RE:RE:RE:RE:RE:RE:RE:Thyroid cancerI will make this argument again, at 300 mg/m2, TH1902 is only 1.3 times the maximum tolerable dose of docetaxel. So even if the concept would not work, i.e., TH1902 would not enter any cells and would be slowly degrarded in the bloodstream generating free docetaxel that would then diffuse passively in every cell and be progressively be eliminated by the liver, it would likely not be more toxic than injectcing the MTD of free docetaxel because, again, TH1902 would behave like a slow release system, The maximal concentration (Cmax) of free docetaxel would likely be lower with TH1902 at 300 mg/m2 than it would be with injecting the MTD of free docetaxel. All that to say that a much higher toxicity for TH1902 at 300 mg/m2 is very unlikely if you compare with toxicity of the MTD of free docetaxel. One advantage of TH1902, is that it uses an approved cytotoxic drug for which the toxicity profile is well established and the dose is only 1.3 times the MTD of free docetaxel. The potential downside is that maybe it's not powerful enough and too many advanced cancers can be resistant to it, even at 1.3 times the MTD.
The only unknown really about toxicity, is related to the proof of concept, which we don't have yet. But let's assume we will have it, and that TH1902's concept is valid, and that the PDC is internalized by cells expressing sortilin, and the more they express it, the more TH1902 is internalized, thus concentrating free docetaxel inside these cells. Then, higher toxicity would come if some normal tissue express enough sortilin that it would end up with a really high concentration of free docetaxel inside of them. That would be the only way at 300 mg/m2 dose, the actual therapeutic dose, that higher toxicity of docetaxel would be possible in healthy tissue.
On a similar subject, as I said in a previous message, I talked with the doctor that gave me a treatment with Lu177-Dotatate two weeks ago. The day of the treatment I spoke a bit with him, and asked him about what was going on with Actinium 225, a radioisotope emiting stronger alpha radiations that could be used wiith Dotate. He told me that there was a problem with that, and that Ac225 was causing problems with the salivary gland, damaging them and leading to dry mouth. It was the first time I heard about that. So back home I made a quick search on that, and it ended up that the problem was not with Ac225-Dotatate for neuroendocrine cancers overexpressing somatostatin receptors. It was for prostate cancers using Ac225-PSMA-617. So the salivary glands are binding a sufficient amount of Ac225-PSMA-617 to cause problems, but I found nothing about Ac225-Dotatate. So it seems somatostatin receptor is not expressed enough in salivary gland to cause problem, while with PSMA-617, the uptake is higher, both specific to the target receptor and non specific.
So all that to show that toxicity with PDCs can occur if it works and the uptake is too high in a healthy organ, likely because of the level of receptor expression. Note that PSMA-617 is a small molecule ligand, not a peptide, but the principle behind the drug is the same as for a PDC, which is ligand affinity to an overexpressed receptor, the ligand being able to carry a cytotoxic payload, in this case Lu177 or Ac225. The non specific uptake they talk about in the article could be related, in my view, to the fact that PSMA-617 is a small molecule, not a peptide. Big peptide cannot enter cells in a non specific way. But nonetheless, this example shows that toxicity could occur because the PDC works in entering healthy cells expressing a higher level of the target receptor. Sorry if this is too technical.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406477/
Wino115 wrote: Here's another poster today analysts are excited about. It's for CytomX who partnered with Bristol Myers for a mono of a Probody CTLA4 and a combo CTLA4 and Nivolumab in advanced cancer patients. These are Phase 1 numbers (mono, combo):
Patients (n): 39, 64
ORR 0%, 16%
Dis Control Rate DCR: 26%, 38% (FYI - it's CR/PR/SD total %)
All AEs: 62%, 86%
Grade 3/4 AEs: 23%, 38%
Discontinuation AE: 13%, 19%
Grade 5 AE (death): 0% 1 event (sepsis death)
There's a clear trade-off between more response and efficacy and more AEs. If you can be the outlier with equal or better efficacy and next to none AEs, you would stand out I think.
Wino115 wrote: We will find out, and it is a very dynamic sector simply because the ability to change the life, even if just for a minor proportion of patients and for a limited time frame, is essentially a priceless trade and thus very valuable commercially.
I think one very clear thing for us to keep in mind, when I see all these other ADC and various other cancer approach results, the SAEs are usually quite severe. Some even have deaths in the trial. The potential for delivering a chemo that is well above the normal dose because of the accurate endocytosis via sortilin and the ability for it not to get spit back out by the MDR efflux resistance pump is really very valuable for us. Safety is that much more --- I mean multiples better --- than what I see in these other trials. The other trials usually have around 20-25% of the population that gets more serious SAEs than what we've seen --SAEs that knock them out of the trial. Most have at least a death or two, which we hope not to see any.
The ability to then throttle dosage and schedule is another aspect TH1902 may just have versus anything else out there right now. So I don't think it's a PR stunt for Levesque/Bellevieu/Marsolais to say they are a first-mover in a potentially "game-changing" approach via a PDC targeting Sortilin. They just need to show us all some efficacy on a wider and deeper patient pool.
Just so you can see what I'm talking about, here's the numbers for all the metastatic NC Prostate tumor trials going on from that Daiichi trial I mentioned earlier today. These are the competitor numbers (Daiichi hasn't released anything beyond that ORR). The other therapies are from Exelixis, MacroGenics, Arcus, Novartis, Merck, Sanofi (they don't all have all these numbers reported).
Grade >=3 TRAEs% 56% (74/132), 50% (43/86), 35% (6/17), 28% (150/529), 40% (42/104), 18% (68/378)
Discontinuation due to AEs: 21%, 7%, 12%, 18%
Deaths due to TRAEs: 1%, 1%, 0%, 1%, 0%, 2%
Really shows you that if we can establish a super safe profile (hopefully), solid response rates and clear efficacy, it will be a game-changer in my opinion.
Lee430 wrote: Seems like most news feed I get these dasys has some new promising breakthrough cancer therapy article almost every day, It does make me question whether I am as Wino said “the genius or the chump here”