RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:TH-1902 pause is no reason to blame management The enrollment pause coming from the investigators makes sense and may also offer the reason why they thought a change may be worth pursuing instead of a stop, which had to be on the table too. Also, by the way, that’s exactly why all the ambulance chasing notes are way off base. Their outside team reviewed data and told them what to do. That’s how it works. Prior to that you had no means to know if you’d see the proverbial 2 out of 10 or not (in fact, they still don’t know that yet). They announced the investigator request exactly when they knew. Good luck with that but it would be a total waste of time and money once they consider the facts. It will die off soon.
If you think about it, the whole early phase is about experimenting with variables to try to figure our some "optimal" balance of working vs safety. The lead doctor is the one who watches the slowly accumulating data and determines if the lab science is coming through in the clinic. If not, it's either so bad you pull the ripcord or you see at least some reasons to rethink. TH1902 data wasn't coming through strongly enough. If there's a reason to rethink, it's probably because there was some view around activity levels and safety learned in the dosage ramp part. I don’t underestimate the hill that they need to climb, that the risk is way higher, but they’re giving it a try for better or worse. Nothing to lose given where they are now.
My hindsight criticism is that the entire cancer team (and me!) were blinded by the really strong pre-clinical data. It almost looked too good to believe (it was), so CMO/Invgt plowed ahead not thinking they should have spent a whole lot more time around the best way to get doses in subjects optimally. I don’t know if the FDA would have allowed that kind of tinkering in humans, but it sure would have been handy information. Some of those charts they show do have way more frequent dosing of the standard taxol dose. I’m looking at their TNBC chart now and it shows they did a normal equivalent dose and gave doses of both at day 0, 7, 14 and then two more TH1902 at 21 and 28 days. Then they stopped and efficacy took over. It looks like they were doing 7 day schedules in all those charts and usually did 5 to 7 cycles.
They stopped because efficacy was strong by then (mice don't report tolerability ;)). How a week in a mouse compares to 3 weeks in a human I have no clue and it’s probably incorrect to conclude much given where everything landed. It seems old habits die hard and the FDA wanted the normal 1 dose every 3 weeks probably to make it a good comp to receiving normal chemo and make reading results comparable too. If you don’t really know where to start, just start there like everyone else. But that doesn’t mean that’s the best way to do it. For Th1902, no ones figured out the best way to dose it —could be three weeks, could be 7 days — and maybe you never figure it out with docetaxol on it. I’m sure it’s way more complex and they know a whole lot more than my simple thought, but sure wish they had explored that more.
Investigators bringing in the Cybrexa and other ADC examples with non-standard dosing is all part of that. I can’t see the FDA not agreeing to a change since other PDCs have similar dosing that they are requesting and they do know that dose should be much safer. (By the way JFM, I think we figured out the new tech around encapsulating PDCs is a quantum leap over what it was when that other PDC trial failed. I recall reading about that. Still, who really knows anyway?). They also have actual human data on the safety in those lower levels from 1A, so it shouldn’t be a mystery. They did the FDA required 2 people, multiple cycles at those levels, before moving on since it triggered no treatment related SAEs to stop it. I put the risk of the FDA not signing on to test dosing as pretty low. It’s the risk of getting broader efficacy that is much higher going forward. None of us would pay for that in the stock now and the market is saying they won’t see it anyway. It’s prove it to me for this version.
There is some data that we even know of that shows dose size matters - that seems obvious. We don't know how timing may or may not, but recall the Endometrial 1a that was on for 33 weeks and starting at 30mg, slowly rising to those higher final doses. There was some activity in tumors seen, the other readings showed limited disease progress, and they went on for over half a year when nothing else was working on them but stopped for personal reasons. It was not enough activity to be a response or make a commercial therapy, but it may be informing them around thinking lower doses can have efficacy, better tolerability, if given frequently. Was there any kind of relationship between the dose timing and the activity readings seen? I’d want to know if right after the doses is when you saw most of that activity and then it faded. After all, these enrollees are really in that final stage of massive rapidly growing and metastasizing tumors, not early stage slow growth. Your fighting an army that brings 3 new battalions up the rear every day so it doesn't matter if you break through the line. That’s the kind of stuff they need to analyze. Do you need frequency to combat crazy out of control tumor growth? Is there a scientific case to be made that lower for longer might help around the stem cell/VM deactivation? Only one way to answer that —try it.
I can see what kind of simplistic questions I’d want to ask, but I’m not a scientist and have been led astray anyway! All the cellular issues Leeds, Qwerty, JFM have asked are super important and maybe unanswerable at this point anyway. They seem to be the real key cellular issues that may be in play around efficacy and maybe dosing won’t change that at all. But I’d want to know from all that P1 data how those who went through the 75 to 240 ramp did with tolerability? Better or worse? Did those who did multiple 100-200 ranges show safety and activity consistently or did it fade by the end of the 3 week cycle? After FDA approves, they’ll have to say something very general around things like that for anyone to believe them.
The actual doctors are the ones out there seeing how experimental therapies are aligning with their theoretical stated MOA, and they certainly have all become way more versed on these targeted therapies. All these conjugates, including the most successful ones that are out there and commercialized, have to figure out a way to get the most of their active ingredient near or into the tumor as quickly as possible, and to then find that balance in dosage/timing such that the inevitable off-target toxicity can be dealt with (it's never non-existent for any of these ADCs/PDCs). There’s no good news with them going back to the dosage drawing board looking to boost activity levels and it dwarfs the tiny positive that the investigators who know this targeted oncology space didn’t pull the ripcord.
What’s that worth now, probably not a whole lot and expectations are at their absolute lowest anyway. We’re in the “unknowables” range now and can only guess sort of wildly. Some of this stuff will always be unknowable so we aren’t going to get a lot of help around that. But it would be worthwhile once the FDA agrees to provide some general characterizations, not answers, around the key theorized issues floating around their KOL cancer team and the ones we’ve seen here and in the Leeds report.
One thing we will know is that if the FDA agrees, which I think from what tiny little bit I see they should, it would mean that THTX and the investigators have shown an outside agency what the human data is, what the problems they’ve encountered were, their analysis around those problems the best they understand them, what they think pre-clinical (discounted at this point) and the trial results showed as far as the key ones to try to overcome and "optiimze", what data they have to convince FDA these changes have a rationale to getting to more potent efficacy and tolerability, and theoretically why it would work. And the whole thing has to have complete buy-in from the investigators, THTX Cancer advisory (Rotemberg, etc.) and the FDA --so a large group of minds. So it’s got to be as comprehensive and well analyzed as possible. In a way, if we do hear of a positive FDA response, then we can also assume their theorized science argument held together amidst a very large group of stakeholders that all looked at the actual, real human data. If not then the science really wasn’t able to get around the issues they have in the trial data in any way. That will be their first decision point test.
What we’d love for them to do is give us that presentation. We really need all that same stuff the FDA is seeing. We will never get that. It’s sort of meaningless because there’s no way any of us want to get hopes up again. The benefit to giving a general characterization to the market is that you can at least start re-establishing credibility around the program. No one will give it much of a value, but maybe you’d have some conclusions that would re-interest some around the new program. They'll have to put in that new page showing the protocol and what they're going to do with the enrollment, what changes are in the clinicalgov site and it would not be right for them to do all that and not explain the what/why/how behind all that.