RE:RE:RE:RE:RE:RE:RE:The full article published yesterday I think "yes" it does need POC. It's also possible we need to revise what we mean by POC now as well. I don't know how Pharma execs think but given we probably have a few dozen non-responders and a hand full of meh responders (I don't think anything has reach the formal definition of Partial Response yet, could be wrong), I think they probably need a couple of real PRs from the next higher dose cohort in order to have any sort of interest.
It's like a yawning gap between the scientific potential in the preclinical data and the lack of commercial potential in the clinical data. It's not a unique situation, I've lived it. It drives you on in your work day and fuels your nightmares at night. I would expect it breaks one way or the other at the end of part 3. Just my guess.
palinc2000 wrote: Your insight is really appreciated as always and I hope you come back to this MB as needed when warranted...
You make reference to juicy pre clinical data that we have seen more and more in the last 2-3 years but as you state humans have not responded yet in the same way during Phase 1 a b c ...Paul said that there remains another 5 millions to be spent in the next few months and then $$ will have to come from a Partner...So must we assume that they have to reach POC by then or otherwise chsnces of partnering will be slim even if juicy pre clinical data keep getting juicier ...
Qwerty54321 wrote: I don't think there's any reason to investigate if weekly dosing is a better option until the first dosing failed and they needed to show the new dosing has some supporting evidence for continuation. You can't expect to investigate every possible permutation in preclinical, you go with standard protocols everybody else uses if there is supporting evidence for that. Which is what they had. And if that fails you move on to other options if that's possible. So I guess the first rationale for doing this work and publishing is to give empirical support for the turn the program has taken in Part 3.
The other point to make is this is a continuation of what they found in earlier preclinical. That is to say super strong evidence of a highly effective drug (in mice). It must continue to be massively perplexing for them why these strong preclinical results aren't reproduced in their patients (yet). It's so hard to bin this program when you are sitting on such juicy preclinical data and at the same time challenging to justify it's continuation while the clinical data continues to look flat. It's often this way and a far more satisfactory situation if it would break one way or the other. Science does this!
palinc2000 wrote: Thx Scarlett.!! Should they have conducted more pre clinical studies before going into phase 1 ?
Still hoping for an experienced deep pocket pharma/biotech getting involved .... Out licensing with double digit royalties even without a front end lump sum payment would be acceptable if there were milestone payments .
scarlet1967 wrote: It is a long and complex article, going through it what they are talking about is the fact that TH1902 has a bystander effect on a molecular level which trigger immune cell infiltration. Also TH1902 again through a cascades of molecular activities reduces anti-tumor immunity leading to increase recognition of cytotoxicity and an increase of the cell surface immunotherapy agent.
That is why the combination of the PDC and anti-PD-L1 can relativly bypass the resistance mechanism. I know it all sounds a bit complicated and quite frankly the molecular mechanism they are talking about is above my paygrade however this is to my knowledge a new discovery and another mechanism of action which was not studied before reinforcing the idea of the synergistic anti-cancer effect of TH1902 together with anti-PD-L1. The point is although very early preclinical stuff each and every one of these findings could potentially lead to a new combo treatment fighting resistant heterogonous cancers. Would they add value to the Sort1 platform’s potentials and make it more attractive to the potential partners my take absolutely yes.
palinc2000 wrote: The reason for me asking what is NEW is to try to handicap if there could be renewed interest by a large pharma to take over or share the responsibility of the Clinical trial......For me this is what needs to happen
palinc2000 wrote: Great post once again!
Are you able to break down what is actually NEW data in this study which appears to be quite extensive.....?
scarlet1967 wrote: "In conclusion, this is the first in vivo preclinical study to document that administration of TH1902 is better tolerated, based on non-significant mice body weight loss, and more effective than docetaxel at inhibiting tumor growth in an immunocompetent syngeneic “cold” tumor model. Among the salient in vivo findings complementing the TH1902-mediated increase in the infiltration of tumor parenchyma by most classes of leukocytes, was that combining TH1902 with an anti-PD-L1 CPI produced a significantly greater reduction in tumor size than did the combination of anti-PD-L1 with docetaxel. In addition, the survival study reported herein clearly demonstrated that animals treated with TH1902 had a dose-dependent increase in survival, an effect potentiated by co-administration with anti-PD-L1 in a cold tumor model. Finally, the sustained and prolonged effects of TH1902 in our preclinical in vivo studies, even off-treatment and following six cycles, reflects the preliminary Phase 1 observations of prolonged clinical benefits, even after treatment discontinuation."
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1355945/full
This is the full article discussing in details the combo effects of TH1902 and anti PD-L1. Apart from details how and why the combo effect works they are also talking about bystander effects and prolonged off-treatment effects similarly to what they saw in the part 1 and 2 of the phase1 clinical trial.