qwerty22 - (12/7/2022 10:43:20 AM)
RE:RE:RE:Open Label?
I think you might be over-optimistic that science will come up with the answer here. Palinc is right they might not move forward but if they do they might still be mostly doing it thru guesswork. Mostly looking at what worked with others. That might be fine purely on the basis that the reward for reactivating the program is so high but it would likely have a high risk of failure. My instinct is that if they are going to solve this with science then that's more likely a months/years project rather than weeks. But who knows maybe the answer is close at hand.
I've been trying to put myself in their shoes. I mostly expect there is a huge sense of disbelief. The preclinical was solid. They went through multiple steps to show the basic MOA was at play here. They did enough expts to show Sortilin was being engaged and the PDC being internalized even in resistant scenarios. As JayJay pointed out earlier the toxicity is another clue that in the patients the PDC is doing it's thing just unfortunately in healthy tissue. The absence of neutropenia (assuming it isn't showing up) would be telling. This is a really fat signal in docetaxel treatment, you'd expect it to show up in even a small number of patients if this was purely docetaxel-like toxicity. If it is absent there is some suggestion the PDC is discriminating between certain tissues. That in my book is a further clue the PDC can work. The scenario being it's finding the Sortilin in eyes and nerves, not hitting white blood cells because they don't have Sortilin. But why not hitting tumours?
I keep coming back in my mind to the tumour micro-environment (TME). We know this is a barrier for many drugs. We know the conditions in the tumour are different to the rest of the body. There's a lot of thought that a mouse Xenograft isn't a great analog to real world human tumours. From the things we know publicly there aren't a lot of clues about how the PDC would handle the TME. The problem could lie there. I identified pH as a possibility largely because I think that is testable in the lab but if they didn't get any quick answers from something like that then I think the complexity of the TME would suggest a long slog to find an answer. I'm speculating here, I'm looking for where there might be holes in the preclinical. There are probably many more, it's was never easy for them to cover every possibility.
I'm still curious what unconvincing efficacy might mean. Almost no efficacy? If it's something more than that what does the pattern of efficacy signals look like? Could it be that the drug works on the smallest tumours (one's most like mouse tumours, my guess) but fails on the bigger tumours picked to be the RECIST tumours? Maybe they have clues like that.
All guessing in the dark here.