RE:RE:RE:RE:RE:Spider PlotWhat would have been much better than a poster presentation of sortilin testing on hundreds tumors samples of patients not involved in the phase I trial. It would have been to reveal that tumor biopsies of the three patients that showed efficacy signs in phase Ia were tested and showed sortilin overexpression and tumors of some patients that did not repond to TH1902 show very low sortilin expression. Remember, Levesque said in the past that they would test patients for sortilin expression afterward.
Also, Levesque said they were working in the lab with SN38 and other cytotoxic agents, was there is no clear update on that. At what stage are they, is there plans to start preclinical work on a new PDC? Also, Marsolais a year ago or more, said that they were to do tests grafting real tumors from patients on nude mice, what is called, what is called "patient derived xenografts". It's been a long while since Marsolais said they would work on that and we still have no news.
We are at the same place we were a year ago with phase Ia. Then, Levesque also promised results in October, then it was January, finally, we got it in July. We thought it would be faster this time with a known dose and no escalation process, but it seems they have problems once again. Also, management was never challenged for how long phase Ia took. No questions were asked as to why it took them twice the initial timeline they gave us. I remember some were complaining during the Tanguay years about opacity and poor communication, Levesque the Pfizer guy was supposed to change that culture of silence. Well, so much for that...
https://www.criver.com/products-services/discovery-services/pharmacology-studies/oncology-immuno-oncology-studies/oncology-study-models/patient-derived-xenografts-pdx-models?region=3601
SPCEO1 wrote: I think we should be assuming the patient recruiting situation is behind schedule until the company states otherwise. First, has the company ever stated that all six sites are up and running efficiently? I don't recall that comment being made, but maybe I missed it. We earlier got a general "enrollment is going well comment" from Paul but we know now he is prone to overstate things (don't be too hard on him, I think it is in the job description of a biotech executive to be good at overstatement). Second, they are adding these other sites in the US, Europe and Canada now, five months into the trial? In July they indicated in a private call they might not pursue the European sites due to the extra hassle and cost involved. I had previously assumed early patient recruiting was going well enough that they had passed on the more difficult European sites as well as the other US sites. On the other hand, adding these sites may reflect the expectation they will almost certainly be adding 25 patients in multiple types of cancer due to early efficacy signs and will need more capacity to add patients. It would have been nice of the company to give us some hints about that on the call last week, if it is accurate. Third, Paul has emphasized the need for Christian to step up enrollment on two occasions I am aware of over the last few months. So, I began to think recruitment is an issue but again could be good news or bad news. Good news if they anticipate needing a lot more paitents due to multiple protocol amendments stemming from good early results and bad news if they are just struggling to find patients. Fourth the trial's timeline has been lengthened. Again, this could be due to good news or bad news on the recruitment front. But without any clarity on the subject from management it is typically best to assume the bad news is more likely. Fifth, TH has not yet reported anything from the phase 1b trial which indicates either enrollment is going well and efficacy is not being seen or enrollment is going poorly so they don't have enough patients yet to make any efficacy claims.
Safety has been raised as a potential issue too. I am less worried about that at this point since TH would be less likely to incur the costs and hassle of expanding the number of testing sites if TH had meaningful safety concerns.
The Chief Legal Counsel's unfortunately timed share sale in late July also is a piece of evidence to consider in this. And there is other pieces of evidence, both good and bad too as some have already pointed out elsewhere.
So, for me, while acknowledging their is a favorable case to explain the murky situation on enrollment, I am leaning toward a negative interpretation until the company clears the situation up. Had TH focused the third quarter press release and conference call on TH-1902 and had they again mentioned they think they might have "the key to unlocking cancer cells" and that "a few, several or maybe many", I would have been more encouraged. That they chose to only regurgitate TH-1902 announcements that had been previously made in the Q3 press release was a change in course for how TH's messaging was headed before the Q3 press release and one has to wonder why. Unless the preclinical work was really done poorly, we still have reason to believe the ultimate outcome will be good on some level for TH-1902 and the preclinical work they highlight at this conference this week will likely suggest the applicability of TH-1902 is going to be very broad. Nevertheless, in my view at least, the risk of TH-1902 falling short has risen as a result of last week's events. I still think it becomes something quite meaningful in the cancer field, but the probability of that being realized has dropped some based on their comments and their lack of certain comments.
Wino115 wrote: Helpful and a fairly realistic portrayal of how these things probably work.
On a different note, I'm not even really sure they are fully recruiting at all places yet. I can't say I really understand how the process works between THTX, the Contract Research Org they hired to compile all the data and run the website for investigators, and the cancer centers. I think I know, but can't say for sure.
But what is also probably happening is that you need a cancer center advocate and I think you all are correct in saying positive data will drive doctors to the trial and there isn't much yet.
We know there have been patients at Detroit and PA. For the others, we really don't know. I can't find the drug in the trials at Cedars Sinai despite them being a site. The doctors (Alain Mita and Monica Mita) seem to have some trials up there, but no TH1902 that I could find. Overall, Cedars has around 5-6 Phase 1 trials for solid tumors. They have a few SeaGen ones, Bristol Myers and even a Bioatla (the Soleus backed guys). So there's definitely competition and this was just a Phase 1 screen. There's probably a few more for Phase 2 and 3 programs for solid tumors. It wouldn't surprise me that they have not had patients enroll in each center yet. I don't know who's responsibility that is --Marsolais pitching, CRO pushing, Lead Investigator (MDAnd) pushing, or maybe you just can't do much.
qwerty22 wrote: This is 23 patients taking pembro every 3 weeks and getting scanned every 9 weeks, there are 23 patients and 5 responders. The top graph is a Spider plot. Every line is a patient, every dot on the line is a scan. People with progressive disease progress quickly and come off trial quickly. Most SD and responders hang around for longer, I only see two SD patients dropping out early, some come off trial when their disease eventually progresses. Most patients who are eligible to stay on trial stick around for at least 5 scans (15 drug cycles).
You can see from this plot that one responder converts at their first scan, two more on 2nd scan, another on 3rd and last on 4th. You need a follow on scan as a responder to confirm these patients so add one scan for confirmed response.
These are patients with metastatic disease. They may well be less sick than THTX's patient (or not) but you can see patients mostly run the course, they mostly don't drop out. It's how their cancer develops that mostly decides when they come off study. I think in 1a they could well have been getting the sickest of the sick. The drug at that stage is completely unproven and as a minimum they just need to complete the first cycle for the company to get the info they need. There should be a move to less sick patients given they have now proved a very little about this drug. If the story continues to progress with positive news that situation should improve as well. We probably shouldn't overplay too much the sickness of these people. There is the general notion that the trial is designed to answer the questions it's meant to, dropout rates should be figured into that.
It's plots like this where I get the idea the first few scans are crucial, at least the first three cycles but as much as first 5. While THTX are keeping us in the dark it's probably useful to try to use the experience from other trials to try to understand the practicalities of our trial.