RE:RE:All comers The way I look at this there are multiple things that have to go right for this technology to work out as a treatment in the clinic. One of those is whether the Sortilin receptor is a common or marginal receptor on tumours. The evidence is it prevalent in some cancers, they have to show that prevalence converts to patient responses.
I remember in summer Christian talking about 75% of the enrolled as potential Sortilin expressors. At the time I thought that was optimistic and was cautiously going for 50% and pessimistically 25%. If we rule out the first half dozen patients because they are on low doses and only think about the next dozen or so then Christians number would give you 9 expessors enrolled. I'd be in the 3-6 range. At the bottom end I think three SORT expressors could easily turn into zero responders given all the things that can go wrong for these patients. But if Sortilin is not marginal and the have 6+ SORT expressors you have to start expecting one of those becomes a responder if things are working out as expected.
Even though the numbers of enrolled are small, for this tech to meet it's expectations I think we should be seeing at least one responder in the first dozen. They may end up refining their target population in future trials but for now this population of late-stage patients is going to continue to be the enrolment population, if they can't show efficacy with these patients then the program is going to really struggle. As Wino has said before, if they can't show 30% response rates in evaluable patients then it's going to struggle as a treatment. They maybe don't need to show 30% in the first dozen but they need to show some evidence they might eventually get there. I think they need a responder or two, it's going to continue to look like a challenging investment without it.
Maybe I'm wrong but my expectation is something like 12 evaluable patients by the end of the dose escalation phase and one (or two) responders. It could easily tip over to zero responders but for this tech to look investable I think they have to be reporting some type of efficacy signal.
(I'm trying to keep my expectations low, anybody think I'm still being optimistic?)
jfm1330 wrote: We knew that they would test afterward for sortilin expression, that may be part of the delay to get results because if there is efficacy, I am sure they will want to report it with correlation with sortilin expression. About the all comers aspect of the process, I think this is not a problem because Thera already knows that some advanced cancer types are overexpressing sortilin almost at 100%. So by selecting some advanced cancer types, thay are selecting patients overexpressing sortilin with a very high probability. My guess is that they made an indirect selection based on cancer types. My guess is that most enrolled patients enrolled have cancer that are overexpressing sortilin. In fact, they needed that to end up with a reliable MTD applicable to the patients they will treat in the future if TH1902 works. A MTD based on patients with cancers that are not expressing sortilin is worthless, but most importantly harmful for this program. You want a MTD established on patients that represent the population that you will hopefully treat if the drug is ever approved. As I said before, I guess that one of the reasons for how slow the escalation process was, is that discrepancy between toxicity in sortilin overexpressing patients and low or non expressing patients. My guess is that they had to talk to FDA during the trial about that. I think that this phase Ia should have been a two arms trial. One for confirmed sortilin overexpressing patients and on for the low or non expressing ones. It would have been clearer that way.
SPCEO1 wrote: THTX as noted several times that the phase 1a will take anyone who meets their criteria for the trial. I am not sure if we new this already or not but Paul told a friend of mine that they will be checking the patients tumors after the test to determine if they were overexpressing sortilin. So, with a small number of patients involved, there is a chance that none of those accepted into the trial will have sortilin overexpressing tumors. Now, I have to believe the chances are still pretty good that some will have sortilin overexpressing tumors but there are no guarantees since they are not pre-screening patients to admit an assortment of expressing and non-expressing patients into the trial.
He also said that Dr, Rothenberg had done a deep dive into TH's science before joining and that he would be helpful in reducing risk in their clinical development and creating multiple pathway to win. I think it is important that Dr. Rothenberg joined because of the science and not because he and Paul were fishing buddies from their time together at Pfizer.