RE:Preclinical resultsThere's a few others looking at different approaches that have gotten past Phase 1. Bicycle Therapeutics has a fancy PDC and they have one with Vedotin for it's toxin (MMAE) and one with DM1 (Mertansine), so we'll see in time if other's have expanded the knowledge level. They have different targets.
In looking at their trials, I also see that they did their trial very differently. For one, they did either weekly injections or every other week, never every 3 weeks. They also spent a whole lot of time on the dosage P1 portion. They did 5 parts to just the dosage portion. One was the typical dose escalation with 40 patients. After that they did one for safety as a monotherapy, then a third and forth for a combination escalation and expansion and then a fifth for a dose "confirmation" trial around renal issues. They were anywhere from 12 to 40 patients in each. This was for their immune cell agonist version.
For the MMAE/Vedotin one they tried both weekly and bi-weekly versions in the escalation phase. Never did they do every 3 or every 4 weeks. They settled on an every other week version to trial and the dose was below what they originally targeted as the "effective range". It was at the low end, so it was a lowish dose, given more frequently.
They did use the All-Comers approach and then zeroed in on specific cancers. It's interesting to see that the "Summary of Efficacy" for their preliminary study only showed an All-Comers/All-Doses preliminary unconfirmed responses of 3/24 (12.5%). For Ovarian all-comers 1 out of 8 (12.5%) - so only 1 30% shrinkage of a tumor. Ovarian IHC positive 1 out of 5 response and 4/5 "disease control" (80%). For Urothelial it was 2 out of 2 responses.
Looking at the spider charts for Ovarian - it only worked on two of the four EphA2+ patients and failed on all the EphA2- patients. For Pancreatic and NSCLC it didn't work on any, and for Urothelial it worked on 2 of 2. They also looked at the data and saw it only worked where the staining for EphA2 was high.
As I look at some of these other PDC company trials, it seems the biggest difference is that THTX had a very limited budget and had to hope to learn a lot in a quick way, and that didn't seem to work. It's probably far better to have these more extensive trials to learn a lot more before moving on and have the means and patience to carry on.
Looking at those early numbers for Bicycle, they only got 3 responses out of 24 That was considered a success because they focused it down to two cancers and high levels of staining. Now, that's still more than the 1 confirmed THTX saw and the 1 we heard about but that didn't go through long enough. All this to say that I think money was and is as much an issue in trying to see if Sort1 is a valid approach as is the science. The science is clearly the most important, but like a lot of lab processes, you really do need the expertise around robust design, what you learn, and seeing through a larger set of patients so you can do those evaluative groups where you may see better results (the staining, cancer types, etc..). Really a shame they don't now have the resources to do that now unless they partnered with someone. Meanwhile, Bicycle keeps moving forward with it's PDCs and has a $900mil market cap.
I don't know if we'll ever learn all the numbers, but if they want to re-enroll they'll have to have some evidence like this to support it -- staining data, sort1 levels, cancer types, other PK/PD patterns etc.. Things that may increase your chances to get to that 2 of 10 in one cancer. If not, it won't be worth spending even the lowish $2mil or so one. Let's see what they come up with over the next months. But once again, these guys did not do the standard every 3 weeks - they did weekly or bi-weekly only.
In their other
jfm1330 wrote: Forget about the activity they saw in vitro on cancer cell lines and in vivo on nude mice grafted again with single cancer cell lines. It means almost nothing about the validity of the drug.
I made a quick search about Zoptarelin, the failed PDC from Atearna Zentaris. It failed on more than 300 patients in phase III on endometrial cancer in 2016. But I found a paper from 2020 where they were testing it in vitro on an uveal melanoma cell line overexpressing LHRH receptors. It was at an university in Hungary and they claim activity on gene expression and angiogenesis and so on in vitro. Their conclusion is that a PDC aiming at LHRH receptors should work. Sure, ask Aeterna Zentaris investors about that.
I really think there is something wrong with PDCs using simple unstable linkers and old cytotoxic drugs. It works in the lab, but not on real patients. The approved ADCs are using newer and more potent cytotoxic drugs, and bigger and more complex linkers. The only approved PDCs are the one using stable linker and very potent radioisotopes. Thera should be able to see that and correct course. Drop TH1902 and desing a new PDC that would not have the flaws TH1902 has.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968782/