SPCEO1 wrote: I wish the company would be a bit more forthcoming on the status of the phase 1a but we can do our best to infer where things are at despite that. This entails assumptions and that means we can be off the mark by a decent amount due to incorrect assumptions. But some on this board may have the knowledge to help hone those assumptions.
Here are a couple of assumptions:
1.) THTX would have to inform us if the trial was halted as that would be viewed as a material event.
2.) If two patients had toxic reactions, the trial would stop moving to higher dose level and a new group of patients would be treated at the lower dose to make sure they did not have toxicity at the lower dose level to confirm the previous result. But apparently, there are also appeal methods regarding whether or not what was judged to be toxicity was actually toxic for the patient. If TH pursued such an appeal process, let's assume the process takes three weeks.
So, since we have not been informed that the trial has stopped, we can pretty much assume it was ongoing at the end of August (three weeks ago assuming a three week appeal process and a notification that the trial was halted tomorrow). If so, and assuming there were not any signiifcant wiggles in the trial's progress earlier, then can we feel confident that patients have received a dosage level that is pretty high without a toxic reaction through the latter part of August?
Clearly, the more Docetaxel that can be pushed into a cancerous cell, the better the potential ouotcome on the efficacy front. In the case of TH-1902, what I am hoping for is not only some efficacy on those phase 1a patients who presented with sortilin overexpressing tumors (hopefully 2/3rds of them) but also no neutropinia so that the combination of efficacy and the length of time treatment can be pursued is better than any other treatment alternative.
Also, another question for the science team - for those patients in the phase 1a who do not have sortilin overexpressing tumors, I assume the PDC washes out through their system without causing any harm. Is that correct? Or would some of the Docetaxel still negatively impact healthy cells if it could not find any sortilin receptor to adhere to? Also, since we are now at higher dose levels, could the non-sortilin expressing tumor patients be facing some nasty side-effects since there likely are some sortilin receptors on healthy cells since the heavier Docetaxel doses are potentially putting more sortilin into healthy cells? Could that lead to the trial being stopped?
For this question you have to think about the amount of drug that interacts with the tumour. Beliveau in the KOL event quote 2-5% of anti-cancer agents effectively reach tumours. I've seen other papers say it's as low as 0.5%. If we took the top number (5%) and combined that with improved uptake from scavenging Sortilin (7X higher accumulation in vitro) then the highest amount of drug interacting with the tumour is about 1/3 of the circulating drug. That's a top end number, accumulation could easily be less in the tumour of a patient. So in a scenario where a patient has Sort+ tumours the majority of the drug just circulates in the bloodstream. So let's say in a SORT+ patient 65% can just circulate in the blood doing harm and in a SORT- patient 100% circulates. Can you spot a different safety signal between those two patients? It's possible but remember in the dose escalation process drug is increased by factors much larger than that and the range of doses for clinical use of docetaxel is also greater than that difference. I think the amount of drug interacting with the tumour is likely to be lower than that 35% and the likelihood of seeing a different safety signal in SORT- versus SORT+ is also likely lower. Maybe with a very, very large cohort of patients you might see a statistical difference appear due to a small quantitative difference. I don't expect to see a qualitative difference between SORT+ and SORT- patients. JFM likes to pump this idea but I've never seen him consider the actual amount of drug that interacts with tumours versus the amount that freely circulates away from the tumour, this to me is a very important factor in considering if SORT+ and SORT- patients react differently. Ultimately though we'll only know for sure by actually seeing how patients react.
Sorry in advance for all the assumptions, questions and general lack of knowledge (or ability to fully remember when these things were addressed previously).
It seems to me that the stock should logically creep upward every day that w e do not have an indication that the trial has stopped as the chances for success are likely improved with each passing day.