SPCEO1 wrote: As noted on prior occasions investment managers are by their very nature risk-takers while scientists are often more on the opposite side of the risk-taking spectrum. So, what readers here are seeing in terms of different approaches to the info the company on TH-1902 has released is just normal variations based on training and disposition. In my case, my biases towards optimism were burnished further by my mentor, Sir John Templeton, who literally had as one of his core investment tenets, "Be Optimistic". So, it is kind of in my DNA and readers should understand that (although long time readers figured it out a long time ago!).
In our conference call, Chrisitan made a point to say that the TH-1902 press release included "everything" - there was no more data to be revealed - we had it all. Now, we all know that Christian has a thousand little factoids about the phase 1a results that we would like to know, but my guess is you are not going to see much more in any article that is published in the future. Which might mean there were not any notable AE's at the 300/360mg dose. Now, I know there are always some in any trial (headaches, nausea, diarhea seem to be the common one in most trials and may not have anything to do with the drug being), but it seems like perhaps whatever there was did not seem relevant enough to report.
You characterize the data as slippery. I am not quite sure what you mean by that but I am seeing data I did not expect to see and it looks quite encouraging. I hoped we would see signs of tumor shrinkage in the 1a but we got a lot more than that:
1.) Were you expecting a report on the percentage of free docetaxel in the patient's bloodsteam - I didn't and the 11% seen versus the amount seen in a normal straight docetaxel dose is pretty encouraging. THTX is putting 150% of the normal dose in and getting 11% of it floating freely in the bloodstream. Clearly, the vast majority of the docetaxel is going elsewhere and it seems reasonable to assume most of that is going to the sortilin overexpressing tumors as the drug was devised to do and as the pre-clinical tests showed it would. I don't think that is some huge leap of faith.
2.) Were you expecting to be told a patient who failed on docetaxel (as well as a similiar taxane) succeeded on TH-1902? That was a bonus from my perspective and a big one too. I suppose that could be a fluke but my optimistic nature says it seems that TH-1902 is working just as it was designed to and in line with the pre-clinical trial data. Clearly, this is a key piece of evidence the drug does exactly what we were hoping it would.
3.) Were you expecting to hear a patient went 11 cycles on TH-1902? I did not think any phase 1a patient would have the life left in them to last that long on this trial. The patient had minimal tumor shrinkage but who knows how long they could have gone on with a stable disease situation. And again, this lines up with what we saw in the pre-clinical work. So, like the other situations above, the data we got seems to confirm what we saw in the pre-clinical trials that had us excited about the drugs prospects in the first place.
It seems to me there is enough room to be optimistic based on what admittedly is a very limited data set.
But let me put on a pessimistic hat and ask some questions we will not get answered, at least by the company:
1.) In the patient who showed 53% tumor shrinkage on the targeted tumors, how many tumors were targetted. We know one tumor 100% resolved so, were there just two tumors being tracked and the other one barely shrunk at all? If so why would that be? Juniper88's wife saw pretty serious tumor shrinkage on some tumors but others grew. What explains these different reactions? If some tumors react and others don't what does that imply for TH-1902's future?
2.) JFM1330 highlighted to us long ago how heterogenuous cancer tumors can be. What is really going on inside the patient's body and can TH-1902 help a lot of patients or only a small subset of them due to the differences among tumors within a single person?
3.) On a cancerous tumor, do only the cells near the surface of the tumor overexpress sortilin. Once those are killed off, does TH-1902 become less useful? One tumor was totally eradicated in the phase 1a but even in pre-clinical studies, the total elimination of a tumor was not seen - why is that? Is there some reason the impact of Th-1902 on the tumors slows over time?
4.) I suppose it was not possible within the confines of a very limited phase 1a dose escalation trial, but we heard nothing about VM or stem cells. Those are two big, big things seen in the pre-clinical trials and it would be really great to get some confirmation in humans that such aspects of TH-1902 are at work too. Again, that was likely impossible to look into in phase 1a but we have no human confirmation of that yet.
5.) Does anyone find it odd that all of the successes were seen at Gettysburg and not in any of the other trial sites? Is that something to be concerned about or is it just a fluke? It sure would have been nice to be able to quote the lead doctor from MD Anderson in the data press release. Having now been to the Gettyburg clinic, I can tell you it is not a bright, shiny, impressive clinic that you would expect to see if you went to MD Anderson of Cedars Sinai. Why are there not more cancer clinics scrambling to be part of the phase 1b trial?
6.) On the free docetaxel issue being at 11% - clearly this is an average among the phase 1a patients. What was the range around that average? Was it narrow or broad? What was the level of free docetaxel in the patients that responded?
7.) Is it something to be concerned about that 2 of the three responders were prostate cancer patients, a cancer type that was not at the top of the list of cancers overexpressing sortilin?
So, despite plenty of unanswered questions (which is only normal at this point so early in a trial), I have been quite encouraged by the data we got in the press release as it was far more and better than I was expecting. To me it was seriously good news. But I recognize it is very limited phase 1a data on 18 super-sick patients, only three of which saw some degree of efficacy. While very pleased with what we know now, there is clearly a ways to go yet. The next big milestone appears to be the press release where THTX tells us they are filing to amend the protocol to take one cancer type up from 10 patients to 25. I am curious to know if they will go for more than one of these protocol amendments - I imagine they should if the evidence is there to do it since they will not know the outcome from the first expanded group right away and they will need success in an expanded group to move onto phase 2, which could end up being a registrational trial. As a result, we may get several protocol amendments along the way in the months to come, which would obviously be encouraging and would also help build the case for a big pharma to pay top dollar for THTX at some point in the future.
I may have mentioned this already but Dr. Shah told my cousin that they were having good success with the two drugs he was considering for her. I can now confirm that one of those two drugs is indeed TH-1902. I am not sure how Dr. Shah defines "good success" or how much of a salesman he might be, but it is another anecdotal reason to be optimistic.
qwerty22 wrote: All this is very slippery. If you are ultra-cautious then you wait. The company is never going to get ahead of the data so they probably wait. I think SPCEO tends to project forward based on what we have now so there is less waiting on his part. I'd be closer to the company than to SPCEO on this issue.
What the company could do at this point that they haven't done is be really clear about what happened on the safety side. I really want a very clear list of the AEs from the 300/360 doses of the drug. I'm piecing together a pretty positive picture of the safety profile from a number of different statements. But at the same time I'm aware that each of those statements could be a cherry picked picture of only a part of the data. I hope when the investor presentation goes up they will have a page setting out clearly all the AEs from at least the 300/360 doses. Beyond that I'm pretty happy we know the state of play so far.
qwerty22 wrote:
ORR and PFS are really the endpoints they are aiming for to get approval. Would these be the "key attributes of success"? In which case we are still a long way from POC based on this definition because we know nothing about these.
I don't like Palinc's definition because it seems to me it really needs some evidence about what is happening at the population level and we are a long way from that.
JFM called what we have anecdotal. Another way to say that is knowing what has happened at the individual level. In that case a good way to think about it is have they proved th1902 has anti-tumour activity. Either making tumours shrink or stopping tumours growing. That would be what the 53% Partial Response patient and the patient with SD for 11 cycles would suggest. As I keep saying the presence of free docetaxel complicates the issue. If you believe the supporting issue around docetaxel being ineffective in these patients as shown by their previous failure on these drugs then we can be certain of anti-tumour activity.
The next step for POC is to take that initial observation of anti-tumour activity and explore a particular population to see how that manifests itself in terms of ORR and PFS. The 1b trial first 10 patients give a crude look at that. An expanded cohort to 25 will give us a pretty good idea where these will land, that I think is the strength of an expansion group.
So again POC is a slippery term.
If you think it revolves around ORR and PFS then we are a long way from it.
If you think it's about showing anti-tumour activity then that is where we are right now. The one confounding factor is "free docetaxel"
If you think they have adequately dealt with free docetaxel then we can assign anti-tumour activity to Th1902 and we have our POC based on anti-tumour activity.
My view is the free docetaxel issue is not completely dealt with. The evidence is too thin but what evidence that does exist is directionally correct. They will get more evidence that is inevitable. There won't really be a gotcha moment because directly distinguishing between free docetaxel activity and th1902 activity is pretty difficult. It will likely be the case of accumulating more directionally correct data.
What I'd like is if they could show the presence of the MDR marker in the tumour material of a responding patient. If they could show responders have good Sortilin levels. And if the could just show one or two more responders that previously failed on taxanes. That would nail the issue of free docetaxel for cautious individuals. We have a little bit of that with the first 1a data. It should be possible to get the rest from the first 1b interim data readout. If you're less cautious you could easily start betting on the data we already have.
palinc2000 wrote:
Everyone is entitled to his opinion .My bigger point is that there has been a lot of rants here with a lot of blame agsinst management because people without scientific knowledge actually think that you are right about the likelyhood of success and cannot comprehend why mgmt is bot spreading the good news across the universe!!!
IF and when there are facts that support a probability of success you will hear about it on TV and read about it everywhere.
Of course everyone is free to believe that success is at hand but so far I have not seen anyone on this board doing any buying even though the best time to buy is NOW if of course you have faith in your opinion
Could management present a rosier picture of the company as a whole ? I think Scarlett had a post the other day with a list of items /facts which could be better disseminated .I do believe that the market cap of THTX is undervalued and should be at least double just based on its commercial activities but I think the market needs to see the pudding in the next 2 quarters
SPCEO1 wrote: Everyone will have their opinion on this but my read is we re already at a point where it is reasonably likely the key attributes for the success of TH-1902 are in place and th ekey causes of failure are absent.
palinc2000 wrote: A Google search of POC will lead to many many definitions none of which to suggest that we are at that point ATM ....
What is worst than fuzzy math is fuzzy science data ...
When and if POC is attained we will know just by seeing the market reaction $$$
“Proof of concept may be defined as the earliest point in the drug development process at which the weight of evidence suggests that it is "reasonably likely" that the key attributes for success are present and the key causes of failure are absent.” POC is a key translational pivot point ...