SPCEO1 wrote: I did not have a chance to read all the posts yesterday afternoon closely but the impression a quick read left one with was that there may be nothing TH can report from the phase 1a that the scientists here will take as a positive, hopeful development that will lead investors to start to pay closer attention to TH's stock. Now, I know that is overstating it a bit but perhaps it would be good for Qwerty and JFM to tell us what they would get excited about if TH reported it as a result of their phase 1a trial. Also, you guys may not know what would trigger a Breakthrough Therapy Designation (BTD) from the FDA but if you have some thoughts on that, it would be great to hear them. Is that something that only comes after phase 1b results?
Let me also share what turned out to be lengthy thoughts on the info I get as well as info that is typically shared on these message boards. Because I am a large shareholder, I have had access to company management over the years. I originally started posting on this board many years ago because I had info from those contacts that I knew could really help my fellow shareholders who did not have that access to management, as well as the analysts reports that were written, and who were posting all kinds of theories that I knew were wildly off the mark. So, I thought it would be pretty easy for me to help those who were info deprived on this board and maybe keep a few of them from having a stroke over false info! Over the years, this board has become a great rersource and the info shared by almost all (the occasional appearance of shorters being the exception) has really come full circle and now many of the goodposters here are keeping me from having an unnnecessary stroke!
Now, I have spoken to company management only once in the last 14.5 months, which was two weeks ago and my main objective there was to speak to them (actually yell at them, unfortunately) to try to wake them up. But when an analyst speaks to any management team, they are fully aware that they are mostly, but not always, getting the truth but are not getting the whole truth. It is management's job to spin the most positive story they can to the market and analysts are constantly trying to understand what they are not being told that would actually give a clearer picture of any company's situation. Additionally, management teams don't know everything either and circumstances can change unexpectedly on them, making something they said last week look like they were lying to you. So, the value of speaking with management is likely not as high as those of you who do not have that opportunity think. You do get to hear nuances that may be helpful (but which can also lead you astray or which you can misinterpret due to your own biases). But, I admit, after weighing the pros and cons, it is still often better than the alternative of not getting that opportunity, but not always. The reason I decided to stop speaking to TH's management was that, after weighing the pros and cons in this particular situation, the cons won out. There were times where the CEO said things where he sounded sincere at the time ("we won't issue new shares until the stock is at $6, $7 or $8" not all that long before selling shares at $3.15 and warrants at $2.75 is one very meaningful example). There were times were the CFO could have walked me back off an incorrect theory I had pretty easily, but he chose not to do so. There was an accumulation of things of this nature that led me to conclude it is better to just listen to their public statements. Now, some of this management misdirection is normal and analysts learn to live with it because it is part of the game, but it is pretty clear from the bad way the analysts treat TH, the way the Caisse has walked away from TH and the general lack of interest in the stock by the capital markets that I am not the only one to feel this way. And I should emphasize, yelling at company management is not something I do. Yelling at anyone is not something I do. So, TH is a pretty extreme situation for that to happen and indicates that TH does have a problem and I was yelling at them because of their unwillingness to admit it and do something about it. But like I said recently, I do not think these folks at TH are fundamentally evil people, they actually seem pretty nice to me, but I know them only professionally. Still, in the end, it hard to ignore their results in the capital markets arena, which have not been good and have been consistently not good over many years. Unfortunately, shareholders are paying a heavy price for these shortcomings and a bad relationship with the capital markets really undermines a company in the long run, particularly one that needs to raise money. If you have to finance at bad prices, the result is sub-optimal at best and can be very bad at worst. So, it is of utmost importance for a growing, capital needy company like TH to optimize its relationship with the capital markets and this has been a point of weakness for TH for way too long. TH's board added someone to help address this issue last year at shareholder's request but we have not yet seen any positive developments as a result. Maybe that will change soon, as a financing of some sort is likely not too far away, and this will give them a chance to start to break out of the historical mess they have fallen into in this area. I sure hope so as Christian's team at TH has been doing an amazing job and deserve not to be let down by the finance area. While NASH may never come to fruition, it is a miracle it got as close as it did and buying Katanna was Christian's idea and he has really worked that hard to get us to where we are right now.
I know many TH shareholders, so I do also get feedback from them when they speak with management. Most of these people, however, do not have the time to dedicate to TH that I have had and therefore are at a bit of a relative disadvantage to me when speaking with management. Still, good information is often obtained from those conversations and I typically share the most meaningful info here on this board. But that info is subject to all the same things noted above so one has to be wary of putting too much credence in it. It is also worth pointing out that since TH has had such a bad run with investors and the capital markets generally, the incentive for them to tilt info in private conversations in ways that do not reveal the whole truth is high. All of this needs to be considered when evaluating what TH says these days. Additionally, the "whisper down the lane" problem is in play too as this is second hand info I am getting. For example, one shareholder said he spoke to Paul and Paul told him they had tested at the 560mg level. Well, either he misheard Paul or I misheard him as it is now clear that Paul was telling him that they tested at the 360mg level. So, gathering info has many pitfalls no matter how you are doing it. Second or third hand hand info brings with it additional problems. And the smaller the company you are talking about, the more consequential those informational pitfalls can be.
So, I have gone down this lengthy path on information because you raised the possibility of inside info. Anytime an analyst speaks to any management person, there is likely some degree of inside info that is indirectly communicated but rarely is any inside info directly communicated. And since it is indirectly communicated (nuanced statements that make your thinking lean in a certain direction, for example although there are many intentional and unintentional ways in which management says something and an analyst can walk away from a meeting thinking they learned something the market does yet not know but would like to. But the problem is typically you cannot be sure about what you think you might have heard). Outright intentional sharing of insider info almost never happens these days, at least to me, and TH has historically been good about not doing that. I do not want insider info either as it locks you up from buying or selling the stock. As a funny aside, I once was given inside info by a broker in Australia when I worked for Templeton back in the 1990's. I told him to please not share inside info with me as it is illegal to do so and prevented me from trading in that stock until the info was made public. He responded, "Mate, down here in Australia we only trade when we have insider information!
Of course, company management is not the only source of info on a stock. People on this board have done a good job of finding interesting info elsewhere since the internet is such an amazing tool. I remember when one poster discovered TH had chosen the name "Trogarzo" for Trogarzo long before the company had announced it by looking over the public trademark application info - that irritated the CFO! Among all of us here we have a lot of good information on all aspects of the stock. In the end, however, what the company says publically is the best, most reliable source. When I am speaking about they have a very high probability of seeing proof of concept in the phase 1a, that is based on patient #2 which, in my interpretation, the company intentionally included in the most recent corporate presentation to communicate to us via public nuance that they likely had seen something positive. Now, maybe they have a partial response in patient #2 and we will find that out later. All I know is they could have told us about patient #2 earlier, they chose not to do so and they are now likely telling us to build some anticipation of good results with investors for the eventual reveal. Which is exactly what they should be doing. Clearly, something happened with that patient and they would have no incentive to note it unless something had happened. We can guess about the extent of what happened but something almost certainly happened. And that is the best indicator we have that something happened. Also, I did not have any conversation with TH about patient #2 since the updated presentation came out after our call.
Now, we face a problem with how to interpret that nuanced info, just like what happens when you think the company may have given you some nuanced info in a phone call with management. I think it is a very good hint but others may interpret patient #2's experience and the company's willingness to share it now differently. You also have to take into account the company's position of having a falling share price, having an unusually long phase 1a where they have repeatedly missed their forecasted timelines and a lot of pressure to deliver something worthwhile from cancer since everything else they havhe looks far less interesting at the moment. So, management is incentivized to spin things as positively as they can and they have done this before. All these factors need to be taken into account when trying to sort this out. But TH is not one to say things in a public forum that are way off the mark. So, I think they are telling us something good occurred and they are acting like something good happened in other ways too.
So, I am thinking we have a lot to look forward to with cancer and am feeling less exposed to possible bad news. I can't tell you what exactly happens from here but I am pretty confident TH will be moving forward and there are a lot of possible ways this could go that are positive. In Wino's terms, the situation with cancer has already been de-risked rom my perspective, even before a formal annuncement of some degree of efficacy/stable disease/partial response (and at this point I don't even know the difference between these three terms - they seem to increasingly overlap or mean the same thing). But my scientist friends here are still poo poohing such things. I understand why you are doing that from a scientific perspective but doesn't the reveal of patient #2 encourage you on some level? Isn't it becoming clearer that something positive likely happened in the phase 1 with patient #2 at a minimum. If they recieved 4 cycles of tretament (it could be more because that assumes just one dose at each dosage level and we are not sure if more than one was given at any dosage level), that means they were on treatment for at least three months which is more than enough of time for TH-1902 to have an impact. Yes, most of the doses were at a lower level but in pre-clinical trials TH-1902 had a posiitve impact at one quarter the normal docetaxel dosage due to the multiplicative effect of the receptor drawing more of the drug into the cancer cell.
OK - that was too long but I am hoping it helps some understand the complexities even folks like me who have access to more info face when trying to evaluate it properly and reach something close to the rght conclusion.
qwerty22 wrote: Yeah I know that. I was just trying to show at what point I think SD becomes meaningful and I guess how much SPCEO's scenario falls short of that.
The other point would be that a benign drug with SD looks attractive. A toxic drug where it's a challenge to remain on it for 12 months is going to look like it has less utility in the clinic and maybe a questionable risk/reward profile.
There is a point to JFM's talk of approval in that you have to be able to imagine what you see in these small patient group as a path to approval and use. There's always lots of extrapolation from these small numbers but doing that with a PR is far easier in my view than doing it from one SD.
I don't necessarily accept SPCEO's scenario as the only or most likely scenario (unless he has some insider knowledge).
juniper88 wrote: You cannot have lots of patients stable for +12 months in this 1a trial. I believe there are only 18 patients who have gotten treatment. From those maybe only 7 or 8 still on treatment, and most just a month or so. And from those 7 or 8 how many from cancer types that actually have highly expressed sortilin? To me if you have a couple of patients with stable disease that would be a good sign. Then the 1b starts and a lot more patients will be enrolled in cancer types that are more likely to highly express sortilin.
qwerty22 wrote: Short periods of SD have no real clinical meaning. The only good thing is it allows the patient to stay on trial longer and so maybe eventually develop a response. Lot's of patients stable for +12 months might begin to be clinically meaningful but I've seen the market ignore that data.
SPCEO1 wrote: Thanks JFM - please see my comments/questions in
Red below:
jfm1330 wrote: Sorry SPCEO, your working definition of proof of concept is impossible. With TH1902, as it is, they cannot see if it goes inside the cells and even less if it's pushed out of cells if it would have entered in. That's why I would want a version of the PDC coupled to Ga68.
I should have mentioned earlier that I had sent that info to Christian a long time ago as you requested when you first brought it up, so if he read my e-mail his is aware of it. With that tool you would be able to see the PDC distribution in the human body, in which organ, tissue and tumor it is internalized, and to which concentration. But TH1902 with docetaxel cannot be traced in that manner. All that to say that the only way to have a proof of concept is through efficacy. If docetaxel alone is no longer efficacious on a patient, but given through TH1902 it is. It is the indirect proof that it goes inside the cells in a different way and in higher concentrations.
It seems to me that there is a good chance patient #2 has seen that. That being said, pharmacokinetic data of TH1902 in the bloodstream over time, after injection, can give hints about proof of concept. The PK profile of a patient with a heavy sortilin burden (high sortilin expression on tumors and high tumor burden) should be different from the PK profile of TH1902 in a patient with low sortilin burden, for the same dose of TH1902 injected. This can give a good hint, but not a proof of concept per se.
I think we can conclude safely that they have such PK data in hand but we cannot know for sure what that data says - right?. Also, patient #2 cannot be considered a proof of concept because he or she got four cycles of TH1902, including three under the MTD of docetaxel alone, and we don't know what happen after the cycle at 300 mg/m2. Maybe he had stable disease during that time, and that's why he continued. But stable disease on one patient is not a proof of efficacy, so not a proof of concept.
Why would stabilizing the disease not be proof of concept? If it is stabilizing the growth of the tumor, it must be having an impact. Also, would a patient remain on an experimental drug for that many cycles if there was not benefit being shown? So, maybe they have hints of proof of concept, or real proof of concept throug efficacy, but without confirmed tumor regression, ideally reaching partial response status, this is just speculation.
I imagine they could get a partial response in phase 1a but since the trial is not designed for that, TH needs to get lucky. Given that they revealed patient #2 to us, that they are busy planning on an expnded phase 1b, that they hired a siRNA scientist and are also studying SN 38, it sure seems like they know they have something already.Until they publish their data, nothing can taken as a fact. That's why it's frustrating to follow. Hopefully, they will give us something reassuring in the next Q1 call in three weeks.
Any idea of how long it might take TH to work on all the data they have collected in the phase 1a before they say something official? SPCEO1 wrote: Now, I know our scientists here are going to remain on edge until they receive official confirmation from TH whenever they release the phase 1a results, but I believe they have already effectively told us they have at least achieved proof of concept by sharing that info on patient #2 in the recent corporate presentation. My guess that was the whole point of putting out a new presentation - to calm everyone's nerves about this and encourage us that the future should be very interesting. My working definition of proof of concept is that they have seen the drug enter the cancer cells and not get pushed back out before they can start damaging those cells. Given how many cycles patient #2 had, they may have also seen actual signs of efficacy. If patient #2 did not show some signs of efficacy, that would actually be a bit disapointing given how long they were on the drug (I know, most of the doses this patient recieved were low but given that the drug is supposed to concentrate in cancer cells even low doses should be beneficial as indicated in the preclinical work).