data so we can start to just eliminate the opacity. I really do hope they do an updated KOL with a few of the investigators once they have some meaty data to share and maybe some anecdotes.
From transcript "
Currently, we have completed the 300-milligram per square meter dosing regimen, equivalent to 1.5 times the indicated therapeutic dose of docetaxel alone for three patients with TH1902, and are nearing the conclusion of this stage of the trial, and establishing the recommended Phase 2 dose." qwerty22 wrote: I think that's a good summary of the situation. There's not much guessing you can do in advance on some of the issues that really matter here you just have to wait for the experience of dosing patients to shed light on the situation. One thing I thought about is toxicity in a tumour and healthy tissue are measured in very different ways. So purely as a hypothetical, toxicity in an epithelial derived cell in the eye might be measured as blurred vision where as your desired toxicity in a tumour might be measured as shrinkage of the tumour by more than 30%. How much drug you need to penetrate the cell to get those two effects might be very differen5 and way above my pay grade to speculate on. The best measure here is empirical data. The rationale for success with th1902 and SORT1 is the same as with every other targeted (ADC) drug. Deregulation of the protein and it's over-expression makes it an exploitable target. So the basic rationale is solid hypothetically. The ongoing good preclinical work points to greater potency for th1902 than docetaxel in certain settings, that's a further good solid foundation. As SPCEO says though exactly where the balance between toxicity and efficacy lands is the true measure of the commercial viability of the drug and we just need to wait and see for that.
Just some basic science as I understand it. It seems Sortilin expression is largely associated with cells that are derived from epithelial cells. Turns out neurons are derived from specialist epithelial cells hence the abundance of Sortilin. Lots of cells and tissues are derived from epithelial cells so may produce toxicities so as SPCEO says expecting no toxicity was always a stretch. I'm not suggesting expect lots of toxicity just that it's fine for it to be a issue that needs to be dealt with. My amateur guess is that some of the same tissues that docetaxel shows toxicity to will show up in th1902's toxicity profile but given the different properties of docetaxel and th1902 that the patterns of toxicity could be different. SPCEO I think it runs a lot deeper than just how much drug is floating around in the blood. These molecules have different properties and that is likely to be at the heart of the balance of toxicity versus efficacy more than just how much is in the patient. It's hard to guess on that in advance though
My view is we are in the darkest hour before the dawn. They were obliged to discuss the toxicity at 420 to explain how thing were to proceed in the short term. And yet they've said very little about what's happening at 300. That leaves the impression the story is dominated by toxicity. Either that is true or it reflects the moment we find ourselves in. I tend to think it's very possible it's the later.
jeffm34 wrote: The bar for approval of TH1902 is actually fairly low. It either has to be slightly more effective than docetaxel alone or as effective but fewer adverse events. I don't think efficacy is going to be an issue with cancers that have high sortlin expression. TH1902 will accumulate docetaxel in higher amounts in those cancer cells even likely at a lower equivalent dose. (unless there are stability issues in the blood) Going with the 300mg dose is not a set back or a disappointment. They don't need a high dose with a targeted therapeutic. The hurdle to overcome has always been what will happen in healthy cells that also express sortilin. TH1902 will also accumulate docetaxel in higher amounts in these cells as well. There is lots of room to work with dosage levels. Even going with a lower equivalent dose over longer periods is likely a viable option that would provide efficacy with manageable adverse events.