Wino115 wrote: I'll let the real scientist answer the hard questions. But you are right that there's loads of studies out there and it's super dynamic. Two interesting points are that there are fewer dealing with the advanced stages THTX is targeting initiallly, The 3+ lines and total resistance, so literally no choices in the current arsenal. And the use of sortilin, which as we know only the Sortina guys are commercially working on with their occupation and cancer t-cell approach, which is different than THTX's PDC approach. Some of the ones I've been posting are for first or second line. So they would go as long as they can on those and then you may have to switch to TH1902 or something else if you become resistant to the others.
I think in the past, this boards science guys have stated that every new combination or new attachment to the peptide is it's own unique molecule and would require it's own trial phases, and each new tumor they're going after would also require a pivotal trial. Then again, Scarlet found some FDA wording around using an approach across different tumor types, so maybe you can get a broader IND around "solid tumors expressing sortilin". I don't know on that.
The good thing is, as we see with Gilead and SeaGen, you don't have to move sequentially and once your concept is proven you can move on many fronts all at once depending on your own internal constraints of people and money. But the money one shouldn't be a problem if there's POC or partnerships on a few of the more unique ones.
It seems the way they do it is that if the new molecule or tumor is something the other party brings far more background and skill to, you partner it with them if they seek your PDC.
But I think you are on to the right way to think about it, which is that everything really revolves around sortilin as both a target, it's large overexpression that is directly correlated to severity of cancer and it's scavenging function to pull in the PDC so it can be cleaved and evade the MDR1 efflux routine. Then we have all those potential extra benefits around VM and how it may regulate other resistance mechanisms in a beneficial way (that Bcl-x interaction with cancer t-cells).
Different attachment bombs may do different things, but if you are providing the rocket and the navigation through something you are uniquely equipped for (and patented for this use), then just showing the power of that is really all we need --that sortilin is a very valuable target and our peptide attaches and internalizes. That would be massive. The payload or partner that wants on to our rocket will happily pay the price for something that is proven to get to the point it's aiming for on the tumor.
Like the scientists on our board have been saying, anything that shows the actual peptide is getting to the sortilin when it's overexpressed, entering the cell, and cleaving is all we need. I gather from their previous posts that we may only really infer the first of those from this phase. Efficacy would show it's in the cell and cleaving so that the toxin is working, but that will likely have to wait.
The things we know that have been studied by others is that:
1. Advanced tumors express a lot more sortilin than adjacent healthy tissue in human samples (2 -3 studies done by others, the breast cancer one had around 500 tissue samples).
2. Sortilin internalizes the peptide in mice studies (THTX).
3. The toxin was cleaved inside the cell in mice (THTX).
We have to hope the safety aspect by targeting a receptor that internalizes and bypasses resistance is so unique that it stands out for it's ability to have a large treatment window, dosage schedule and duration possibility, let alone perhaps more efficacious. We'll just have to see how all those variables play out but the potential is there to see all three unique outcomes.
SPCEO1 wrote: Given all the drugs in trials to fight cancer, the drug that TH-1902 might ultimately have to beat may also not have reported results yet. We are shooting at a moving target. There are many drugs that using a different MOA to attack the same cancer and none yet that we know of that use the sortilin receptor. So, we have to hope TH's approach is a superior one to all the other approaches. Of course, there are a lot of ways to slice and dice the cancer market and even if other drugs perform better, using them in combination with TH-1902, or even ultimately attached to TH-1902, may yield some impressive opportunities for TH-1902 even if the phase 1b results from TH-1902 are not superior to one of these other drug efforts. Sort1+ is a platform, or drug delivery system, more than it is a new drug itself.
I wonder how the FDA will view the Sort1+ platform. For example, if the drug you noted below becomes the standard of care, how much will the FDA require to be known about how it would work linked to TH's sortilin seeking peptide before letting this new PDC move forward? Could one of the most important purposes of the TH-1902 trial just be to confirm that its MOA works and then attaching whatever approved chemo agent you want would be something that would need to go through a long FDA trial process? If the FDA knows the chemo agent is approved and the sortilin seeking peptide works to getthe drug into the cancer cell, would a whole bunch of trials be required or would one simple trial be all that was needed for approval?
Wino115 wrote: Here’s some Phase 1 results from the drug most see as the nearest direct competitor in TNBC to Trodelvy at this point (because TH1902 is not very well known!). It’s from Daiichi Sankyo and Astra Zeneca and called DS-1062.
Data is from cutoff of Jul30 and for 44 TNBC patient cohort of the TROPION study. Recall it’s a Topo1 inhibitor ADC.
—-Objective Response Rate was 32% — in line with Trodelvy
—- Disease Control Rate was 77% (disease control is total of complete, partial and stable disease).
—- In TOPO-1 ADC Naive subset, ORR was 48% —better than Trodelvy in apples-to-apples cohort
—- Baseline had 11% with brain metastases, 68% 2 prior lines, 30% treated with TOPO-1 ADCs
—- Disease Control “observed” beyond 7 months in patients with ongoing response
—- No median Duration of Response reached at current date cutoff
Safety Summary:
—-Grade 3 or higher TEAE’s in 23% (TEAE = Treatment Emergent Adverse Event)
—- Serious treatment related TEAE’s in 5%
—- Common ones of nausea, stomatitis in 50-60%
So seems the hurdle to beat is still around 35% ORR or maybe 50% ORR for those with high sortilin expression (so it’s proper cohort) and having a disease control rate that’s pretty high —so at least a bunch of stables and some partial and complete responses of 50% or hugher.