You basically have it SoT and I think you have captured their...

You basically have it SoT and I think you have captured their thinking.
CPPs are inherently nonselective, they associate with the first cells they come into contact with, and many other things in your bodies, and basically your body acts as a big sink for them, meaning the percent that actually gets to the desired cell or target is very very low. So basically 2 options as SoT explained, better release or targeting (or a combination of both...this what I believe will be needed). PYC appears to have made good progress on finding a better CPP compared to the current versions, so they are moving the needle, little by little. The issue with the cell based assay and the animal xeno-graft model, is that there is no sink effect, and this is why they do it, and this is why other CPPs also work here, although PYC's is looking more potent. Richard even states that the animal model was a "very low bar" and just to show function without the need to account for all the other issues. So what are the other problems with CPP use, well they deliver to almost all cells (of course it varies a bit and also where the cargo is delivered varies a bit) but basically you get off-target effects (bad). Now they chose Myc, my guess in part, because Omomyc, surprisingly appears to have no effect if it gets into normal cells. If true, and it looks like it is, that would be great, dont have to worry about the side effects from off-target. This doesnt alleviate the sink effect, but at least if it is accumulating in other cells it shouldnt do anything bad. So next is getting it to the desired cell, and this is where blood cancer comes in, since if inject IV, blood cells will be first to see it, so largest dose should go into those cells, or so the thinking goes. So easiest path forward, and of course there is a need, although many other companies are using this same logic. Because of this sink effect SoT, the dose is going to increase significantly in the IV animal, so dont get to wrapped up in the 1uM dose, that is more cell experiment related, but for all scientific presentations, and basically in drug development at all, if it isnt under a 1uM in the cell-based assay, it is a nonstarter...most antibodies or small molecules have pM to single nM IC50s at the cell-level before moving to animal studies, of course exceptions, but just for relative reference. The assays they run have different detection windows, basically the sensitivity of the assay to determine relative differences, and it is not clear how much better their CPP is over others (3-5fold, 10fold maybe at current??...if only the CPP approach, no targeting functionality, I think it needs to be 100fold plus to even consider next steps or broad use, but whatever, blood cancer may not need that level, so it may be the ideal starting point for validating this).

One more aspect, certainly targeting specific cells or cell populations is the future of medicine, versus the drug just going everywhere, and this is shown by ADCs and PDCs and other targeting vectors that have been created, and there are 100s of companies working on this, to deliver all sorts of things and using different vehicles to do this. They do not all get stuck in the endosomes like CPPs, so there is much more of a landscape then sometimes is suggested on these forums, which is fine, cause while it is important, it has no bearing on the short term issue of validation at PYC of their concept and strategy. I think they are on the right track (which I cant say I have said in a long time for this company), but the time horizons are long. They have a nice cash runway, and hopefully that allows them to see how far they can get, and that will be important for the next CR, which hopefully is for taking something to the next step of preparing for a clinical trial (2-3 years away from even being able to start one if everything went well). I hope that if they can validate their CPP and show in vivo functionality, then keep working on own internal pipeline, but also I hope they entertain the idea of non-exclusively licensing it out to other companies. They could give it to companies (under an MTA with no commercial rights) for companies to test drive with their favorite cargo, and if it was validated, then the company would have to come back to PYC for a license (nonexclusive or exclusive for the specific cargo-target). This way they could license a single CPP out over and over again, for various cargos, and have these efforts run parallel to their own internal work. Guess we will see.

Richard is good. If you go back and look at my posts, I said many years ago that PYC should get rid of Nick and Paul and all they need is Richard. I got some great responses to that that I was an idiot and other things. Now Nick is gone, Richard is CEO, and hopefully Paul goes back to academia where he belongs (he is a follow the next hot idea guy or has a new idea every couple of years but never finishes the past one, great for grant writing, but terrible for biotech....and I believe this is why PYC has changed strategies so often over the years). Richard has set things straight and I think has the best chance of success, so that is a big plus for PYC nowadays.

I will not invest in PYC, I admit they peaked my interest years ago, but it didnt work out the way i hoped and I didnt get confidence in it at the time. Nowadays, my own strategy has changed, now investing in Series A's from startups that are recently spun out from universities, it is just the opportunity that I have, so I have only a few share holdings of public biotechs anymore (do have the big boys however). So I AM NOT trying to influence PYC's share price at all, I honestly could care less. The HC community specific to PYC is interesting, so I check it once in a while, as I check alot of forums. Gotta catch a flight!!!