jfm1330 wrote: You need to compare apples with apples. The MTD of docetaxel alone is 100 mg/m2. In TH1902 terms, it's 230 mg/m2. So if the MTD of TH1902 ends up being 300 mg/m2, it would mean the MTD of TH1902 would be 1.3 times the MTD of docetaxel alone. That's only 30% higher on a MTD basis, and a much narrower therapeutic window than hoped for. All that without a proof of concept.
Even if they end up with a proof of concept, it is clear now that TH1902 is not working on humans in the way they saw on xenograft mice. On these mice, they achieved three times the MTD of docetaxel alone. So they are much, much lower than that. Again, 300 mg/m2 dose is about the lowest possibility for a valid MTD. Turn it the way you want, the potential of this drug as we know right now is much lower than hoped for. That's why I am so frustrated.
They dropped the 300 mg/m2 bomb yesterday, but without any other info that could help understand why they still plan to go in phase Ib. No hint at all about signs of efficacy. Last August, Levesque sais they would let the market know as soon as they would see something significant. On what are they basing this decision to still go to phase Ib? We don't know. All we know, is that they will do it a t a lower dose than hoped for. They talked about that as if it was not a problem. But for any scientific mind on the outside, it is problematic. I was good with a 420 mg/m2 MTD, but 300 mg/m2 is too close to docetaxel alone to my taste.
This program was speculative from the get go, but now it is highly speculative. The frustrating part is that now we know they are at 300 mg/m2, but we ignore all the rest and they were not challenged on that yesterday by analyst's questions. Why was the escalation process so slow? What were the adverse events and what are your explainations for them? Did you see a difference in toxicity between low and high sortilin patients? Did you see a difference in PK/PD data between low and high sortilin patients?
What I try to say is that maybe there is sound explainations that would allow us to understand why they are still positive on TH1902's potential, but yesteday they said nothing to reassure anybody that is scientifically knowledagable enough to be worry by the 300 mg/m2 dose. The problem is that we have no freakin clue about the proof of concept of TH1902, and again, this trial was ill designed from the beginning. You cannot have such a design for a targeted drug with all comers accepted into the trial.
Undestand me well. I am not saying that TH1902 is doomed. I say that we, on the outside, are placed with yesterday's news in the worst possible situation. It is clear that this trial did not go as planned. It was not a straightforward process. The desing was poor for a targeted PDC, and it looks that even if the PDC concept works, they will end up with a dose that is not optimal for real patients expressing a lot of sortilin. Maybe they will try to work on regimens in the future to overcome that, or maybe they will do another trial in the future on screened patients to reassess the MTD in proper patients. I don't know. But to me, it is clear that we are left mostly in the dark, knowing the negative part (300 mg/m2 dose), but with no positive info that would allow to have a more balanced picture of the situation, if a more balanced picture exists.
From where we were at the beginning of this trial last March, it has only been negative. It was supposed to last six months, then maybe nine months, and now it will take 14 or 15 months. All that to end up with a much lower MTD than hoped for, much lower than what the preclinical data suggested, and without a freakin reassuring word about efficacy or proof of concept. So, good for those who saw yesterday's news as a positive, but for me it's not. Again, it does not mean it will be a total failure, but I think we are already in diminished expectations territory. Forget about the hope of spectacular results. It won't happen.
SPCEO1 wrote: Someone I know who has a friend who is a doctor sent this to me and I thought I would share it in case it helped:
TH1902 contains 2 dox molecules per peptide.
It’s weight contribution to 1902 is 43% (2x800/3700x100). Therefore, 300 mg of TH1902 is 129 mg of Dox.
Approved dose of dox is 70-100 mg/m2.
So 1902 delivers about 1.5 fold more dox per cycle.
Does this mean more efficacy?
Abraxane is delivers 100 mg Dox and has 20% neutropenia in phase 3 trials.
I expect that 1902 will be dosed around 250 mg/m2 in chronic treatment. The dose titration is due to toxicity due to drug accumulation and recovery of white cells.
So 250 mg of 1902 means 107 mg of Dox similar to Abraxane.
Sortillin may be over-expressed in cancers but normal cells also have sortillin. So it is the difference of expression.
qwerty22 wrote: Just to clarify. This paper from THTX's scientists
https://onlinelibrary.wiley.com/doi/10.1111/cas.15086
states " Note that 35 mg/kg TH1902 and 15 mg/kg docetaxel contain equimolar amounts of docetaxel. "
When you do the calculations ther is 100mg of docetaxel in 233.33mg of th1902
So 300mg is exactly 1.5x higher than a 100mg dose of docetaxel. So THTX's numbers are correct but it's hard to know what point Loe is making here. All that aside it's a pretty positive note in my view, he's acknowledging the progress they've made but still putting that valuation point in the future. That seems to be a fair assessment to me.
The point I was mostly trying to make yesterday is IF those 420 AEs had not arisen then they probably would have continued to move forward with 420 dosing and we may have been at that valuation point for Loe now. As Paul said this process isn't always linear, they had to take a step back and that has added 3 or so months to the process.
qwerty22 wrote:
It does sound like he's mis-understanding that but given he doesn't state his own multiple it's hard to say. It could just be that he thinks by picking 100mg/mm2 that THTX are at the cautious end of this equivalent estimate. Does it say what he thinks the multiple is anywhere else in the report?
Wino115 wrote: I belive one of our science experts once discussed how to convert what the PDC level attached means in relation to the normal IV administration levels. Revolved around the fact the peptide has two units attached and there's some sort of molecular weight conversion you have to do to make it an apples-to-apples conversion. I think Loe is not doing that so it's not the proper comparison. Sorry, can't get more specific but I think JFM is the molecular chemist that did those comps before.
SPCEO1 wrote: Thera provided an update on its Phase I solid tumor testing with TH-1902, indicating that it has likely identified a maximum (barely) tolerable dose that is at or above 420 mg per square meter of body surface area, and this observation motivated the decision to shift all future patient dosing to a lower level of 300 mg/m2. Thera indicated that this represents a 1.5x elevated dosing level over that commonly used for docetaxel itself in solid tumor chemotherapy, but in our review of the literature, it is far higher than that (docetaxel as a monotherapy tends to be administered initially in most tumor types at 75-to-100 mg/m2). Accordingly, we believe that dosing at or above 300 mg/m2 still reflects favorably on the tumor targeting pharmacology that conjugation to sortilin receptor-binding peptides confers in TH-1902. As stated above, the concept of incorporating sortilin biochemistry into TH-1902 for targeted chemotherapy still seems reasonable to us and we are optimistic that justification for us to ascribe formal market value to this program will be forthcoming.